Drug Information Handbook For Dentistry

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2019 -202 0 L E X I CO M P D E N TA L R E F E R E N C E L I B R A RY
UPDATES TO THIS EDITION

52 New Drug Monographs
Lexicomp®
Handbook for Dentistry

Drug Information
Lexicomp®
New Field of Information:
• Warnings: Additional Pediatric Considerations
Drug Information
Updated Oral Medicine Topics:
• Management of the Chemically Dependent Patient
• Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
• Osteonecrosis of the Jaw
Handbook
• Periodontal Diseases
• Systemic Viral Diseases
• Endocrine Disorders and Pregnancy
• Management of the Patient with Anxiety or Depression
• Antibiotic Prophylaxis
for Dentistry
• And more
Updated Appendix Information:
• Dentifrices Without Sodium Lauryl Sulfate
• Calcium Channel Blockers and Gingival Hyperplasia
25
• Vasoconstrictor Interactions with Antidepressants
th
A N N I V E R S A RY E D I T I O N
The Lexicomp Drug Information Handbook for Dentistry is the best-selling dental reference that
has been helping dental professionals reach clinically relevant information on medications,
Including Oral Medicine for
OTCs, and herbal products for 25 years.
Medically Compromised Patients
Information is presented in an easy-to-use, two-column format, with medications alphabetically
indexed by brand and generic names, as well as index terms. Within individual drug monographs,
dental-specific fields are highlighted in red, a timesaving feature within an information-
& Specific Oral Conditions
rich resource. Drug content is complemented by special sections dedicated to medically
compromised patients, specific oral conditions, and sample prescriptions.
Statistics
• 1562 Drug Monographs Senior Editors:
• Up to 55 Fields of Information per Monograph Richard L. Wynn, BSPharm, PhD
• 200 Natural Products Timothy F. Meiller, DDS, PhD
• 102 Sample Prescriptions
Harold L. Crossley, DDS, MS, PhD
• More Than 160 Pages of Special Topics and Appendix Information
The information contained in this handbook is also available in
electronic formats, which are updated daily.
• Lexicomp® Online
• Lexicomp® Mobile Apps
25th Edition 25th Edition
For more information, visit www.wolterskluwerCDI.com.
Information contained in this handbook is derived

from the Lexi-Drugs ® database.
Use of This Handbook
How do I find information on a drug?
The Drug Information Handbook for Dentistry follows an easy-to-use format. Medications
are presented alphabetically (by generic name) in the main drug section of the
handbook. A handy alphabetical index, found at the back of the book, contains generic
product names and index terms, as well as US, Canadian, and Mexican brand names.
What information is included in the Sample Prescriptions?

Drug prescriptions shown in this section represent prototype drugs and
popular prescriptions. They are examples only, applicable to the following
topics/conditions:
1. Oral Pain
2. Antimicrobial Oral Rinse
3. Bacterial Infections and Periodontal Diseases
4. Fungal Infections
5. Prevention of Endocarditis and to Reduce the Risk of Late Infections of
Joint Prostheses
6. Sinus Infection Treatment
7. Viral Infections
8. Sedation (Prior to Dental Treatment)
9. Ulcerative and Erosive Disorders
What information is included in the Oral Medicine sections?

PART I: Dental Management and Therapeutic Considerations in Medically Compromised
Patients focuses on common medical conditions and their associated drug therapies
with which the dentist must be familiar. Patient profiles with commonly associated drug
regimens are described.
PART II: Dental Management and Therapeutic Considerations in Patients with Specific
Oral Conditions focuses on therapies the dentist may choose to prescribe for patients
suffering from oral disease or who are in need of special care.
How often is Lexicomp information updated?

Wolters Kluwer is dedicated to maintaining the depth and relevance of our Lexicomp
information and providing customers with new information as quickly as possible. While
the information in this handbook is derived from our database system and current as of
the publication date, our electronic offerings, Lexicomp Online for Dentistry (Web-based
platform) and Lexicomp Mobile Apps (smartphone/tablet applications), are updated daily
with new content.
www.wolterskluwerCDI.com/markets/dentistry
https://t.me/DentalBooksWorld
Lexicomp®
Drug Information
Handbook
for Dentistry
25th Edition
Lexicomp®
Drug Information
Handbook
for Dentistry
Richard L. Wynn, BSPharm, PhD

Professor of Pharmacology
Baltimore College of Dental Surgery
Dental School
University of Maryland Baltimore
Baltimore, Maryland
Timothy F. Meiller, DDS, PhD
Professor
Oncology and Diagnostic Sciences
Professor of Oncology
Marlene and Stewart Greenebaum Cancer Center
University of Maryland Medical System
Baltimore, Maryland
Professor Emeritus
Dental School
University of Maryland Baltimore
Baltimore, Maryland
NOTICE
This data is intended to serve the user as a handy reference and not as a complete drug information resource. It does not
include information on every therapeutic agent available. The publication covers over 1,500 commonly used drugs. In
addition, it does not include all potentially relevant information about any particular drug. Instead, it is intended to present
important aspects of drug data in a more concise and accessible format than is typically found in medical literature or
product material supplied by manufacturers.
The nature of drug information is that it is constantly evolving because of ongoing research and clinical experience and is
often subject to interpretation. While Wolters Kluwer Clinical Drug Information makes reasonable efforts to publish
accurate information, users are advised that the authors, editors, reviewers, contributors, and publishers cannot be
responsible for the continued currency of the information or for any errors, omissions, or the application of this information,
or for any consequences arising therefrom. Therefore, the authors, editors, reviewers, contributors, and publishers shall
have no liability to any person or entity with regard to claims, loss, or damage caused, or alleged to be caused, directly or
indirectly, by the use of information contained herein. Because of the dynamic nature of drug information and the
characteristics and needs unique to individual patients, readers are advised that decisions regarding drug therapy must be
based on the independent judgment of the clinician. Users must regularly consult multiple sources (eg, medical literature
and a manufacturer's most current product information) to remain aware of changing information about a drug and medical
practices regarding its use. Therefore, this data is intended to be used in conjunction with other necessary information and
is not intended to be solely relied upon by any user. The user of this data hereby and forever releases the authors, editors,
reviewers, contributors, and publishers of this data from any and all liability of any kind that might arise out of the use of
this data. The authors, editors, reviewers, contributors, and publishers are not responsible for any inaccurate source
materials developed by third-parties or for any user misunderstandings that may arise from the data.
Certain of the authors, editors, reviewers, and contributors have written portions of this book in their individual capacities.
The inclusion of content is not intended to indicate that it has been reviewed or endorsed by any federal or state agency,
pharmaceutical company, or regulatory body.
The publishers have made reasonable efforts to avoid reproducing without permission, any content that may be subject to
third-party copyright claims. Any questions regarding content that may be subject to such claims will be addressed at the
first opportunity.
If you have any suggestions or questions regarding any information presented in this data, please contact our drug
information pharmacists at (855) 633-0577. Book revisions are available at our website at http://www.wolterskluwercdi.
com/clinical-notices/revisions/.
© 2019 Wolters Kluwer Clinical Drug Information, Inc. and its affiliates and/or licensors. All rights reserved
© 1996 to 2018, 1st to 24th Editions, Wolters Kluwer Clinical Drug Information, Inc. and its affiliates and/or licensors. All
rights reserved
Natural product content is adapted from The Review of Natural Products. Facts & Comparisons [database online]. Clinical
Drug Information, LLC; 2019
Printed in the United States. No part of this publication may be reproduced, stored in a retrieval system, used as a source
of information for transcription into a hospital information system or electronic health or medical record, or transmitted in
any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written
permission of the publisher. Should you or your institution have a need for this information in a format we protect, we
have solutions for you. Please contact our office at the number above.
This manual was produced using LIMS — a complete publishing service of Wolters Kluwer Clinical Drug Information, Inc.
ISBN 978-1-59195-378-4
INTRODUCTORY INFORMATION
TABLE OF CONTENTS
About the Editors.................................................................................................................................................................. 3
Drug Interactions Editorial Advisory Panel...........................................................................................................................4
Editorial Advisory Panel....................................................................................................................................................... 5
Preface to the Twenty-Fifth Edition.......................................................................................................................................15
Description of Sections and Fields Used in This Handbook............................................................................................. 16
Description of Dental Use.................................................................................................................................................. 20
Controlled Substances....................................................................................................................................................... 21
Pregnancy Categories........................................................................................................................................................ 22
FDA Name Differentiation Project: The Use of Tall-Man Letters....................................................................................... 23
Prescription Writing............................................................................................................................................................ 27
Preventing Prescribing Errors............................................................................................................................................ 28
SAMPLE PRESCRIPTIONS...............................................................................................................................................31
Oral Pain - Sample Prescriptions....................................................................................................................................... 32
Antimicrobial Oral Rinse - Sample Prescriptions............................................................................................................... 35
Bacterial Infections and Periodontal Diseases - Sample Prescriptions............................................................................. 36
Fungal Infections - Sample Prescriptions.......................................................................................................................... 39
Prevention of Endocarditis and to Reduce the Risk of Late Infections of Joint Prostheses - Sample Prescriptions....... 41
Sinus Infection Treatment - Sample Prescriptions.............................................................................................................42
Viral Infections - Sample Prescriptions.............................................................................................................................. 44
Sedation (Prior to Dental Treatment) - Sample Prescriptions........................................................................................... 46
Ulcerative and Erosive Disorders - Sample Prescriptions................................................................................................. 47
ALPHABETICAL LISTING OF DRUGS............................................................................................................................. 51
ALPHABETICAL LISTING OF NATURAL PRODUCTS.................................................................................................1377
MEDICALLY-COMPROMISED PATIENTS ....................................................................................................................1441

Cardiovascular Diseases................................................................................................................................................ 1442
Antiplatelet and Anticoagulation Considerations in Dentistry.........................................................................................1454
Clinical Risk Related to Drugs Prolonging QT Interval..................................................................................................1462
Gastrointestinal Disorders.............................................................................................................................................. 1465
Respiratory Diseases..................................................................................................................................................... 1467
Endocrine Disorders and Pregnancy..............................................................................................................................1471
HIV Infection and AIDS.................................................................................................................................................. 1477
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis.................................................................................................1484
Osteonecrosis of the Jaw............................................................................................................................................... 1486
Sexually-Transmitted Diseases...................................................................................................................................... 1494
Systemic Viral Diseases................................................................................................................................................. 1496
Antibiotic Prophylaxis..................................................................................................................................................... 1502
Management of the Chemically Dependent Patient.......................................................................................................1511
SPECIFIC ORAL CONDITIONS.................................................................................................................................... 1519

Oral Pain.........................................................................................................................................................................1520
Bacterial Infections......................................................................................................................................................... 1525
Periodontal Diseases......................................................................................................................................................1534
Fungal Infections............................................................................................................................................................ 1538
Viral Infections................................................................................................................................................................ 1540
Ulcerative, Erosive, and Painful Oral Mucosal Disorders.............................................................................................. 1544
Dentin Hypersensitivity, Acid Erosion, High Caries Index, Management of Alveolar Osteitis, and Xerostomia........... 1548
Temporomandibular Dysfunction (TMD), Chronic Pain, and Fibromyalgia................................................................... 1559
Management of the Patient With Anxiety or Depression...............................................................................................1564
Perioral Premalignant Lesions and Management of Patients Undergoing Cancer Therapy.........................................1567
Dentist's Role in Recognizing Domestic Violence, Abuse, and Neglect....................................................................... 1574
1
TABLE OF CONTENTS
APPENDIX......................................................................................................................................................................... 1577
Abbreviations and Measurements

Abbreviations, Acronyms, and Symbols...................................................................................................................... 1578
Average Weights and Surface Areas...........................................................................................................................1588
Body Surface Area of Children and Adults..................................................................................................................1589
Metric Conversions.......................................................................................................................................................1590
Pounds/Kilograms Conversion..................................................................................................................................... 1591
Drug Interactions: Metabolism/Transport Effects
Drug Interactions: Metabolism/Transport Effects......................................................................................................... 1592
Laboratory Values
Laboratory Values/Body Measurements...................................................................................................................... 1594
Miscellaneous
Calcium Channel Blockers and Gingival Hyperplasia................................................................................................. 1601
Dentifrices Without Sodium Lauryl Sulfate (SLS)a...................................................................................................... 1604
Vasoconstrictor Interactions With Antidepressants...................................................................................................... 1606
PHARMACOLOGIC CATEGORY INDEX .........................................................................................................................1609
ALPHABETICAL INDEX ................................................................................................................................................... 1635
2
ABOUT THE EDITORS

Richard L. Wynn, BSPharm, PhD
Richard L. Wynn, PhD, is Professor of Pharmacology at the Baltimore College of Dental Surgery, Dental School,
University of Maryland Baltimore. Dr Wynn has served as a dental educator, researcher, and teacher of dental
pharmacology and dental hygiene pharmacology for his entire professional career. He holds a BS in Pharmacy, an MS
(physiology), and a PhD (pharmacology) from the University of Maryland. He was a practicing pharmacist for 10 years in
the Baltimore area. Dr Wynn chaired the Department of Pharmacology at the University of Maryland Dental School from
1980 to 1995. From 1990 to 1995 he was also the appointed Chair of the Department of Biochemistry at the Dental
School. Previously, he chaired the Department of Oral Biology at the University of Kentucky College of Dentistry, for six
years.
Dr Wynn has to his credit over 400 publications, including original research articles in scientific journals, textbooks,
textbook chapters, monographs, and articles in continuing education journals. He has given over 600 continuing education
seminars to dental professionals in the US, Canada, and Europe. Dr Wynn has been a consultant to the drug industry for
over 30 years and his research laboratories have contributed to the development of new analgesics and anesthetics. He is
a former consultant to the Academy of General Dentistry, the American Dental Association, and a former consultant to the
Council on Dental Education, Commission on Accreditation. One of his primary interests continues to be keeping dental
professionals informed on all aspects of drug use in dental practice.
Timothy F. Meiller, DDS, PhD

Dr Meiller is Professor of Oncology and Diagnostic Sciences at the University of Maryland Dental School and Professor of
Oncology at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical
System in Baltimore. He is Director of the Oral Medicine Program in the dental school and the cancer center. He has held
his position at the Dental School for 42 years.
Dr Meiller is a Diplomate of the American Board of Oral Medicine and a graduate of Johns Hopkins University and the
University of Maryland Dental and Graduate Schools, holding a DDS and a PhD in Immunology/Virology. He has over 200
publications to his credit, maintains an active general dental practice, and is a consultant to the National Institutes of
Health and the Veterans Administration. He is currently engaged in ongoing investigations into cellular immune
dysfunction in premalignant oral lesions, oral diseases associated with AIDS, in patients receiving therapies for cancer,
and in other medically-compromised patients.

Dr Crossley is Professor Emeritus at the University of Maryland Dental School. A native of Rhode Island, Dr Crossley
received a Bachelor of Science degree in Pharmacy from the University of Rhode Island in 1964. He later was awarded
the Master of Science (1970) and Doctorate degrees (1972) in Pharmacology. The University of Maryland Dental School in
Baltimore awarded Dr Crossley the DDS degree in 1980. The liaison between the classroom and his dental practice, which
he maintained on a part-time basis in the Dental School Intramural Faculty Practice, produced a practical approach to
understanding the pharmacology of drugs used in the dental office.
Dr Crossley has coauthored a number of articles and four books dealing with a variety of topics within the field of
pharmacology. Other areas of expertise include the pharmacology of street drugs and chemical dependency. He serves on
the Maryland State Dental Association's Well-Being Committee. He is an active member of Phi Kappa Phi, Omicron Kappa
Upsilon Honorary Dental Society, the American College of Dentists, International College of Dentists, and an honorary
member of the Thomas B. Hinman Dental Society. He was the recipient of the 2008 Gordon Christensen Lecturer
Recognition award presented by the Chicago Dental Society, and the recipient of the 2012 Award of Distinction presented
by the Academy of Dentistry International for his efforts in continuing dental education. He has been a consultant for the
United States Drug Enforcement Administration and other law enforcement agencies since 1974. Drawing on this unique
background, Dr Crossley has become nationally and internationally recognized as an expert on street drugs and chemical
dependency as well as the clinical pharmacology of dental drugs.
3
DRUG INTERACTIONS EDITORIAL ADVISORY PANEL
DRUG INTERACTIONS EDITORIAL ADVISORY PANEL

Nina Bemben, PharmD, BCPS
Senior Clinical Content Specialist
Wolters Kluwer
Melody Berg, PharmD, MPH, BCPS-AQ ID, AAHIVP
Wolters Kluwer
Kay Burke, PharmD
Wolters Kluwer
Nadia Haque, PharmD, MHSA, BCPS, FASHP
Wolters Kluwer
Jamie Hoffman, PharmD, BCPS
Wolters Kluwer
Carrie Nemerovski, PharmD, BCPS, AQ-Cardiology
Wolters Kluwer
Kandace M. Schuft, PharmD
Wolters Kluwer
Steve Sklar, PharmD
Senior Clinical Manager
Wolters Kluwer
Stephen Marc Stout, PharmD, MS, BCPS
Director, Clinical Content
Wolters Kluwer
Daniel S. Streetman, PharmD, MS, RPh
Clinical Manager, Metabolism, Interactions, & Genomics Group
Wolters Kluwer
Sarah Warren, PharmD
Senior Clinical Content Specialist, Clinical Decision Support Pharmacogenomics Content
Wolters Kluwer
David M. Weinstein, PhD, RPh
Senior Director, Clinical Content
Wolters Kluwer
4
EDITORIAL ADVISORY PANEL

Jane Acton, PharmD Elizabeth J. Beckman, PharmD, BCPS, BCPPS,
Senior Clinical Content Specialist, Drug Files BCCCP
Wolters Kluwer Clinical Knowledge Management Analyst, Office of the
Executive Vice President for Health Affairs
Joseph F. Alexander Jr., MD
UK Healthcare
Clinical Professor of Internal Medicine
Northeast Ohio Medical University (NEOMED) Judith L. Beizer, PharmD, CGP, FASCP, AGSF
Allergist/Immunologist Clinical Professor
Summa Health System Department of Clinical Pharmacy Practice, St John's Uni-
versity College of Pharmacy and Health Sciences
Roaa Al-Gain, PharmD, BCPS, BCACP
Drug Information Pharmacist and Clinical Pharmacist, Anti- Nina Bemben, PharmD, BCPS
coagulation Senior Clinical Content Specialist
King Faisal Specialist Hospital & Research Center Wolters Kluwer
Abdulrazaq Al-Jazairi, PharmD, FCCP, BCPS- Emily C. Benefield, PharmD, BCPS, BCPPS
AQ, Cardiology Advanced Clinical Pharmacist – Pediatric Solid Organ
Head, Medical/Critical Care Pharmacy Services and Clin- Transplant
ical Pharmacist, Cardiology Intermountain Medical Center
Department of Pharmacy Services, King Faisal Specialist
Hospital & Research Center Melody Berg, PharmD, MPH, BCPS-AQ ID,
AAHIVP
Nada Al-Qadheeb, PharmD, BCPS, BCCCP, Senior Clinical Content Specialist
FCCP, FCCM Wolters Kluwer
Clinical Pharmacy Consultant, Critical Care
Hafer Al-Batin Central Hospital Tarun Bhalla, MD, MBA, FAAP
Chair of Anesthesiology and Pain Medicine
Aljohara Al-Sakran, PharmD, BCPS Akron Children's Hospital
Clinical Pharmacy Specialist, Pediatrics
King Faisal Specialist Hospital & Research Center Jeffrey R. Bishop, PharmD, MS, BCPP
Associate Professor
William Alvarez Jr., BS, PharmD, BCPS Department of Experimental and Clinical Pharmacology,
Clinical Director, Content Harmonization University of Minnesota College of Pharmacy
Wolters Kluwer
Amie Blaszczyk, PharmD, CGP, BCPS, FASCP
Tracy Anderson-Haag, PharmD, BCPS Associate Professor and Division Head – Geriatrics
Clinical Pharmacy Specialist, Kidney Transplantation Texas Tech University Health Sciences Center
Hennepin County Medical Center
Nicole M. Bohm, PharmD, BCPS
Lauren B. Angelo, PharmD, MBA Clinical Specialist, Internal Medicine
Associate Professor Medical University of South Carolina
Rosalind Franklin University of Medicine and Science
Peter Bonis, MD
Christina L. Aquilante, PharmD, FCCP Chief Medical Officer
Associate Professor Wolters Kluwer
Department of Pharmaceutical Sciences
Co-Director Douglas J. Borys, PharmD, DABAT, FAACT
Center for Translational Pharmacokinetics & Pharmacoge- Professor in Pharmaceutical Sciences
nomics, University of Colorado Denver School of Pharmacy Concordia University Wisconsin, School of Pharmacy
Kylie Barnes, PharmD, BCPS Karrie Boss, MSN, RN, CCRN

Clinical Pharmacist Critical Care Clinical Nurse Specialist and Stroke Program
Kansas City Care Clinic Coordinator
Clinical Assistant Professor Wooster Community Hospital
Department of Pharmacy Practice, University of Missouri Larissa Bossaer, PharmD, BCPS
Kansas City, School of Pharmacy
Clinical Content Specialist
Seth R. Bauer, PharmD, FCCM, FCCP, BCPS, Wolters Kluwer
BCCCP Diedra L. Bragalone, PharmD, MBA, BCOP,
Clinical Coordinator, Critical Care BCPS
Cleveland Clinic
Verna L. Baughman, MD Wolters Kluwer
Professor Lee Bragg, PharmD
Anesthesiology and Neurosurgery, University of Illinois
Wolters Kluwer
5
Tamra Brennan, AGACNP-BC Celeste R. Caulder, PharmD

Nurse Practitioner Associate Professor
Lowell General Hospital University of South Carolina College of Pharmacy
Leslie A. Briscoe, MSN, PMHNP-BC Larisa H. Cavallari, PharmD, BCPS, FCCP
Certified Nurse Practitioner, Psychiatry Associate Professor and Director
Louis Stokes Cleveland Department of Veteran Affairs Center for Pharmacogenomics, University of Florida Col-
Medical Center lege of Pharmacy
Susan P. Bruce, PharmD, BCPS Shawn Chase, PharmD
Chair and Associate Professor Clinical Content Specialist, Clinical Decision Support Dos-
Department of Pharmacy Practice, Northeast Ohio Medical ing Content
University (NEOMED) Wolters Kluwer
Whitney Redding Buckel, PharmD, BCPS Ashley H. Chasick, PharmD
Clinical Pharmacist Clinical Pharmacy Specialist, Oncology/Bone Marrow
Intermountain Medical Center Transplant
Ochsner Medical Center
Mitchell S. Buckley, PharmD, FASHP, FCCM,
FCCP, BCCCP Katleen W. Chester, PharmD, BCCCP, BCGP
Clinical Pharmacist – Medical Intensive Care Unit Clinical Pharmacist Specialist, Neurocritical Care
Banner – University Medical Center Phoenix Grady Health System, Marcus Stroke and Neuroscience
Center
Wendy Moore Bullington, PharmD, BCPS
Clinical Pharmacy Specialist, Pulmonary Medicine and Angela Clark, PharmD, BCPS
Clinical Coordinator, Internal Medicine Clinical Pharmacy Specialist, Cardiothoracic Intensive
Medical University of South Carolina Care Unit and Cardiology Team Lead
University of Michigan Health System
Kay Burke, PharmD
Senior Clinical Content Specialist M. Petrea Cober, PharmD, BCNSP
Wolters Kluwer Clinical Pharmacy Coordinator
Neonatal Intensive Care Unit, Akron Children's Hospital
Naomi Burns, BSc (hons), Clin Dip
Medicines Safety Pharmacist Christine M. Cohn, PharmD, BCPS
Western Sussex Hospitals NHS Trust (UK) Senior Clinical Content Specialist
Wolters Kluwer
William F. Buss, PharmD
Clinical Pharmacist Mellaknese Coker, BSN, RN, CAPA, CPN, CRT
Neonatal Intensive Care Unit, Indiana University Health, Clinical Nurse Manager
James Whitcomb Riley Hospital for Children Sibley Memorial Hospital/Johns Hopkins Medicine
Ben Caldwell, RPh Michelle Condren, PharmD, BCPPS, AE-C, CDE,

Clinical Content Specialist, Clinical Decision Support Dos- FPPAG
ing Content Professor, Director of Pediatric Research, andDirector of
Wolters Kluwer Pharmacology
University of Oklahoma School of Community Medicine,
Angela Campbell, RPh Department of Pediatrics
Wolters Kluwer Jessica Connell, RN, BSN
Pharmacotherapy Contributor
Todd Canada, PharmD, BCNSP, BCCCP, FASHP, Tifton, Georgia
FTSHP
Clinical Pharmacy Services Manager Kim Connell, PharmD
University of Texas MD Anderson Cancer Center Pharmacotherapy Contributor
Thomasville, Georgia
Katie E. Cardone, PharmD, BCACP, FNKF, FASN,
FCCP Elizabeth V. Connor, MD
Associate Professor Division of Gynecologic Oncology
Albany College of Pharmacy and Health Sciences Cleveland Clinic Foundation Women's Health Institute
Katie Carls, PharmD, BCPP Ann P. Conrad, ANP-BC, RN, ACRN

Clinical Manager, International Content Advanced Practice Nurse
Wolters Kluwer Community Hospitalists
Romulo Carvalho Marilyn Cortell, RDH, MS, FAADH

Pharmacotherapy Contributor Associate Professor
Rio de Janeiro, Brazil New York City College of Technology, City University of
New York
Jared Cash, BS, PharmD, MBA, BCPS, FPPAG
Pharmacy Director Harold L. Crossley, DDS, MS, PhD
Intermountain Healthcare, Primary Children's Hospital Professor Emeritus
Baltimore College of Dental Surgery, University of Maryland
6
Melanie W. Cucchi, BS, PharmD, RPh Vicki L. Ellingrod, PharmD, BCPP

Clinical Manager, Pediatric & Neonatal Content Head, Clinical Pharmacogenomics Laboratory and Asso-
Wolters Kluwer ciate Professor
Department of Psychiatry, Colleges of Pharmacy and Med-
Judy Cvetinovich, RPh icine, University of Michigan
Clinical Manager, Clinical Decision Support Dosing Content
Wolters Kluwer Jacqueline Ellis, RN, MSN
Mitchell J. Daley, PharmD, FCCM, BCPS Twinsburg, Ohio
Clinical Pharmacy Specialist – Critical Care
University Medical Center Brackenridge Kelley K. Engle, BSPharm
Kathryn E. Dane, PharmD, BCPS Stow, Ohio
Clinical Pharmacy Specialist, Inpatient Anticoagulation and
Hematology Christopher Ensor, PharmD, BCPS (AQ-CV),
The Johns Hopkins Hospital FAST, FCCP
Pharmacotherapy Specialist, Thoracic Transplantation and
Emily E. Davies, PharmD, CPE
Clinical Coordinator
Clinical Pharmacist
Florida Hospital
University Hospital Home Health
Gregory A. Eschenauer, PharmD, BCPS (AQ-ID)
Lacey Davis, PharmD, BCPS
Clinical Associate Professor of Pharmacy and Clinical
Clinical Pharmacist, Hospice, Palliative Care, and Post-
Pharmacist
Acute Care
University of Michigan Health System
Aultman Hospital
Jennifer Eshelman, PharmD, BCPPS
Beth Deen, PharmD, BDNSP
Pediatric Heart Institute Clinical Pharmacy Specialist
Senior Pediatric Clinical Pharmacy Specialist
Children's Hospital Colorado
Cook Children's Medical Center
Kirk Evoy, PharmD, BCACP, BC-ADM, CTTS
Dave L. Dixon, PharmD, FACC, FCCP, FNLA,
Ambulatory Clinical Pharmacist
BCACP, BCPS, CDE, CLS Southeast Clinic, University Health System
Associate Professor, Ambulatory Care
Virginia Commonwealth University School of Pharmacy Nicole L. Eye, PharmD
Pain Clinical Specialist Pharmacist
Renee K. Dixon, MD Avera McKennan Hospital
Pulmonary Attending/Pulmonologist
Christiana Care Hospital Erin Fabian, PharmD, RPh, BCPS
Elisabeth Donahey, PharmD, BCPS, BCCCP Wolters Kluwer
Lead Clinical Pharmacist, Neurosciences Critical Care
Clinical Pharmacist Michael Fahey, BSc, MSc, PhD, MRPharmS
Loyola University Medical Center Director
Alignment Consulting
Mary Drago, BSN, RN
Clinical Nurse Manager Margie Farrar-Simpson
Barnes Jewish Hospital Manager, Ambulatory Case Management
Children's National Medical Center
Kim S. Dufner, PharmD
Clinical Content Specialist Jessica F. Farrell, PharmD
Wolters Kluwer Associate Professor
Albany College of Pharmacy and Health Sciences
Kelly Dunn, PA-C
Physician Assistant Elizabeth A. Farrington, PharmD, FCCP, FCCM,
Troy Sleep Center and AAIRS Clinic FPPAG, BCPS
Pharmacist III - Pediatrics
Ijeoma Julie Eche, MSN, FNP-BC, AOCNP,
New Hanover Regional Medical Center
CPHON, BMT-CN
Family Nurse Practitioner, Staff Nurse Salia Farrokh, PharmD, BCPS, BCCP
Beth Israel Deaconess Medical Center, Boston Children's Neuro ICU Clinical Pharmacist Specialist
Hospital The John Hopkins Hospital
Mary Eche, PharmD, BCPS, BCCCP J. Emanuel Finet, MD
Clinical Pharmacist II Staff, Section of Heart Failure and Transplantation Medi-
Beth Israel Deaconess Medical Center cine
Cleveland Clinic
Megan Jo Ehret, PharmD, MS, BCPP
Associate Professor Christine Fitzgerald, PharmD, BCPS
University of Maryland, School of Pharmacy Pharmacotherapy Contributor
Valleio, California
7
Jeffrey J. Fong, PharmD, BCPS Shellee A. Grim, PharmD, MS-CTS, BCPS,

Clinical Pharmacy Specialist BCIDP
UMASS Memorial Medical Center Senior Clinical Content Specialist
Wolters Kluwer
David Frame, PharmD
Hematology/Oncology/BMT Clinical Specialist Kelly Gruver, RDH, EFDA, MHHS
University of Michigan Health System Preceptor and Clinical Coordinator
Cuyahoga Community College
Kristina M. Frangella, PharmD, BCPS, CDE,
BCACP Tracy Hagemann, PharmD
Clinical Pharmacy Specialist, Ambulatory Care Associate Dean and Professor of Clinical Pharmacy
Louis Stokes Cleveland Department of Veteran Affairs University of Tennessee College of Pharmacy
Medical Center
Kat Hall, MPharm, IPresc, PGCertClinEd,
Carole W. Fuseck, MSN, RN, ACCNS-AG, VA-BC PGDipGPP, MFRPSII, MRPharmS, FHEA
Clinical Nurse Specialist, Critical Care Director of Centre for Inter-Professional Postgraduate Edu-
Louis Stokes Cleveland Department of Veteran Affairs cation and Training
Medical Center University of Reading
Jennifer Gatsos-Walter, PharmD Nadia Haque, PharmD, MHSA, BCPS, FASHP
Senior Clinical Content Specialist , Clinical Decision Sup- Senior Clinical Content Specialist
port Dosing Content Wolters Kluwer
Wolters Kluwer
Steve Hart, MD
Charles Gaudet, BSN, RN, CCRN Director, Clinical Decision Support Precautions Team
Staff Nurse Wolters Kluwer
Tufts Medical Center
Kristin L. Harter, PharmD, BCPS
Laura Gaudet, BDN, RN-BC Clinical Pharmacist
Staff Nurse San Francisco General Hospital
Massachusetts General Hospital
Eric Henry, PharmD
Bruce Gaynes, BS, OD, MS, PharmD Clinical Content Specialist, Drug Files
Staff Optometrist Wolters Kluwer
Edward Hines, Jr. VA Hospital, Department of Veterans
Affairs Medical Center Carla Hernandez, RN, BSN
Clinical Research Nurse
Joyce Generali, RPh, MS, FASHP University Hospitals Cleveland Medical Center
Senior Clinical Manager, In-depth Content
Wolters Kluwer Jacob Hirsekorn, PharmD
Angela G. German, PharmD, BCOP Wolters Kluwer
Clinical Pharmacy Specialist
Henry Ford Hospital Jane Hurlburt Hodding, PharmD
Executive Director, Inpatient Pharmacy Services and Clin-
Riane Ghamrawi, PharmD, BCPS ical Nutrition Services
Antimicrobial Stewardship Pharmacist Specialist Long Beach Memorial Medical Center and Miller Children's
West Chester Hospital Hospital
Vi Gilmore, PharmD, BCPS Jamie Hoffman, PharmD, BCPS
Clinical Pharmacy Specialist, Internal Medicine Senior Clinical Content Specialist
The Johns Hopkins Hospital Wolters Kluwer
Heather L. Girand, PharmD Mark T. Holdsworth, PharmD
Professor of Pharmacy, Pediatrics Associate Professor of Pharmacy & Pediatrics and Phar-
Pharmacy Practice, Ferris State University College of macy Practice Area Head
Pharmacy College of Pharmacy, The University of New Mexico
Meredith D. Girard, MD, FACP Christine Holman, PharmD, BCGP, BCPS
Medical Staff Pharmacotherapy Contributor
Department of Internal Medicine, Summa Health Systems Veterans Affairs Salt Lake City Medical Center
Julie A. Golembiewski, PharmD Amy P. Holmes, PharmD, BCPPS
Clinical Associate Professor and Clinical Pharmacist, Anes- Neonatal Intensive Care Clinical Specialist
thesia/Pain Novant Health Forsyth Medical Center
Colleges of Pharmacy and Medicine, University of Illinois
Edward Horn, PharmD, BCPS
Jeffrey P. Gonzales, PharmD, BCPS Clinical Specialist, Transplant/Cardiothoracic Surgery
Senior Clinical Content Specialist Allegheny General Hospital
Wolters Kluwer
Collin A. Hovinga, PharmD, MS, FCCP
Tania H. Gregorian, PharmD Director of Research Support Services
Clinical Pharmacist, Ambulatory Care Seton Healthcare Family, Dell Children's Medical Center
Cedars-Sinai Medical Care Foundation
8
Joanna Hudson, PharmD, BCPS, FASN, FCCP, Omer N. Koc, MD

FNKF Staff Physician
Clinical Pharmacist, Nephrology Hematology and Medical Oncology Department, Cleveland
Methodist University Hospital Clinic
Makiko Iwasawa, PharmD, BCPS Jill M. Kolesar, PharmD, FCCP, BCPS

Chief Pharmacist, Drug Information Center Associate Professor
National Cerebral and Cardiovascular Center School of Pharmacy, University of Wisconsin Paul P. Car-
bone Comprehensive Cancer Center
Adam B. Jackson, PharmD, BCPS
Clinical Pharmacy Specialist in Infectious Diseases Matthew D. Kostoff, PharmD, FNLA, BCPS,
Kaiser Permanente BCACP, CLS
Clinical Lead Pharmacist
Anna M. Wodlinger Jackson, PharmD, BCPS-AQ Summa Health
Cardiology
Pharmacotherapy Contributor Amy Kramer, PharmD
Fort Lauderdale, Florida Clinical Content Specialist, Clinical Decision Support Pre-
cautions Team
Annette Jenkins, RPh Wolters Kluwer
Wolters Kluwer Donna M. Kraus, PharmD, FAPhA, FPPAG, FCCP
Associate Professor of Pharmacy Practice and Pediatric
Beth Outland Jones, RPh Clinical Pharmacist
Clinical Content Specialist, Clinical Decision Support Pre- Departments of Pharmacy Practice and Pediatrics, Univer-
cautions Team sity of Illinois
Wolters Kluwer
Daniel L. Krinsky, RPh, MS
Christine M. Jones, MPA-C Assistant Professor
Clinical Content Specialist, Clinical Decision Support Pre- Department of Pharmacy Practice, Northeast Ohio Medical
cautions Team University (NEOMED)
Wolters Kluwer
Rachel M. Kruer, PharmD, BCCCP, CNSC
Shari Jones, BSN, RN, CDE Clinical Coordinator
Diabetes Clinical Instructor Indiana University Health Adult Academic Health Center
Children's National Health System
Jamie Kuelker, BSN, RN
Michael P. Kane, PharmD, FCCP, BCPS, BCACP Clinical Operations Manager
Professor, Department of Pharmacy Practice Mercy Virtual Care Center
Albany College of Pharmacy and Health Sciences
Tim T.Y. Lau, PharmD, ACPR, FCSHP
Julie J. Kelsey, PharmD Pharmacotherapeutic Specialist in Infectious Diseases
Clinical Specialist Pharmaceutical Sciences, Vancouver General Hospital
Women's Health and Family Medicine, Department of
Pharmacy Services, University of Virginia Health System Elaine Law, PharmD, BCPS, FCSHP
Assistant Clinical Professor
Patricia Kelsey, RPh, CPHIMS University of the Pacific, Thomas J. Long School of Phar-
Clinical Content Specialist, Clinical Decision Support Dos- macy and Health Sciences
ing Content
Wolters Kluwer Lauren Denise Leader, PharmD
Clinical Pharmacy Specialist, Obstetrics and Gynecology
Polly E. Kintzel, PharmD, BCPS, BCOP Von Voigtlander Women's Hospital, University of Michigan
Clinical Pharmacy Specialist − Oncology
Spectrum Health Lisiane Leal
Ty Heath Kiser, PharmD, FCCM, FCCP, BCPS Porto Alegre, Brazil
Critical Care Pharmacy Specialist
University of Colorado Skaggs School of Pharmacy and Mandy C. Leonard, PharmD, BCPS
Pharmaceutical Sciences System Director, Drug Use Policy and Formulary Manage-
ment
Michael Klepser, PharmD, FCCP, FIDP Cleveland Clinic
Professor of Pharmacy
Department of Pharmacy Practice, Ferris State University Anthony K. Leung, DO, FACP, FIDSA, FASCP
Physician
Jessica Kline, DO Department of Medicine Infectious Disease, Summa Health
Cardiovascular Medicine Fellow System
Summa Health System
Jonathan Leung, PharmD, BCPS, BCPP
Shilpa Klocke, PharmD, BCPS Neuropsychiatric Clinical Pharmacist
Clinical Pharmacy Specialist, Neurology Mayo Clinic
Kaiser Permanente
Debbie Lewis, RPh
Sandra Knowles, RPh, BScPhm Clinical Content Specialist, Drug Files
Drug Information Pharmacist Wolters Kluwer
Sunnybrook Health Sciences Centre
9
Jeffrey D. Lewis, PharmD, MACM Joseph Mazur, BScPharm, PharmD, BCPS

Dean and Professor Clinical Specialist – MICU/Pulmonary
Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic Medical University of South Carolina
University
Shawn Mazur, PharmD
John Lindsley, PharmD, BCPS Clinical Pharmacy Manager, Infectious Diseases
Cardiology Clinical Pharmacy Specialist New York-Presbyterian/Weill Cornell Medical Center
The Johns Hopkins Hospital
Jamie L. McConaha, PharmD, NCTTP, BCACP,
Nicholas A. Link, PharmD, BCOP CDE
Clinical Specialist, Oncology Associate Professor of Pharmacy Practice
Cleveland Clinic Hillcrest Hospital Duquesne University Mylan School of Pharmacy
Lisa K. Lohr, PharmD Joseph McGraw, PharmD, MPH, PhD, BCPS
Oncology Pharmacy Specialist Assistant Professor of Pharmaceutical Science and Metab-
Masonic Cancer Clinic olism Laboratory Director
Concordia University Wisconsin, School of Pharmacy
Julie Lothamer, RPh
Clinical Content Specialist, Clinical Decision Support Dos- Shawn McKinney, RPh
ing Content Clinical Manager, Drug Files
Wolters Kluwer Wolters Kluwer
Jennifer Loucks, PharmD, BCPS Ann Marie McMullin, MD
Solid Organ Transplant Clinical Pharmacist Associate Staff
The University of Kansas Hospital Emergency Services Institute, Cleveland Clinic
Jennifer Fisher Lowe, PharmD, BCOP Christopher McPherson, PharmD
Clinical Oncology Pharmacist Clinical Pharmacist
IU Health Simon Cancer Center Neonatal Intensive Care Unit, St. Louis Children's Hospital
Sherry Luedtke, PharmD Timothy F. Meiller, DDS, PhD
Associate Professor Professor
Department of Pharmacy Practice, Texas Tech University Oncology and Diagnostic Sciences, Baltimore College of
HSC School of Pharmacy Dental Surgery
Viki Lui, BPharm, MPH, MSHP Micheline Meiners, MSc, PhD
Lead Education Pharmacist for Pharmacy Department Pharmacotherapy Contributor
The Royal Melbourne Hospital Lago Norte, Brazil
Shannon N. Lukez, RN, MSN, ANP-BC Cathy A. Meives, PharmD
Adult Nurse Practitioner − Orthopedics Clinical Manager, Core Pharmacology
Mountaineer Orthopedic Specialists Wolters Kluwer
Jordan D. Lundberg, PharmD, BCOP Megan Menon, PharmD, BCOP
Clinical Specialist Pharmacist Clinical Pharmacy Specialist
The Arthur G. James Cancer Hospital at The Ohio State Roswell Park Cancer Institute
University
Jenna Meredith, APRN, MSN, NNP-BC
Scott Lundy, MD, PhD Neonatal Nurse Practitioner
Resident Physician MetroHealth Medical Center
Cleveland Clinic Foundation
Karin Meyer, RPh, MBA
Jason Makii, PharmD, BCPS Clinical Content Specialist, Clinical Decision Support Dos-
Manager, Clinical Services , Department of Pharmacy ing Content
Services Wolters Kluwer
University Hospitals Cleveland Medical Center
Jessica Beth Michaud, PharmD, BCPS
Melissa Makii, PharmD, BCPS Clinical Pharmacist
Clinical Pharmacy Specialist, Pediatric Oncology Froedtert & the Medical College of Wisconsin
Rainbow Babies & Children's Hospital
Patty Milazzo, RPh
Marketa Marvanova, PharmD, PhD, BCGP, BCPP Senior Director, Drug Files
Chair of the Pharmacy Practice Department Wolters Kluwer
College of Health Professions, School of Pharmacy, North
Dakota State University Julie Miller, PharmD
Pharmacy Clinical Specialist, Cardiology
Kelly Matatics, BSN, RN-BC, OCN Nationwide Children's Hospital
Clinical Nurse Research Specialist
University Hospitals Cleveland Medical Center Stacy E. Miller, PharmD, BCPS, BCPP
Vincent F. Mauro, BS, PharmD, FCCP Wolters Kluwer
Professor of Clinical Pharmacy and Adjunct Professor of
Medicine Katherine Mills, PharmD
Colleges of Pharmacy and Medicine, The University of Pharmacotherapy Contributor
Toledo Bristow, Virginia
10
Stephanie S. Minich, PharmD, BCOP Charla E. Miller Nowak, RPh, PharmD

Senior Clinical Content Specialist Neonatal Clinical Pharmacy Specialist
Wolters Kluwer Wolfson Children's Hospital
Molly Minze, PharmD, BCACP Hye-Won Veronica Oh, PharmD
Associate Professor, School of Pharmacy Adjunct Professor and Preceptor
Texas Tech University Health Sciences Center Dongguk College of Pharmacy
Jay M. Mirtallo, MS, RPh, BCNSP, FASHP, Neeta O'Mara, PharmD, BCPS
FASPEN Clinical Pharmacist
Professor of Clinical Pharmacy – Director, MS in Health Dialysis Clinic
System Pharmacy
Carol Ott, BSPharm, PharmD, BCPP
Ohio State University
Clinical Pharmacy Specialist, Psychiatry
J. Cameron Mitchell, PharmD, BCPS, BCPP Midtown Community Mental Health
Pharmacy Clinical Specialist, Psychiatry
Manjunath P. Pai, PharmD, FCP
UNC Hospitals at WakeBrook
Associate Professor of Clinical Pharmacy
Maggie Monogue, PharmD University of Michigan
Infectious Diseases Clinical Pharmacy Specialist
Tom Palma, MS, RPh, BCPS
Texas Health Resources, Fort Worth
Scott Monte, PharmD Wolters Kluwer
Clinical Pharmacist, Department of Bariatric Surgery
Ji Hyun Park, PharmD, RPh
University of Buffalo School of Pharmacy
Clinical Pharmacist
Lauri Moore, RPh, MBA KEPCO Medical Center, Hanjeon Hospital, KMC
Vice President, Content Development
Susie H. Park, PharmD, BCPP
Wolters Kluwer
Assistant Professor of Clinical Pharmacy
John M. Moorman, PharmD, BCPS University of Southern Califormia
Pharmacotherapy Specialist, Endocrinology
Mary Herring Parker, PharmD, FASHP, FCCP,
Cleveland Clinic Akron General
BCPS, BCCP
Michael P. Moranville, PharmD, FCCP, BCCP, Clinical Pharmacist Specialist
BCPS Durham VA HealthCare System
Nicole Passerrello, PharmD, BCPPS, BCPS
Wolters Kluwer
Jennifer L. Morris, PharmD, FCCM, BCPPS, Wolters Kluwer
BCPS Neha Patel, PharmD, BCPS
Clinical Pharmacy Specialist, Renal/Renal Transplant/ Clinical Specialist, Solid Organ Transplant, Adjunct Facility
Extracorporeal Therapies Medical University of South Carolina
Texas Children's Hospital
Nisha K. Patel, PharmD, MBA, BCPS
Kara M. Morris, DDS, MS Clinical Pharmacy Specialist
Pediatric Dentist The Johns Hopkins Hospital
Olentangy Pediatric Dentistry
Alicia Perry, MSN, APRN, AGNP-C, CCRN
Naoto Nakagawa, PharmD, PhD Lead Adult Geriatric Nurse Practitioner
Chief Pharmacist Mercy Virtual Care Center
Drug Information Center, Japan
Brent Pettijohn Sr., RPh
Lynne Nakashima, PharmD Clinical Content Specialist, Drug Files
Professional Practice Leader, Clinical Professor Wolters Kluwer
B.C. Cancer Agency, Vancouver Centre, University of BC
Rebecca Pettit, PharmD, MBA, BCPS
Carrie Nemerovski, PharmD, BCPS, AQ- Pediatric Pulmonary Clinical Pharmacy Specialist
Cardiology Riley Hospital for Children, Indiana University Health,
Senior Clinical Content Specialist Department of Pharmacy
Wolters Kluwer
Hanna Phan, PharmD, FCCP
Jessica Neurohr, RD Clinical Pharmacy Specialist, Pediatric Pulmonology and
Dietician Sleep
Cincinnati VA Medical Center Banner University Medical Center, Tucson
Timothy Nguyen, PharmD, BCPS, CCP, FASCP Cameron Phillips, BPharm, MClin Pharm
Associate Professor, Division of Pharmacy Practice Clinical Pharmacist
Long Island University, LIU Pharmacy Flinders Medical Center
Kristen Rose Nichols, PharmD, BCPS-AQ ID, Julie Pingel, PharmD, BCPPS
BCPPS Pediatric Critical Care Clinical Pharmacy Specialist
Clinical Pharmacist, Pediatric Infectious Diseases Monroe Carell Jr. Children's Hospital at Vanderbilt
Indiana University Health Riley Hospital for Children
11
Jennifer L. Placencia, PharmD Shannon Saldana, PharmD, MS, BCPP

Neonatal Clinical Pharmacy Specialist Psychiatry Advanced Clinical Pharmacist
Texas Children's Hospital Primary Children's Hospital
Karen Post, RPh Marile L. Santamarina, MS, PharmD, CDE, CPT
Clinical Manager, Drug Files Assistant Professor of Pharmacy Practice
Wolters Kluwer Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic
University
Ted Post, MD
Editor-in-Chief Reem Santos, BPharm, MSc
Wolters Kluwer Specialist Antimicrobial Pharmacist
Cambridge University Hospitals
Amy L. Potts, PharmD, BCPS
Assistant Director Cheryl Sargel, PharmD
Department of Pharmacy Advanced Patient Care Pharmacist
PGY1 & PGY2 Residency Program Director Nationwide Children's Hospital
Monroe Carell Jr. Children's Hospital at Vanderbilt
Mia Schmiedeskamp-Rahe, PharmD, BCPS
Erin Powell, PharmD Clinical Pharmacist
Clinical Content Specialist, Drug Files University of Illinois Hospital and Health Sciences System
Wolters Kluwer
Kandace M. Schuft, PharmD
Saira Rab, PharmD, BCPS (AQ-ID), AAHIVP Senior Clinical Content Specialist
Infectious Diseases/HIV Clinical Pharmacist Specialist Wolters Kluwer
Grady Health System
Todd P. Semla, MS, PharmD, BCPS, FCCP, AGSF
Sally Rafie, PharmD, BCPS National PBM Clinical Program Manager − Mental Health &
Medical Safety Pharmacist Geriatrics
UC San Diego Health System Department of Veterans Affairs, Pharmacy Benefits Man-
agement Services
Esta Razavi, PharmD, MBA
Clinical Content Specialist, Clinical Decision Support Pre- Chasity M. Shelton, PharmD, BCPS, BCNSP,
cautions Team FCCP
Wolters Kluwer Clinical Pharmacy Specialist
Pediatric Infectious Diseases and Antimicrobial Steward-
Brent Reed, BS, PharmD, BCPS-AQ Cardiology,
ship, Le Bonheur Children's Hospital
FAHA
Clinical Pharmacy Specialist, Heart Transplantation Clinic Nicole M. Sifontis, PharmD, FCCP, BCPS
University of Maryland Heart Center Clinical Professor, Department of Pharmacy Practice and
Clinical Pharmacist, Abdominal Organ Transplant Service
James Reissig, PharmD, BCPS Temple University School of Pharmacy
Pharmacy Specialist, Residency Program Director
UH Parma Medical Center Richard Silvia, PharmD, BCPP
Clinical Pharmacist
Neil Reynolds, BPharm, MSc Codman Square Health Center
Senior Pharmacist
Fiona Stanley Hospital Pamela J. Sims, PharmD, PhD
Professor
Vanitra Richards, PharmD Department of Pharmaceutical, Social, and Administrative
Clinical Content Specialist, Clinical Decision Support Pre- Sciences, McWhorter School of Pharmacy, Samford Uni-
cautions Teams versity
Wolters Kluwer
Steve Sklar, PharmD
Linda Riski-Lindorff, RPh Senior Clinical Manager
Senior Clinical Content Specialist, Drug Files Wolters Kluwer
Wolters Kluwer
Amy Skyles, PharmD
Melissa E. Rotz, PharmD, BCPS Clinical Pharmacist Specialist
Staff Pharmacist University of Michigan Health System
Cooper University Hospital
April N. Smith, PharmD, MA, BCPS
Lisa Ryan, MD Clinical Pharmacist, Adult Acute Care & Bariatric Surgery
General Pediatrician CHI Immanuel Medical Center
BJC Medical Group
Michael Smith, PharmD, BCPS
Amy Rybarczyk, PharmD, BCPS Clinical Assistant Professor
Pharmacy Clinical Manager University of Michigan
Wooster Community Hospital
Sarah Smith, RPh, PharmD, BCPS
Rikki L. Rychel, PharmD, BCPS, CDE Clinical Director, Clinical Decision Support Dosing Content
Clinical Pharmacy Specialist, Ambulatory Care Wolters Kluwer
Louis Stokes Cleveland Department of Veterans Affairs
Medical Center
12
Tiffeny T. Smith, PharmD Sandra R. Tolbert, PharmD, BCGP

Clinical Pharmacy Specialist, Infectious Diseases/Antimi- Pharmacotherapy Contributor
crobial Stewardship North Royalton, Ohio
UT Southwestern Medical Center
Lindsey Toman, PharmD, BCPS
Timothy Smith, MD Clinical Pharmacy Specialist, Solid Organ Transplantation
Pediatric Anesthesiologist The Johns Hopkins Hospital
Nationwide Children's Hospital
Elizabeth A. Tomsik, PharmD, BCPS
Winter J. Smith, PharmD, BCPS Senior Clinical Director, Drug Content
Clinical Pharmacy Specialist, Acute Care Wolters Kluwer
VA North Texas Health Care System
Dana Travis, RPh
Joseph Snoke, RPh, BCPS Clinical Content Specialist
Director, Core Pharmacology Group Wolters Kluwer
Wolters Kluwer
Heidi Trinkman, PharmD
John Speakman, PharmD Pediatric Hematology/Oncology Clinical Pharmacy Special-
Clinical Content Specialist, Drug Files ist
Wolters Kluwer Cook Children's Medical Center
Patricia L. Spenard, PharmD Tanya Uritsky, PharmD, BCPS
Clinical Content Specialist, Clinical Decision Support Pre- Clinical Pharmacy Specialist in Pain and Palliative Care
cautions Team Hospital of the University of Pennsylvania
Wolters Kluwer
Andriette van Jaarsveld, BPharm, MScMed
Joni Lombardi Stahura, BS, PharmD, RPh Clinical Pharmacy Specialist
Senior Clinical Content Specialist Mediclinic Southern Africa (Stellenbosch)
Wolters Kluwer
Amy Van Orman, PharmD, BCPS
Stephen Marc Stout, PharmD, MS, BCPS Senior Clinical Content Specialist
Director, Clinical Content Wolters Kluwer
Wolters Kluwer
Carlos Vidotti
Daniel S. Streetman, PharmD, MS, RPh Pharmacotherapy Contributor
Clinical Manager, Metabolism, Interactions, & Genomics Brasilia DF, Brazil
Group
Wolters Kluwer Polly Waggoner, RPh
Clinical Director, Drug Files
Darcie-Ann Streetman, PharmD, RPh Wolters Kluwer
Wolters Kluwer Sarah Warren, PharmD
Carol K. Taketomo, PharmD Wolters Kluwer
Director of Pharmacy and Nutrition Services
Children's Hospital Los Angeles Kristin Watson, PharmD, BCPS
Clinical Pharmacy Specialist, Heart Failure Clinic
Ken Yu Tan, PharmD, CGP, BCACP, BCPS Veterans Affairs Medical Center
Senior Clinical Pharmacist
Singapore General Hospital JoEllen L. Weilnau, PharmD
Clinical Coordinator
Kimberly B. Tallian, PharmD, APH, BCPP, Department of Hematology/Oncology/Bone Marrow Trans-
FASHP, FCCP, FCSHP plant, Akron Children's Hospital
Advanced Practice Pharmacist, Neuropsychiatry
David M. Weinstein, PhD, RPh
Scripps Mercy Hospital, San Diego
Senior Director, Clinical Content
Mary Temple-Cooper, PharmD Wolters Kluwer
Pediatric Clinical Research Specialist
Paula Welker, RPh
Cleveland Clinic Hillcrest Hospital
Jennifer Thackray, PharmD, BCPS, BCPPS Wolters Kluwer
Pediatric Oncology Clinical Pharmacist
Cindy Wethington, RPh
Memorial Sloan-Kettering Cancer Center
Clinical Content Specialist, Clinical Decision Support Dos-
Christopher Thomas, PharmD ing Content
Clinical Pharmacy Manager Wolters Kluwer
Phoenix Children's Hospital
Regine L. White, PharmD, RPh
Kelan Thomas, PharmD, MS, BCPS, BCPP Senior Clinical Content Specialist
Clinical Pharmacist Wolters Kluwer
St. Helena Hospital Center for Behavioral Health Office
Ashley Whitley, APRN, FNP-C
Alexandra L. Thompson, RN Family Nurse Practitioner
Staff RN, Inpatient Pediatrics USAF GUARD
Newton Wellesley Hospital
13
Greg Wiggers, PharmD, PhD Lisa A. Wood, PharmD, BCPS, BCPPS

Clinical Content Specialist Clinical Pharmacist, Critical Care
Wolters Kluwer Ann & Robert H. Lurie Children's Hospital of Chicago
Sheilia M. Wilhelm, PharmD, FCCP, BCPS Wende Wood, RPh, BSPharm, BCPP
Associate Professor (Clinical), Department of Pharmacy Pharmacotherapy Contributor
Practice Toronto, Ontario, Canada
Wayne State University, Eugene Applebaum College of
Pharmacy Richard L. Wynn, BSPharm, PhD
Professor of Pharmacology
Andrea Williams, RPh Baltimore College of Dental Surgery, University of Maryland
Wolters Kluwer Sevasti Yeropoli, MD
OB/GYN
Nathan Wirick, PharmD, BCPS Paragon Obstetrics and Gynecology
Clinical Specialist in Infectious Diseases and Antibiotic
Management Jessica Zatroch, DDS
Cleveland Clinic Hillcrest Hospital Private Practice Dentist
Willoughby Hills, Ohio
Adrian Wong, PharmD, MPH, BCPS, BCCCP
Assistant Professor, Pharmacy Practice Roberta Ziccarelli, RPh
MCPHS University Clinical Content Specialist, Drug Files
Wolters Kluwer
14
PREFACE TO THE TWENTY-FIFTH EDITION

As in each previous edition, the Oral Medicine chapters have been updated offering a clearly highlighted selection of
common dental office prescription choices and Rx examples for management of common oral conditions often
encountered during patient care. These example prescriptions have been updated and are presented in a stand-alone
section for quicker reference.
The editors of the 25th edition of the Drug Information Handbook for Dentistry are extremely proud that the book remains
as popular and as successful as its readers have affirmed. We thank each practitioner and student who has made the
previous editions so widely accepted in the field of dentistry. In this new 25th edition, we have responded to all of the
comments and creative suggestions that come from our readership each year. We know that our text remains the premier
companion to the daily practice of dentistry and that it complements Oral Medicine and medical reference libraries that
every clinician has available in their office.
The latest Guidelines for Antimicrobial Stewardship endorsed by the ADA have been added, including the guideline effects
on the management of patients at risk of endocarditis or those with joint prostheses. The chapter related to the dentist's
involvement with the cancer patient now has an expanded section for salivary testing for HPV and HPV vaccines as well as
addresses diagnostic testing in the dental office. Stand-alone sections have been updated for the crucial topics of
Antiplatelet and Anticoagulation Considerations in Dentistry, adding information on the newly approved reversal agent for
one of the novel anticoagulation drugs. Medication related osteonecrosis of the jaw (MRONJ) information has been
updated. Recommended readings have been edited for chapter subsections. Sections have been expanded and added
related to prescribing medications with NSAIDs including their risk association with MI and stroke, acetaminophen, and
sarcoidosis. Prescribing information options are outlined and are available for easy cross-referencing for the busy dental
practitioner.
There have been expanded discussions inserted of how opioid prescribing guidelines and non-narcotic alternative
medication choices can be prudently evaluated by dentists to manage acute and chronic oral pain.
The monographs now include over 1,500 drugs and these have been updated in the 25th edition with the fields expanded
in common monographs to make them easier to read and identify for all of the drugs. The fields most important to
practicing dentists have been enhanced. The drugs most commonly used in dentistry have the added fields regarding
specific use considerations in dentistry. Medical drugs also include dosing and dose formulation information. In addition,
the adverse reaction section and the important uses and effects on dental treatment for all drugs have been updated
throughout the text.
In addition to the extensive information presented, we are confident that the dental practitioners and dental hygienists who
utilize the text will find the size format to be easy to navigate. The complete cross-referencing of generic and brand names
along with the foreign brands, makes the text the truly complete drug reference guide for dental practice.
The alphabetical index at the back of the text continues to guide the reader through the text. The natural products section;
drug synonyms; and US, Canadian, and Mexican brand names have all been updated. We hope that the active general
dentist, the specialist, the dental hygienist, and the advanced student of dentistry remain better prepared for patient care
while using this new 25th edition of the DIHD.
Richard L. Wynn
Timothy F. Meiller
Harold L. Crossley
15
DESCRIPTION OF SECTIONS AND FIELDS USED IN THIS HANDBOOK
DESCRIPTION OF SECTIONS AND FIELDS USED IN

THIS HANDBOOK
The Drug Information Handbook for Dentistry, 25th Edition is organized into six sections: Introductory text; sample
prescriptions, alphabetical listing of drug monographs; natural products; oral medicine topics; appendix; and indexes
which include pharmacologic categories and alphabetical listings containing generic product names and index terms, as
well as US, Canadian, and Mexican brand names.
INTRODUCTORY TEXT
Helpful guides to understanding the organization and format of the information in this handbook.
SAMPLE PRESCRIPTIONS
Examples provided for prototype drugs and popular prescriptions. Prescriptions included for the following uses: Prevention
of endocarditis and to reduce the risk of late infections of joint prostheses, oral pain, bacterial infections and periodontal
diseases, sinus infection treatment, antimicrobial oral rinse, fungal infections, viral infections, ulcerative and erosive
disorders, sedation (prior to dental treatment).
DRUG MONOGRAPHS
This alphabetical listing of drugs contains comprehensive monographs for medications commonly prescribed in dentistry
and concise monographs for other popular drugs which dental patients may be taking. Monographs may contain the
following fields:
Generic Name US adopted name

Pronunciation Phonetic pronunciation guide
Related Information Cross-reference(s) to pertinent information in other sections of this
handbook
Related Sample Prescriptions Cross-reference(s) to sample prescriptions.
Brand Names: US Trade names found in the United States (manufacturer-specific). The
symbol [DSC] appears after trade names that have been recently
discontinued.
Brand Names: Canada Trade names found in Canada.
Generic Availability (US) Indicates availability of generic products in the United States
Pharmacologic Category Indicates one or more systematic classifications of the drug
Dental Use Information in the Dental Use field indicates when a drug has an
established use specific to dentistry and/or oral medicine. In some
cases, these uses are considered to be unlabeled, as they are not
included in the FDA-approved product labeling (see Description of
Dental Use).
Use Statements under the Use field reflect the approved labeling by the
FDA based on accepted clinical evaluation on safety and efficacy of the
drug as submitted in the New Drug Application (NDA). The "gold
standard" of clinical testing of a new drug requires a randomly selected
cohort of subjects, using a double-blind and placebo controlled
protocol and an acceptable method of assessment to test differences
between test compound and placebo. It is assumed that by their
approval of the labeling, the FDA considers the new drug "safe and
effective" for treating a particular condition in a given patient
population.
Local Anesthetic/Vasoconstrictor Specific information for the dental health professional to prevent
Precautions potential drug interactions related to anesthesia
Effects on Dental Treatment Includes significant side effects of drug therapy which may directly or
indirectly affect dental treatment or diagnosis; may also contain
suggested management approaches and patient handling or care.
Effects on Bleeding How the product affects bleeding during dental procedures
Adverse Reactions Side effects are grouped by percentage of incidence (if known) and/or
body system; in the interest of saving space, <1% effects are grouped
only by percentage.
Dental Usual Dosage The amount of the drug to be typically given or taken during dental
treatment for children and adults
16
(continued)
Dosing The amount of drug to be typically given or taken during therapy; may
include the following:
Adult The recommended amount of drug to be given to adult patients
Adult & Geriatric This combined field is only used to indicate that no specific
adjustments for elderly patients were identified. However, other issues
should be considered (eg, renal or hepatic impairment). Also refer to
Geriatric Considerations for additional information related to elderly
patients.
Geriatric A suggested amount of drug to be given to elderly patients; may
include adjustments from adult dosing (lack of information in the
monograph may imply that the drug is not used in the elderly patient or
no specific adjustments could be identified)
Renal Impairment: Adult Suggested dosage adjustments for adults based on compromised
renal function; may include dosing instructions for patients on dialysis
Hepatic Impairment: Adult Suggested dosage adjustments for adults based on compromised liver
function
Obesity: Adult Dosing adjustment or dosing considerations for the obese adult
patient. Obesity is defined as a BMI ≥30 kg/m2 (based on the World
Health Organization [WHO]).
Adjustment for Toxicity: Adult Suggested adult dosage adjustments in the event specific toxicities
related to therapy are noted, such as hematologic toxicities related to
cancer chemotherapy
Pediatric The amount of the drug to be typically administered during therapy;
may include dosing information for infants, children, and adolescents
(up through 18 years of age) and other suggested dosing adjustments
for toxicity or concomitant medication(s). Dosing information not from
product labeling will be preceded with "Limited data available" and
have a citation.
When both fixed-doses and weight-directed doses (eg, milligram per
kilogram [mg/kg]) are listed, the preferred method is the weight-
directed. When weight-directed dosing (eg, mg/kg) and maximum
doses are provided, use the weight-directed (mg/kg) dose to calculate
the milligram dose for the patient, but do not exceed the maximum
dose listed, unless otherwise noted. Do not exceed adult maximum
dosage for a given indication, unless otherwise noted. If using fixed
dosing based upon age, special care and lower doses should be
considered in pediatric patients who have a low weight for their age.
When ranges of doses are provided, initiate therapy at the lower end of
the range and titrate the dose accordingly, unless otherwise indicated.
The following age group definitions are utilized to characterize age-
related dosing, unless otherwise specified in the monograph: Neonate
(0 to 28 days of age), infant (>28 days to 1 year of age), children (1 to
12 years of age), and adolescent (13 to 18 years of age).
Renal Impairment: Pediatric Suggested dosage adjustments for pediatric patients based on
compromised renal function; may include dosing instructions for
patients on dialysis
Hepatic Impairment: Pediatric Suggested dosage adjustments for pediatric patients based on
compromised liver function
Mechanism of Action How the drug works in the body to elicit a response
Contraindications Information pertaining to inappropriate use of the drug as dictated by
approved labeling
Warnings/Precautions Precautionary considerations, hazardous conditions related to use of
the drug, and disease states or patient populations in which the drug
should be cautiously used. Boxed warnings, when present, are clearly
identified and are adapted from the FDA approved labeling. Consult
the product labeling for the exact black box warning through the
manufacturer's or the FDA website.
Warnings: Additional Pediatric Provides further details for precautionary considerations that are
Considerations specific to pediatric and neonatal patients
Drug Interactions
Metabolism/Transport Effects If a drug has demonstrated involvement with cytochrome P450
enzymes, or other metabolism or transport proteins, this field will
identify the drug as an inhibitor, inducer, or substrate of the specific
enzyme(s) (eg, CYP1A2 or UGT1A1). CYP450 isoenzymes are
identified as substrates (minor or major), inhibitors (weak, moderate, or
strong), and inducers (weak or strong).
17
DESCRIPTION OF SECTIONS AND FIELDS USED IN THIS HANDBOOK
(continued)
Avoid Concomitant Use Designates drug combinations which should not be used
concomitantly, due to an unacceptable risk:benefit assessment.
Frequently, the concurrent use of the agents is explicitly prohibited or
contraindicated by the product labeling.
Increased Effect/Toxicity Drug combinations that result in an increased or toxic therapeutic effect
between the drug listed in the monograph and other drugs or drug
classes.
Decreased Effect Drug combinations that result in a decreased therapeutic effect
between the drug listed in the monograph and other drugs or drug
classes.
Food Interactions Possible important interactions between the drug listed in the
monograph and food, alcohol, or other beverages.
Dietary Considerations Specific dietary modifications and/or restrictions (eg, information about
sodium content)
Pharmacodynamics/Kinetics
Onset of Action The time after drug administration when therapeutic effect is observed;
may also include time for peak therapeutic effect.
Duration of Action Length of therapeutic effect.
Half-life Elimination The reported half-life of elimination for the parent or metabolites of the
drug
Time to Peak Describes the relative time after ingestion when concentration
achieves the highest serum concentration
Pregnancy Risk Factor Five categories established by the FDA to indicate the potential of a
systemically absorbed drug for causing risk to the fetus; the FDA is
replacing this category system with scientific data and other
information specific to the use of the drug in pregnant women as new
drugs and product labeling on existing drugs are approved
Pregnancy Considerations A summary of human and/or animal information pertinent to or
associated with the use of the drug as it relates to clinical effects on the
fetus, newborn, or pregnant women.
Breastfeeding Considerations Information pertinent to or associated with the human use of the drug
as it relates to clinical effects on the breastfeeding infant or postpartum
woman.
Product Availability Provides availability information on products that have been approved
by the FDA but are not yet available for use. Estimates for when a
product may be available are included, when this information is known.
May also provide any unique or critical drug availability issues.
Controlled Substance Contains controlled substance schedule information as assigned by
the United States Drug Enforcement Administration (DEA) or Canada's
Controlled Drugs and Substance Act (CDSA). CDSA information is
only provided for drugs available in Canada and not available in the
US.
Prescribing and Access Restrictions Provides information on any special requirements regarding the
prescribing, obtaining, or dispensing of drugs, including any unique
access restrictions
Dosage Forms Considerations More specific information regarding product concentrations,
ingredients, package sizes, amount of doses per container, and other
important details pertaining to various formulations of medications
Dosage Forms: US Information with regard to form, strength, and availability of the drug in
the United States. Note: Additional formulation information (eg,
excipients, preservatives) is included when available. Please consult
product labeling for further information.
Dosage Forms: Canada Information with regard to form, strength, and availability of the drug in
Canada. The symbol [DSC] appears after trade names that have been
recently discontinued.
Dental Health Professional Considerations Pharmacology-related comments and considerations relevant to the
dental professional
NATURAL PRODUCTS: HERBAL AND DIETARY SUPPLEMENTS

The natural product content is adapted from The Review of Natural Products a Facts & Comparisons online database.
This section consists of a clinical overview that summarizes the uses, dosing, contraindications, pregnancy/lactation,
interactions, adverse reactions, and toxicology information for each natural product. The dental-specific information is also
included to further assist the dental professional in patient care.
18
ORAL MEDICINE TOPICS

This section is divided into two major parts and contains text on Oral Medicine topics. In each subsection, the systemic
condition or the oral disease state is described briefly, followed by the pharmacologic considerations with which the dentist
must be familiar.
I. Dental Management and Therapeutic Considerations in Medically Compromised Patients: Focuses on
common medical conditions and their associated drug therapies with which the dentist must be familiar. Patient
profiles with commonly associated drug regimens are described.
II. Dental Management and Therapeutic Considerations in Patients With Specific Oral Conditions: Focuses on
therapies the dentist may choose to prescribe for patients suffering from oral disease or who are in need of special
care. Some overlap between these sections has resulted from systemic conditions that have oral manifestations
and vice-versa. Cross-references to the descriptions and the monographs for individual drugs described elsewhere
in this handbook allow for easy retrieval of information. Example prescriptions for drugs commonly used in the
treatment of each condition are presented so that the clinician can evaluate alternate approaches to treatment.
Seldom is there a single drug of choice.
Note: Prescriptions listed represent prototype drugs and popular prescriptions and are examples only. The
pharmacologic category index is available for cross-referencing if alternatives or additional drugs are sought.
APPENDIX
The appendix is broken down into various sections for easy use and offers a compilation of tables and guidelines which
can often be helpful when considering patient care.
INDEXES
This section includes a pharmacologic category index with an easy-to-use classification system in alphabetical order and
an alphabetical index which provides a quick reference for generic names, index terms, US, Canadian, and Mexican brand
names. From this index, the reader can cross-reference to the monographs.
19
DESCRIPTION OF DENTAL USE
DESCRIPTION OF DENTAL USE

Unlabeled Use and Routes of Administration in Dentistry and Oral Medicine
The off-label use of a medication may involve differences in either the intended purpose or the route of administration of a
particular medication. In dentistry, there are some situations which are common (clindamycin for endocarditis prophylaxis),
and uncommon (application of Oralone paste to the oral mucosa) which may be termed "unlabeled use". Depending on
the degree of familiarity, the prescription of a drug for an off-label purpose may create concern on the part of healthcare
professionals who are less familiar with the dental use of these medications. For example, a pharmacist may note the
statement "for external use only" on the label of a tube of topical cream and question whether the drug should be applied to
the oral mucosa. Usually, reinforcement of the use of a drug as well as an analysis of the likely systemic exposure/toxicity,
can address these concerns.
The dentist who prescribes a drug bears the responsibility for deciding on the purpose of the prescription and the detail of
the dosing regimen. These professional decisions are based on information from a variety of sources, including (but not
limited to) the official labeling, sound scientific evidence, expert medical judgment, or published literature. In selected
situations, these sources may justify the use of a drug in an off-label manner. Accepted professional standards indicate off-
label use of a drug must be initiated in good faith, serve the best interest of the patient, and must be undertaken without
fraudulent intent. Healthcare providers should recognize that the approved labeling is not intended to limit the practitioners
in the exercise of his or her best professional judgment in serving the interest of patients. However, it should be noted that
a practitioner may be accountable for the negligent use in a civil action regardless of whether the FDA has approved the
use of the drug in question. Based on these assertions, at least one medical organization (the American Academy of
Pediatrics) has published in an official policy statement that the practice of medicine may actually require a practitioner to
use drugs in an off-label manner in order to provide the most appropriate treatment for a given patient. Off-label use in
dentistry and oral medicine is a frequently encountered issue. A discussion of the off-label use of drugs in dentistry
appears in the ADA/PDR Guide to Dental Therapeutics, 5th Edition, edited by Sebastian G. Ciancio, DDS in cooperation
with the ADA Division of Legal Affairs.
20
CONTROLLED SUBSTANCES
Schedule I = C-I
The drugs and other substances in this schedule have no legal medical uses except research. They have a high potential
for abuse. They include selected opiates such as heroin, opium derivatives, and hallucinogens.
Schedule II = C-II
The drugs and other substances in this schedule have legal medical uses and a high abuse potential which may lead to
severe dependence. They include former "Class A" opioids, amphetamines, barbiturates, and other drugs.
Schedule III = C-III
The drugs and other substances in this schedule have legal medical uses and a lesser degree of abuse potential which
may lead to moderate dependence. They include former "Class B" opioids and other drugs.
Schedule IV = C-IV
The drugs and other substances in this schedule have legal medial uses and low abuse potential which may lead to
moderate dependence. They include barbiturates, benzodiazepines, propoxyphenes, and other drugs.
Schedule V = C-V
The drugs and other substances in this schedule have legal medical uses and low abuse potential which may lead to
moderate dependence. They include opioids cough preparations, diarrhea preparations, and other drugs.
Note: These are federal classifications. Your individual state may place a substance into a more restricted category. When
this occurs, the more restricted category applies. Consult your state law.
21
PREGNANCY CATEGORIES
PREGNANCY CATEGORIES
Pregnancy Categories (sometimes referred to as pregnancy risk factors) are a letter system presented under the
Teratogenic Effects subsection of the product labeling. The system was initiated in 1979. The categories were required
to be part of the package insert for prescription drugs that are systemically absorbed. The Food and Drug Administration
(FDA) has updated prescribing labeling requirements and as of June 2015, the pregnancy categories will no longer be part
of new product labeling. Prescription products which currently have a pregnancy category letter will be phasing this out of
their product information.
The categories are defined as follows:
A Adequate and well-controlled studies in pregnant women have not shown that the drug increases the risk of fetal
abnormalities.
B Animal reproduction studies show no evidence of impaired fertility or harm to the fetus; however, no adequate and well-
controlled studies have been conducted in pregnant women.
or
Animal reproduction studies have shown adverse events; however, studies in pregnant women have not shown that the drug
increases the risk of abnormalities.
C Animal reproduction studies have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in
humans and the benefits from the use of the drug in pregnant women may be acceptable, despite its potential risks.
or
Animal reproduction studies have not been conducted.
D Based on human data, the drug can cause fetal harm when administered to pregnant women, but the potential benefits from
the use of the drug may be acceptable, despite its potential risks.
X Studies in animals or humans have demonstrated fetal abnormalities (or there is positive evidence of fetal risk based on
reports and/or marketing experience) and the risk of using the drug in pregnant women clearly outweighs any possible benefit
(for example, safer drugs or other forms of therapy are available).
In 2008, the Food and Drug Administration (FDA) proposed new labeling requirements which would eliminate the use of
the pregnancy category system and replace it with scientific data and other information specific to the use of the drug in
pregnant women. These proposed changes were suggested because the current category system may be misleading. For
instance, some practitioners may believe that risk increases from category A to B to C to D to X, which is not the intent. In
addition, practitioners may not be aware that some medications are categorized based on animal data, while others are
based on human data. The new labeling requirements will contain pregnancy and lactation subsections, each describing a
risk summary, clinical considerations, and section for specific data.
For full descriptions of the final rule, refer to the following website: http://www.fda.gov/Drugs/DevelopmentApprovalPro-
cess/DevelopmentResources/Labeling/ucm093307.htm
22
FDA NAME DIFFERENTIATION PROJECT: THE USE OF

TALL-MAN LETTERS
Confusion between similar drug names is an important cause of medication errors. For years, The Institute For Safe
Medication Practices (ISMP), has urged generic manufacturers to use a combination of large and small letters as well as
bolding (ie, chlorproMAZINE and chlorproPAMIDE) to help distinguish drugs with look-alike names, especially when they
share similar strengths. Recently the FDA's Division of Generic Drugs began to issue recommendation letters to
manufacturers suggesting this novel way to label their products to help reduce this drug name confusion. Although this
project has had marginal success, the method has successfully eliminated problems with products such as diphenhydr-
AMINE and dimenhyDRINATE. Hospitals should also follow suit by making similar changes in their own labels, preprinted
order forms, computer screens and printouts, and drug storage location labels.
Lexi-Comp, Inc. Medical Publishing will use "Tall-Man" letters for the drugs suggested by the FDA or recommended by
ISMP.
The following is a list of generic and brand name product names and recommended revisions.
Drug Product Recommended Revision

acetazolamide acetaZOLAMIDE
alprazolam ALPRAZolam
amiloride aMILoride
amlodipine amLODIPine
aripiprazole ARIPiprazole
atomoxetine atoMOXetine
atorvastatin atorvaSTATin
Avinza AVINza
azacitidine azaCITIDine
azathioprine azaTHIOprine
bupropion buPROPion
buspirone busPIRone
carbamazepine carBAMazepine
carboplatin CARBOplatin
cefazolin ceFAZolin
cefotetan cefoTEtan
cefoxitin cefOXitin
ceftazidime cefTAZidime
ceftriaxone cefTRIAXone
Celebrex CeleBREX
Celexa CeleXA
chlordiazepoxide chlordiazePOXIDE
chlorpromazine chlorproMAZINE
chlorpropamide chlorproPAMIDE
cisplatin CISplatin
clobazam cloBAZam
clomiphene clomiPHENE
clomipramine clomiPRAMINE
clonazepam clonazePAM
clonidine cloNIDine
clozapine cloZAPine
cycloserine cycloSERINE
cyclosporine cycloSPORINE
dactinomycin DACTINomycin
daptomycin DAPTOmycin
daunorubicin DAUNOrubicin
Depo-Medrol DEPO-Medrol
diazepam diazePAM
diltiazem dilTIAZem
dimenhydrinate dimenhyDRINATE
diphenhydramine diphenhydrAMINE
dobutamine DOBUTamine
23
FDA NAME DIFFERENTIATION PROJECT: THE USE OF TALL-MAN LETTERS
(continued)
docetaxel DOCEtaxel
dopamine DOPamine
doxorubicin DOXOrubicin
duloxetine DULoxetine
ephedrine ePHEDrine
epinephrine EPINEPHrine
epirubicin epiRUBicin
eribulin eriBULin
fentanyl fentaNYL
flavoxate flavoxATE
fluoxetine FLUoxetine
fluphenazine fluPHENAZine
fluvoxamine fluvoxaMINE
glipizide glipiZIDE
glyburide glyBURIDE
guaifenesin guaiFENesin
guanfacine guanFACINE
Humalog HumaLOG
Humulin HumuLIN
hydralazine hydrALAZINE
hydrochlorothiazide hydroCHLOROthiazide
hydrocodone HYDROcodone
hydromorphone HYDROmorphone
hydroxyprogesterone HYDROXYprogesterone
hydroxyzine hydrOXYzine
idarubicin IDArubicin
idarucizumab idaruCIZUmab
infliximab inFLIXimab
Invanz INVanz
isotretinoin ISOtretinoin
Klonopin KlonoPIN
Lamictal LaMICtal
Lamisil LamISIL
lamivudine lamiVUDine
lamotrigine lamoTRIgine
levetiracetam LevETIRAcetam
levocarnitine levOCARNitine
levofloxacin levoFLOXacin
levoleucovorin LEVOleucovorin
lorazepam LORazepam
medroxyprogesterone medroxyPROGESTERone
metformin metFORMIN
methazolamide methazolAMIDE
methimazole methIMAzole
methylprednisolone methylPREDNISolone
methyltestosterone methylTESTOSTERone
metolazone metOLazone
metronidazole metroNIDAZOLE
metyrapone metyraPONE
metyrosine metyroSINE
mifepristone miFEPRIStone
misoprostol miSOPROStol
mitomycin mitoMYcin
mitoxantrone MitoXANTRONE
Nexavar NexAVAR
Nexium NexIUM
nicardipine niCARdipine
24
(continued)
nifedipine NIFEdipine
nimodipine niMODipine
Novolin NovoLIN
Novolog NovoLOG
olanzapine OLANZapine
oxcarbazepine OXcarbazepine
oxycodone oxyCODONE
Oxycontin OxyCONTIN
oxymorphone oxyMORphone
paclitaxel PACLitaxel
paroxetine PARoxetine
pazopanib PAZOPanib
pemetrexed PEMEtrexed
penicillamine penicillAMINE
pentobarbital PENTobarbital
phenobarbital PHENobarbital
ponatinib PONATinib
pralatrexate PRALAtrexate
prednisolone prednisoLONE
prednisone predniSONE
Prilosec PriLOSEC
Prozac PROzac
quetiapine QUEtiapine
quinidine quiNIDine
quinine quiNINE
rabeprazole RABEprazole
ranitidine raNITIdine
rifampin rifAMPin
rifaximin rifAXIMin
rimantadine riMANTAdine
Risperdal RisperDAL
risperidone risperiDONE
rituximab riTUXimab
romidepsin romiDEPsin
romiplostim romiPLOStim
ropinirole rOPINIRole
Sandimmune sandIMMUNE
Sandostatin SandoSTATIN
saxagliptin SAXagliptin
Seroquel SEROquel
Sinequan SINEquan
sitagliptin SITagliptin
Solu-Cortef Solu-CORTEF
Solu-Medrol SOLU-Medrol
sorafenib SORAfenib
sufentanil SUFentanil
sulfadiazine sulfADIAZINE
sulfasalazine sulfaSALAzine
sumatriptan SUMAtriptan
sunitinib SUNItinib
Tegretol TEGretol
tiagabine tiaGABine
tizanidine tiZANidine
tolazamide TOLAZamide
tolbutamide TOLBUTamide
tramadol traMADol
trazodone traZODone
25
FDA NAME DIFFERENTIATION PROJECT: THE USE OF TALL-MAN LETTERS
(continued)
Trental TRENtal
valacyclovir valACYclovir
valganciclovir valGANciclovir
vinblastine vinBLAStine
vincristine vinCRIStine
zolmitriptan ZOLMitriptan
Zyprexa ZyPREXA
Zyrtec ZyrTEC
FDA and ISMP lists of look-alike drug names with recommended tall man letter. http://www.ismp.org/tools/tallmanletters.pdf. Accessed January 6,
2011.
Name differentiation project. http://www.fda.gov/Drugs/DrugSafety/MedicationErrors/ucm164587.htm. Accessed January 6, 2011.
US Pharmacopeia. USP quality review: use caution − avoid confusion. March 2001, No. 76. http://www.usp.org
26
PRESCRIPTION WRITING
Doctor's Name
Address
Phone Number
Patient's Name/Date
Patient's Address/Age
Rx
Drug Name/Dosage Size
Disp: Number of tablets, capsules, ounces to be dispensed (roman numerals added as precaution for abused drugs)
Sig: Direction on how drug is to be taken
Doctor's signature
State license number
DEA number (if required)
PRESCRIPTION REQUIREMENTS
1. Date
2. Full name and address of patient
3. Name and address of prescriber
4. Signature of prescriber
If Class II drug, Drug Enforcement Agency (DEA) number necessary.
If Class II and Class III opioid, a triplicate prescription form (in the state of California) is necessary and it must be
handwritten by the prescriber.
Please turn to appropriate oral medicine chapters for examples of prescriptions.
27
PREVENTING PRESCRIBING ERRORS
PREVENTING PRESCRIBING ERRORS

Prescribing errors account for the majority of reported medication errors and have prompted health care professionals to
focus on the development of steps to make the prescribing process safer. Prescription legibility has been attributed to a
portion of these errors and legislation has been enacted in several states to address prescription legibility. However,
eliminating handwritten prescriptions and ordering medications through the use of technology [eg, computerized
prescriber order entry (CPOE)] has been the primary recommendation. Whether a prescription is electronic, typed, or
hand-printed, additional safe practices should be considered for implementation to maximize the safety of the prescribing
process. Listed below are suggestions for safer prescribing:
• Ensure correct patient by using at least 2 patient identifiers on the prescription (eg, full name, birth date, or
address). Review prescription with the patient or patient's caregiver.
• If pediatric patient, document patient's birth date or age and most recent weight. If geriatric patient, document
patient's birth date or age.
• Prevent drug name confusion: For more information, see http://www.ismp.org/tools/confuseddrugnames.pdf.
– Use TALLman lettering (eg, buPROPion, busPIRone, predniSONE, prednisoLONE). For more information,
see http://www.fda.gov/drugs/drugsafety/medicationerrors/default.htm.
– Avoid abbreviated drug names (eg, MSO4, MgSO4, MS, HCT, 6MP, MTX), as they may be misinterpreted and
cause error.
– Avoid investigational names for drugs with FDA approval (eg, FK-506, CBDCA).
– Avoid chemical names such as 6-mercaptopurine or 6-thioguanine, as sixfold overdoses have been given
when these were not recognized as chemical names. The proper names of these drugs are mercaptopurine
or thioguanine.
– Use care when prescribing drugs that look or sound similar (eg, look- alike, sound-alike drugs). Common
examples include: CeleBREX vs CeleXA, hydrOXYzine vs hydrALAZINE, ZyPREXA vs ZyrTEC.
• Avoid dangerous, error-prone abbreviations (eg, regardless of letter-case: U, IU, QD, QOD, µg, cc, @). Do not use
apothecary system or symbols. Additionally, text messaging abbreviations (eg, "2Day") should never be used.
– For more information, see http://www.ismp.org/tools/errorproneabbreviations.pdf.
• Always use a leading zero for numbers <1 (0.5 mg is correct and .5 mg is incorrect) and never use a trailing zero
for whole numbers (2 mg is correct and 2.0 mg is incorrect).
• Always use a space between a number and its units as it is easier to read. There should be no periods after the
abbreviations mg or mL (10 mg is correct and 10mg is incorrect).
• For doses that are ≥1,000 dosing units, use properly placed commas to prevent 10-fold errors (100,000 units is
correct and 100000 units is incorrect).
• Do not prescribe drug dosage by the type of container in which the drug is available (eg, do not prescribe "1 amp",
"2 vials", etc).
• Do not write vague or ambiguous orders which have the potential for misinterpretation by other health care
providers. Examples of vague orders to avoid: "Resume pre-op medications," "give drug per protocol," or "continue
home medications."
• Review each prescription with patient (or patient's caregiver) including the medication name, indication, and
directions for use.
• Take extra precautions when prescribing high alert drugs (drugs that can cause significant patient harm when
prescribed in error). Common examples of these drugs include: Anticoagulants, chemotherapy, insulins, opioids,
and sedatives.
– For more information, see http://www.ismp.org/tools/institutionalhighalert.asp.
To Err Is Human: Building a Safer Health System, Kohn LT, Corrigan JM, Donaldson MS, eds. Washington, D.C.: National Academy Press. 2000.
A Complete Outpatient Prescription1

A complete outpatient prescription can prevent the prescriber, the pharmacist, and/or the patient from making a mistake
and can eliminate the need for further clarification. The complete outpatient prescription should contain:
• Patient's full name
• Medication indication
• Allergies
• Prescriber name and telephone or pager number
• For pediatric patients: Their birth date or age and current weight
• For geriatric patients: Their birth date or age
• Drug name, dosage form and strength
28
• For pediatric patients: Intended daily weight-based dose so that calculations can be checked by the pharmacist (ie,
mg/kg/day or units/kg/day)
• Number or amount to be dispensed
• Complete instructions for the patient or caregiver, including the purpose of the medication, directions for use
(including dose), dosing frequency, route of administration, duration of therapy, and number of refills.
• Dose should be expressed in convenient units of measure.
• When there are recognized contraindications for a prescribed drug, the prescriber should indicate knowledge of this
fact to the pharmacist (ie, when prescribing a potassium salt for a patient receiving an ACE inhibitor, the prescriber
should write "K serum leveling being monitored").
Upon dispensing of the final product, the pharmacist should ensure that the patient or caregiver can effectively
demonstrate the appropriate administration technique. An appropriate measuring device should be provided or recom-
mended. Household teaspoons and tablespoons should not be used to measure liquid medications due to their variability
and inaccuracies in measurement; oral medication syringes are recommended.
1
Levine SR, Cohen MR, Blanchard NR, et al. Guidelines for preventing medication errors in pediatrics. J Pediatr
Pharmacol Ther. 2001;6:426-442.
29
Drug prescriptions shown in this section represent prototype drugs and popular prescriptions and are examples only. The
pharmacologic category index is available for cross-referencing if alternatives and additional drugs are sought. See the
Oral Medicine Chapters for a complete description of Diagnosis and Management considerations.
TABLE OF CONTENTS
Oral Pain - Sample Prescriptions....................................................................................................................................... 32

Antimicrobial Oral Rinse - Sample Prescriptions............................................................................................................... 35
Bacterial Infections and Periodontal Diseases - Sample Prescriptions............................................................................. 36
Fungal Infections - Sample Prescriptions.......................................................................................................................... 39
Prevention of Endocarditis and to Reduce the Risk of Late Infections of Joint Prostheses - Sample Prescriptions....... 41
Sinus Infection Treatment - Sample Prescriptions.............................................................................................................42
Viral Infections - Sample Prescriptions.............................................................................................................................. 44
Sedation (Prior to Dental Treatment) - Sample Prescriptions........................................................................................... 46
Ulcerative and Erosive Disorders - Sample Prescriptions................................................................................................. 47
31
ORAL PAIN - SAMPLE PRESCRIPTIONS

The patient with existing acute or chronic oral pain requires appropriate treatment and sensitivity on the part of the dentist,
all for the purpose of achieving relief from the oral source of pain. Pain can be divided into mild, moderate, and severe
levels and requires a subjective assessment by the dentist based on knowledge of the dental procedures to be performed,
the presenting signs and symptoms of the patient, and the realization that most dental procedures are invasive often
leading to pain once the patient has left the dental office. The practitioner must be aware that the treatment of the source of
the pain is usually the best management. Opioid analgesics can be used on a short-term basis or intermittently in
combination with nonopioid therapy in the chronic pain patient. Judicious prescribing, monitoring, and
maintenance by the practitioner are imperative, particularly whenever considering the use of an opioid analgesic
due to the abuse and addiction liabilities. For all prescribers of extended release and long-acting opioid analgesics,
patient information as noted below is required. The CDC has released guidelines for opioid prescriptions. Numerous
states have adopted prescription monitoring programs particularly targeting opioids and benzodiazapines; refer to your
home state guidelines for specific regulations and reporting requirements. In general opioids should not be the first-line
therapy choice for chronic pain except for active cancer, palliative therapy, or end of life care. Please visit www.cdc.gov/
drugoverdose/prescribing/guideline.html for more specific details. The FDA also has a required Opioid Analgesic Risk
Evaluation and Mitigation Strategy (REMS) for opioid analgesic drug products used in the outpatient setting, see
www.opioidanalgesicrems.com.
DOs and DON'Ts of Extended Release/Long-Acting Opioid Analgesics
DO:
• Read the Medication Guide.
• Take your medicine exactly as prescribed.
• Store your medicine away from children and in a safe place.
• Check with pharmacy about disposal of unused medicine.
• Call your health care provider for medical advice about side effects. You may report side effects to the FDA at (800)
FDA-1088.
Call 911 or your local emergency service right away if:
• You take too much medicine.
• You have trouble breathing or shortness of breath.
• A child has taken this medicine.
Talk to your health care provider:
• If the dose you are taking does not control your pain.
• About any side effects you may be having.
• About all the medicines you take, including over-the-counter medicines, vitamins, and dietary supplements.
DON'T:
• Do not give your medicine to others.
• Do not take medicine unless it was prescribed for you.
• Do not stop taking your medicine without talking to your health care provider.
• Do not break, chew, crush, dissolve, or inject your medicine. If you cannot swallow your medicine whole, talk to
your health care provider.
• Do not drink alcohol while taking this medicine.
MILD/MODERATE ORAL PAIN

General Prescription Comments
The FDA has formally requested manufacturers to limit the amount of acetaminophen in prescription combina-
tion products (eg, Vicodin, Lortab) to no more than 325 mg per dosage unit. The FDA is also requiring
manufacturers to update labeling of all prescription combination acetaminophen products to warn of the
potential risk for severe liver injury (see Oral Pain on page 1520 for more information). Most manufacturers
have already reduced acetaminophen amounts to 300 to 325 mg per tablet in combination prescription products.
Note: Numerous brand name products for infants and children that contain ibuprofen or acetaminophen have been
voluntarily recalled by manufacturers due to investigation by the FDA.
Closely monitor and reevaluate response at least every 2 weeks. If response is inadequate, reevaluate diagnosis,
medication choice, and dosage.
Note: The following sample prescriptions are for adults.
Sample Prescriptions
For additional information, see Acetaminophen on page 60, Diflunisal on page 432, Ibuprofen on page 694, Naproxen on
page 949
Rx:
Acetaminophen 325 mg tablets
Disp: To be determined by practitioner
Sig: Take 2 tablets every 4 hours
Note: Products include Tylenol and others.
32
Note: Acetaminophen can be given if patient has allergies, bleeding problems, or stomach upset secondary to aspirin or
NSAIDs.
Rx:
Ibuprofen 200 mg tablets
Sig: Take 1 to 2 tablets every 4 hours
Note: Ibuprofen is an available OTC as Advil, Motrin IB, and many store brand generic names. NSAIDs should not be
combined with aspirin. NSAIDs may increase post-treatment bleeding. Use with caution in patients receiving anti-
coagulants or antiplatelet drugs.
Rx:
Naproxen sodium 220 mg tablets
Sig: Take 1 to 2 tablets every 8 hours
Note: Naproxen sodium is an available OTC as Aleve and many store brand generic names.
Rx:
Disp: 20 tablets
Sig: Take 1 tablet every 4 to 6 hours as needed for pain
Note: Prescription strength ibuprofen is available as the brand name Motrin.
Rx:
Dolobid 500 mg tablets
Disp: 16 tablets
Sig: Take 2 tablets initially, then 1 tablet every 12 hours as needed for pain
Ingredient: Diflunisal
MODERATE/MODERATELY SEVERE ORAL PAIN

For additional information, see Acetaminophen and Codeine on page 65, Acetaminophen and Tramadol on page 70,
Hydrocodone and Acetaminophen on page 669, Hydrocodone and Ibuprofen on page 674, Ibuprofen on page 694,
Naproxen on page 949, TraMADol on page 1281
Rx:
Disp: 16 tablets
Sig: Take 1 tablet 3 times/day as needed for pain
Note: For severe pain can be given up to 4 times/day. Also available as 600 mg tablets.
Rx:
TraMADol 50 mg tablets
Disp: 36 tablets
Sig: Take 1 to 2 tablets every 4 to 6 hours as needed for pain (maximum: 400 mg/day)
Note: Also available as the brand name Ultram.
Important notification regarding TraMADol: Effective August 18, 2014, Tramadol will be classified as a Schedule IV
controlled dangerous substance (CDS) under federal regulation. If you dispense Tramadol to your patients, you are
required to report this to the Prescription Drug Monitoring Program (PDMP). If you write a prescription for Tramadol, but
do not dispense this medication, you are not required to report to the PDMP. The Division of Drug Control (DDC) has
posted the following information on its website: USDOJ/DEA, 21 CFR (Federal Register) Part 1308: Schedules of
Controlled Dangerous Substances: Placement of Tramadol Into Schedule IV (Final Rule). DEA (CFR Final Rule)
Tramadol Schedule IV Placement (Effective: 8/18/14).
Rx:
Ultracet tablets
Disp: 36 tablets
Sig: Take 2 tablets every 4 to 6 hours as needed for pain, not to exceed 8 tablets in 24 hours
Ingredients: Acetaminophen 325 mg and Tramadol 37.5 mg
33
Rx:
Vicoprofen tablets
Disp: 16 tablets
Sig: Take 1 to 2 tablets every 4 to 6 hours as needed for pain (maximum: 5 tablets/day)
Note: Restrictions: C-II; no refills
Ingredients: Hydrocodone 7.5 mg and ibuprofen 200 mg; available as generic equivalent
Rx:
Vicodin ES tablets 7.5 mg hydrocodone/300 mg acetaminophen (per tablet)
Disp: 16 tablets
Sig: Take 1 tablet every 4 to 6 hours as needed for pain (maximum: 5 tablets/day)
Ingredients: Hydrocodone bitartrate 7.5 mg and acetaminophen 300 mg; available as generic equivalent.
Rx:
Norco 10 mg
Disp: 16 tablets
Sig: Take 1 or 2 tablets every 4 hours as needed for pain; not to exceed 8 tablets in 24 hours
Ingredients: Hydrocodone 10 mg and acetaminophen 325 mg; available as generic equivalent
Rx:
Tylenol #3
Disp: 16 tablets
Sig: Take 1 tablet every 4 hours as needed for pain
Note: Restrictions: C-III; no refills
Ingredients: Codeine 30 mg and acetaminophen 300 mg; available as generic equivalent
Rx:
Naproxen 275 mg tablets
Disp: 16 tablets
Sig: Take 2 tablets initially, then one tablet 3 times/day as needed for pain
SEVERE ORAL PAIN

Liquid volumes are suggested for a typical 2-week course. Check with pharmacist for available sizes.
Cream and ointment tube sizes may vary based on availability. Refer to individual monograph or check with pharmacist for
available sizes.
For additional information, see Oxycodone and Acetaminophen on page 1019, Oxycodone and Ibuprofen
Rx:
Percocet tablets
Disp: 16 tablets
Ingredients: Oxycodone 5 mg and acetaminophen 325 mg; available as generic equivalent; triplicate prescription
required in some states
Rx:
Oxycodone and Ibuprofen tablets
Disp: 16 tablets
Ingredients: Oxycodone 5 mg and ibuprofen 400 mg; triplicate prescription required in some states
34
ANTIMICROBIAL ORAL RINSE - SAMPLE

PRESCRIPTIONS
Liquid volumes for antimicrobial rinses are suggested for a typical 1 month course. Check with pharmacist for available
sizes.
For additional information, see Chlorhexidine Gluconate (Oral) on page 296, Mouthwash (Antiseptic) on page 933.
Rx:
Chlorhexidine gluconate 0.12% oral rinse
Disp: 32 oz bottle
Sig: Rinse vigorously twice daily with 15 to 20 mL for 30 seconds and expectorate
Note: Chlorhexidine gluconate available as the following brands: Peridex Oral Rinse, PerioGard, GUM Paroex, ORO-
Clense, Perichlor; it is also available in an alcohol-free formulation in most pharmaceutical locations. Advise patient of
risk of reversible tooth staining.
Rx:
Listerine antiseptic mouthwash [OTC]
Disp: Various size bottles
Sig: Rinse vigorously twice daily with 15 to 20 mL for 30 seconds and expectorate
Note: Various formulations, such as Cool Mint, are also available in an alcohol-free formulation.
35
BACTERIAL INFECTIONS AND PERIODONTAL DISEASES - SAMPLE PRESCRIPTIONS
BACTERIAL INFECTIONS AND PERIODONTAL

DISEASES - SAMPLE PRESCRIPTIONS
For the use of all antibiotic medications, prescribers should review the guidelines related to antimicrobial stewardship
endorsed by the ADA that is cited in Bacterial Infections on page 1525. Sample prescription dosing is for adults. Closely
monitor and reevaluate response at least every 2 weeks. If response is inadequate, reevaluate diagnosis, medication
choice, and dosage.
For additional information, see Bacterial Infections on page 1525, Amoxicillin on page 116, Amoxicillin and Clavulanate on
page 121, Azithromycin (Systemic) on page 182, Cephalexin on page 286, Clindamycin (Systemic) on page 326,
Doxycycline on page 457, Erythromycin (Systemic) on page 512, LevoFLOXacin (Systemic) on page 789,
MetroNIDAZOLE (Systemic) on page 888, Minocycline on page 908, Penicillin V Potassium on page 1063
Rx:
Penicillin V potassium 500 mg
Disp: 40 tablets
Sig: Take 1 tablet 4 times/day for 7 to 10 days (consider a loading dose of 1 g for acute infection)
Rx:
Clindamycin (Systemic) 150 mg
Disp: 40 capsules
Sig: Take 1 capsule 4 times/day for 7 to 10 days
Note: Prescription usually selected for patients allergic to penicillin; may be prescribed for 3 or 4 times/day. Recommend
to be taken after food to reduce GI concerns.
Rx:
Disp: 40 capsules
Note: Prescription usually selected for patients allergic to penicillin; may be prescribed for 3 or 4 times/day. Recommend
to be taken after food to reduce GI concerns.
Rx:
Azithromycin (Systemic) 250 mg
Disp: 1 Z-Pak
Sig: 2 tablets day 1, then 1 tablet/day until gone
OTHER ANTIBIOTICS:
Rx:
Amoxicillin 250 mg
Disp: 30 capsules
Rx:
Amoxicillin 500 mg
Disp: 30 capsules or tablets
Sig: Take 1 capsule or tablet 3 times/day for 7 to 10 days
Rx:
Amoxicillin 875 mg
Disp: 20 tablets
Sig: Take 1 tablet twice daily
Rx:
Augmentin 250 mg
Disp: 30 tablets
Sig: Take 1 tablet 3 times/day for 7 to 10 days
Rx:
Augmentin 500 mg
Disp: 30 tablets
36
Rx:
Augmentin 875 mg
Disp: 20 tablets
Sig: Take 1 tablet twice daily for 7 to 10 days
Rx:
Augmentin XR 1,000 mg
Disp: 20 tablets
Sig: Take 1 tablet twice daily for 7 to 10 days; not the same as taking two 500 mg tablets
Rx:
Cephalexin 250 mg
Disp: 40 capsules
Rx:
MetroNIDAZOLE (Systemic) 500 mg
Disp: 40 tablets
Sig: Take 1 tablet 3 or 4 times/day for 7 to 10 days
Note: For acute periodontal infections or as therapy in osteonecrosis of the jaw, usually used in combination with
amoxicillin or amoxicillin plus clavulanic acid; may be prescribed for 3 or 4 times/day. When prescribed at 500 mg tid the
patient can take both medications together enhancing compliance.
Rx:
Erythromycin (Systemic) 250 mg
Disp: 40 tablets
Note: Prescription for patients allergic to penicillin, however, is seldom prescribed due to concern over general efficacy
and considerable GI effects.
Rx:
Zithromax TRI-PAK 500 mg
Disp: 1 PAK
Sig: Follow package insert directions until gone
Ingredient: Azithromycin (Systemic)
Rx:
Levaquin 500 mg
Disp: 10 tablets
Sig: Take 1 tablet/day until gone
Ingredient: LevoFLOXacin, available as 250, 500, and 750 mg tablets
Note: Not the ideal drug for general dental and/or periodontal infections; however, levofloxacin is approved for treatment
of acute bacterial rhinosinusitis.
PERIODONTAL DISEASE
Note: Sample prescriptions based on dosing suggestions from the American Academy of Periodontology
Rx:
Azithromycin (Systemic) 500 mg tablets
Disp: Dispense a dose pack
Sig: Take 1 tablet daily for 4 to 7 days as directed
Rx:
Clindamycin (Systemic) 300 mg tablets
Disp: 24 tablets
Sig: Take 1 tablet 3 times/day for 8 days
Rx:
Doxycycline or Minocycline 100 to 200 mg tablets
Disp: 21 tablets of selected dose
Sig: Take 1 tablet daily for 21 days
Rx:
Doxycycline 100 mg tablets
Disp: 42 tablets
Sig: Take 1 tablet twice daily for 21 days
Note: Prescription used for Lyme disease: Early stage (erythema migrans)
37
BACTERIAL INFECTIONS AND PERIODONTAL DISEASES - SAMPLE PRESCRIPTIONS
Rx:
MetroNIDAZOLE (Systemic) 500 mg
Disp: 24 tablets
Sig: Take 1 tablet 3 times/day for 8 days
Note: Metronidazole is often used in acute periodontal infections and in the early management of infected osteonecrosis
of the jaw in combination with amoxicillin, or amoxicillin plus clavulanic acid.
Rx:
MetroNIDAZOLE (Systemic) and Amoxicillin 250 mg or 500 mg tablets
Disp: 24 tablets of each drug
Sig: Take 1 tablet of each drug 3 times/day for 8 days
38
FUNGAL INFECTIONS - SAMPLE PRESCRIPTIONS

FUNGAL INFECTIONS REQUIRING TOPICAL THERAPY
Cream and ointment tube may vary from 5 g, 15 g, 30 g, 45 g, or 60 g sizes, based on availability. Refer to individual
monograph or check with pharmacist for available sizes.
For additional information, see Fungal Infections on page 1538, Clotrimazole (Oral) on page 351, Nystatin (Oral) on page
984, Nystatin (Topical) on page 985
Rx:
Nystatin (Oral) 100,000 units/mL oral suspension
Disp: 300 mL
Sig: Rinse with 1 teaspoon (5 mL) for 2 minutes 4 to 5 times/day and expectorate
Rx:
Nystatin (Topical) ointment
Disp: 15 g tube
Sig: Apply locally as directed with a thin coat to inner surface of denture and the affected area 4 to 5 times/day
Rx:
Mycelex 10 mg troches
Disp: 70 troches
Sig: Dissolve 1 troche in mouth 4 to 5 times/day until gone; leave any prosthesis out during treatment and soak
prosthesis in nystatin liquid suspension overnight
Ingredient: Clotrimazole (Oral)
FUNGAL INFECTIONS REQUIRING SYSTEMIC THERAPY

Note: Decision to use systemic antifungals should be based on diagnostic culture results or positive smear.
For additional information, see Fluconazole on page 592, Itraconazole on page 748, Posaconazole on page 1096,
Voriconazole on page 1351
Rx:
Diflucan 100 mg tablets
Disp: 14 tablets
Sig: Take 2 tablets on day 1, then take 1 tablet/day until gone
Note: Sometimes a shorter course is adequate. However, oral infections are more commonly difficult to eradicate and
often a 21-day course, or even a second course, may be necessary.
Ingredient: Fluconazole
Rx:
Sporanox oral solution 10 mg/mL
Disp: 300 mL
Sig: Take 200 mg (4 teaspoonfuls) once daily for 14 days
Ingredient: Itraconazole
Rx:
Noxafil oral suspension 40 mg/mL
Disp: 210 mL
Sig: Take 400 mg (2 teaspoonfuls) twice daily for 3 days, then 400 mg (2 teaspoonfuls) once daily for 14 days
Ingredient: Posaconazole
Note: For use in patients refractory to itraconazole or fluconazole
39
FUNGAL INFECTIONS - SAMPLE PRESCRIPTIONS
Rx:
Voriconazole 200 mg tablets
Disp: 28 tablets
Sig: Take 1 tablet twice daily for 14 days
ANGULAR CHEILITIS
medication choice, and dosage. Other associated etiologies for angular cheilitis must also be considered, such as loss of
vertical dimension, trauma, and vitamin deficiencies.
Cream and ointment tube may vary from 15 g, 30 g, or 45 g sizes, based on availability. Refer to individual monograph or
check with pharmacist for available sizes.
For additional information, see Iodoquinol and Hydrocortisone on page 739
Rx:
Nystatin and Triamcinolone acetonide ointment
Disp: 30 g tube
Sig: Dry affected area of angular cheilitis, apply locally as directed to affected area 4 times/day for 10 to 14 days and then
reevaluate
Rx:
Iodoquinol and Hydrocortisone cream
Disp: 45 g tube
Sig: Dry affected area of angular cheilitis, apply locally as directed 3 to 4 times/day for 10 days to 2 weeks and then
reevaluate
40
PREVENTION OF ENDOCARDITIS AND TO REDUCE THE

RISK OF LATE INFECTIONS OF JOINT PROSTHESES -
For any patients requiring preprocedural antibiotics for prevention of infective endocarditis or to reduce the risk of late
infections in joint prostheses, the dental team must be aware of significant changes in the practice guidelines endorsed by
the American Dental Association, the American Heart Association, and the American Association of Orthopedic Surgeons.
The American Association of Orthopedic Surgeons (AAOS) has developed Appropriate Use Criteria (AUC) for thirteen
selected situations encountered by orthopedists, including, "Management of patients with orthopedic implants undergoing
dental procedures". This was added as of November 2016. Please review the chapter on preprocedural antibiotics for the
complete discussion.
Regarding antibiotic selection, when after consultation preprocedural antibiotics are deemed necessary, one important
change occurred. In the latest release from the AAOS, clindamycin is no longer recommended as the suggested
alternative in patients allergic to penicillins. The AAOS now recommends, in allergic patients still able to take oral
medication, 2 g cephalexin, or 500 mg of azithromycin or clarithromycin, in that order of selection. Since this release the
ADA and the AHA have not taken any steps to alter their endocarditis recommendations. Terico AT, Gallagher JC. Beta-
lactam hypersensitivity and cross-reactivity. J Pharm Pract. 2014;27(6):530-544 is cited as the reference for consid-
erations of cross-allergenicity of cephalosporins and penicillins.
Preprocedural antibiotics are only recommended in very specific medical circumstances relative to endocarditis and they
are generally not recommended for patients with joint prostheses. The dentist is encouraged as always to record a
thorough medical history to determine risks and to consult with the appropriate physician in order to make the final
decision to prescribe antibiotic prophylaxis or not. See Antibiotic Prophylaxis on page 1502 for additional information
regarding high-risk patients and the goals of consultation.
Prescriptions dispense amounts are for three visits. These numbers can be adjusted for each patient treatment plan.
For additional information, see Amoxicillin on page 116, Azithromycin (Systemic) on page 182, Cephalexin on page 286,
Clarithromycin on page 320, Clindamycin (Systemic) on page 326
Rx:
Amoxicillin 500 mg
Disp: 12 tablets
Sig: 4 tablets (2 g) 30 to 60 minutes prior to dental visit and repeat at each appointment
Rx:
Disp: 12 capsules
Sig: 4 capsules (600 mg) 30 to 60 minutes prior to dental visit and repeat at each appointment
Rx:
Cephalexin 500 mg
Disp: 12 tablets
Sig: 4 tablets (2 g) 30 to 60 minutes prior to dental visit and repeat at each appointment
Note: Clindamycin is no longer recommended in the AAOS guidelines but is still an alternative in the AHA and ADA
guidelines.
Rx:
Disp: 3 tablets
Sig: 1 tablet 30 to 60 minutes prior to dental visit and repeat at each appointment
Rx:
Clarithromycin 500 mg
Disp: 3 tablets
Sig: 1 tablet 30 to 60 minutes prior to dental visit and repeat at each appointment
41
SINUS INFECTION TREATMENT - SAMPLE PRESCRIPTIONS
SINUS INFECTION TREATMENT - SAMPLE

PRESCRIPTIONS
Please review the guidelines related to antimicrobial stewardship endorsed by the ADA that is cited in Bacterial Infections
on page 1525. Closely monitor and reevaluate response at least every 2 weeks. If response is inadequate, reevaluate
diagnosis, medication choice, and dosage.
Sinus infections represent a common condition which may present with confounding dental complaints. Treatment is
sometimes instituted by the dentist, but due to the often chronic and recurrent nature of sinus infections, early involvement
of an otolaryngologist is advised. These infections may require antibiotics of varying spectrum, as well as requiring the
management of sinus congestion. Although amoxicillin is usually adequate, many otolaryngologists initially prescribe
Augmentin. Second generation cephalosporins, azithromycin, and clarithromycin are sometimes used depending on the
chronicity of the problem. Although not the ideal drug for general dental and/or periodontal infections, levofloxacin
(Levoquin) is approved for treatment of acute bacterial rhinosinusitis.
For additional information, see Amoxicillin on page 116, Amoxicillin and Clavulanate on page 121, Azithromycin
(Systemic) on page 182, Chlorpheniramine on page 302, LevoFLOXacin on page 789, Oxymetazoline (Nasal) on
page 1031, Pseudoephedrine on page 1135
Rx:
Afrin nasal spray [OTC]
Disp: 15 mg
Sig: Spray once in each nostril every 6 to 8 hours for no more than 3 days
Ingredient: Oxymetazoline (Nasal)
Rx:
Sudafed 60 mg tablets [OTC]
Disp: 30 tablets
Sig: Take 1 tablet every 4 to 6 hours as needed for congestion
Note: Some reports have suggested alterations in blood pressure with pseudoephedrine which can range from minor to
significant. This should be considered prior to prescribing.
Ingredient: Pseudoephedrine
Rx:
Chlor-Trimeton 4 mg [OTC]
Disp: 14 tablets
Ingredient: Chlorpheniramine
ANTIBIOTICS:
Note: Antibiotics are not always required but may be useful in acute management of infection.
Rx:
Disp: 1 Z-Pak
Sig: 2 tablets day 1, then 1 tablet/day until gone
Rx:
Amoxicillin 250 mg
Disp: 30 capsules
Rx:
Amoxicillin 500 mg
Disp: 30 capsules or tablets
Sig: Take 1 capsule or tablet 3 times/day for 7 to 10 days
Rx:
Amoxicillin 875 mg
Disp: 20 tablets
Rx:
Augmentin 250 mg
Disp: 30 tablets
42
Rx:
Augmentin 500 mg
Disp: 30 tablets
Rx:
Augmentin 875 mg
Disp: 20 tablets
Sig: Take 1 tablet twice daily for 7 to 10 days
Rx:
Augmentin XR 1,000 mg
Disp: 20 tablets
Sig: Take 2 tablets twice daily for 7 to 10 days
Rx:
LevoFLOXacin
Disp: Either five 750 mg tablets or seven or fourteen 500 mg tablets
Sig: Depending on the reference therapy you are following, select 1 tablet/day from the dosage and durations above
Note: For Acute Bacterial Rhinosinusitis, available as 500 mg or 750 mg tablets. Not generally recommended for dental or
periodontal infections.
43
VIRAL INFECTIONS - SAMPLE PRESCRIPTIONS
VIRAL INFECTIONS - SAMPLE PRESCRIPTIONS

HERPES SIMPLEX (INITIAL or PRIMARY)
Closely monitor and reevaluate response. If response is inadequate, reevaluate diagnosis, medication choice, and
dosage.
For additional information, see Acyclovir (Systemic) on page 73, Acyclovir (Topical) on page 81, Famciclovir on page
557, ValACYclovir on page 1316
Rx:
Zovirax 200 mg capsules
Disp: 35 to 60 capsules depending on regimen selected
Sig: Take 1 capsule 5 times/day or 2 capsules 3 times/day for 7 to 10 days
Ingredient: Acyclovir (Systemic)
Note: Regimens for HSV initial infections using valacyclovir or famciclovir are considered Off-Label Use (ie, not approved
by the FDA).
Rx:
Famciclovir 500 mg tablets
Disp: 14 tablets
Sig: Take 1 tablet every 12 hours for 7 days
Rx:
Valacyclovir 1 g tablet
Disp: 14 tablets
Sig: Take 1 tablet every 12 hours for 7 days
Rx:
Zovirax cream 5%
Disp: 5 g tube
Sig: Apply thin layer to lesions 5 times/day for the duration of the external lesions
Ingredient: Acyclovir (Topical)
HERPES SIMPLEX (RECURRENT)

Therapy should be initiated at the first sign of any prodrome such as tingling, burning, or itching.
available sizes.
For additional information, see Acyclovir (Topical) on page 81, Docosanol on page 443, Famciclovir on page 557,
Penciclovir on page 1060, ValACYclovir on page 1316
Rx:
Denavir topical cream 1%
Disp: 1.5 g tube
Sig: Apply locally as directed to lesion every 2 hours during waking hours (begin when prodromal symptoms first occur)
Ingredient: Penciclovir
Rx:
Famciclovir 500 mg tablets
Disp: 3 tablets
Sig: Take 3 tablets (1,500 mg) as a single dose; therapy should be initiated at the first sign of any prodrome such as
tingling, burning, or itching
Note: Dispense in multiples of 3 so that patient has drug on hand for any recurrences; available as generic equivalent
Rx:
ValACYclovir 500 mg
Disp: 8 caplets
Sig: 4 caplets twice daily for 1 day (separate doses by 12 hours); therapy should be initiated at the first sign of any
prodrome such as tingling, burning, or itching
44
Rx:
Abreva cream [OTC]
Disp: 2 g tube
Sig: Apply to lesion 5 times/day during waking hours for the duration of the external lesions (begin when prodrome/
symptoms first occur)
Ingredient: Docosanol
Rx:
Zovirax cream 5%
Disp: 2 g tube; 5 g tube
Sig: Apply 5 times/day for the duration of the external lesions
Ingredient: Acyclovir (Topical)
SHINGLES (VARICELLA-ZOSTER VIRUS)

Closely monitor and reevaluate response. If response is inadequate, reevaluate diagnosis, medication choice, and
dosage.
For additional information, see Acyclovir (Systemic) on page 73, Famciclovir on page 557, ValACYclovir on page 1316
Rx:
Zovirax 200 mg capsules
Disp: 200 capsules
Sig: Take 4 capsules 4 times/day for 5 days
Ingredient: Acyclovir (Systemic)
Rx:
ValACYclovir 500 mg
Disp: 42 caplets
Sig: Take 2 caplets 3 times/day for 7 days
Rx:
Famciclovir 500 mg
Disp: 21 tablets
Sig: 1 tablet 3 times/day for 7 days
45
SEDATION (PRIOR TO DENTAL TREATMENT) - SAMPLE PRESCRIPTIONS
SEDATION (PRIOR TO DENTAL TREATMENT) - SAMPLE

PRESCRIPTIONS
Sample prescription doses are for healthy adults. Use of these drugs and/or dosage may not be appropriate for children,
elderly, and/or debilitated patients. Dental sedation should be used cautiously in these patients. Patients receiving
sedative agents must be advised that they will need to have someone drive them to and from their appointment.
Sample Prescriptions for Adults
For additional information, see ALPRAZolam on page 100, DiazePAM on page 417, HydrOXYzine on page 689,
LORazepam on page 818, Triazolam on page 1303
Rx:
Valium 5 mg
Disp: 1 tablet
Sig: Take 1 tablet 1 hour before appointment
Note: Also available as 2 mg and 10 mg
Ingredient: DiazePAM
Rx:
Ativan 1 mg
Disp: 2 tablets
Sig: Take 2 tablets 1 hour before appointment
Note: Also available as 0.5 mg and 2 mg
Ingredient: LORazepam
Rx:
Xanax 0.5 mg
Disp: 1 tablet
Ingredient: ALPRAZolam
Rx:
Vistaril 25 mg
Disp: 2 capsules
Sig: Take 2 capsules 1 hour before appointment
Ingredient: HydrOXYzine
Rx:
Halcion 0.25 mg
Disp: 1 tablet
Ingredient: Triazolam
46
ULCERATIVE AND EROSIVE DISORDERS - SAMPLE

PRESCRIPTIONS
RECURRENT APHTHOUS STOMATITIS
Some intraoral uses are off-label. Write directions as "use locally as directed" and closely monitor and reevaluate
response at least every 2 weeks. If response is inadequate, reevaluate diagnosis, medication choice, and dosage.
Cream, gel, and ointment tube sizes may vary based on availability. Refer to individual monograph or check with
pharmacist for available sizes. Ointments, creams, and gels work well when the lesions are few in number and/or
localized to the anterior areas of the oral cavity. When the lesions are more extensive or in the posterior areas of the
mouth, steroid rinses and/or systemic steroids or other medications that suppress inflammation may be necessary.
For additional information, see Betamethasone (Topical) on page 210, Clobetasol on page 334, Dexamethasone
(Systemic) on page 406, DiphenhydrAMINE (Systemic) on page 438, Fluocinonide on page 608, Triamcinolone (Topical)
on page 1301
Palliative
Rx:
Orabase Protective Barrier [OTC]
Disp: 1 package
Sig: Apply locally as directed, every 6 hours as needed
Rx:
Benadryl liquid 12.5 mg per 5 mL (mix 50/50) with Kaopectate
Disp: 8 oz total
Sig: Rinse with 1 to 2 teaspoonfuls every 2 hours and expectorate
Note: Maalox can be used in place of Kaopectate if constipation is a problem. Benadryl is available as a generic
DiphenhydrAMINE liquid.
Rx:
Benadryl liquid 12.5 mg per 5 mL / Kaopectate / Lidocaine viscous (mix 1/3, 1/3, 1/3)
Disp: 8 oz total
Note: Maalox can be used in place of Kaopectate if constipation is a problem. Benadryl is available as a generic
DiphenhydrAMINE liquid. Lidocaine viscous is available as a prescription only. Combinations of medications like these
are often called MAGIC MOUTHWASH and are not a direct treatment for the oral ulcerations but may provide some
relief as the ulcers are present.
Rx:
Benadryl liquid 12.5 mg per 5 mL
Disp: 4 oz bottle
Note: Benadryl is available as a generic DiphenhydrAMINE liquid.
Therapy-Based (Contain Steroids)
Rx:
Oralone 0.1%
Disp: 5 g tube
Sig: Apply locally as directed to the lesion after each meal and at bedtime
Ingredient: Triamcinolone (Topical)
Rx:
Fluocinonide 0.05% gel
Disp: 45 g tube
Sig: Apply locally as directed to lesion 4 times/day
47
ULCERATIVE AND EROSIVE DISORDERS - SAMPLE PRESCRIPTIONS
Rx:
Temovate 0.05%
Disp: 45 g tube
Sig: Apply locally as directed a small quantity with a Q-tip to affected area 3 to 4 times/day
Ingredient: Clobetasol propionate
Note: Pharmacies can be asked to compound drugs with higher potency, such as clobetasol with Orabase to achieve
bioadhesive properties to help deliver the steroid effects.
Rx:
Betamethasone 0.1% ointment
Disp: 45 g tube
Sig: Apply a small quantity with a Q-tip locally as directed to affected area 3 to 4 times/day
Rx:
Decadron elixir 0.5 mg per 5 mL
Disp: 500 mL
Sig: Rinse with 1 teaspoon for 4 to 5 minutes 3 to 4 times/day and expectorate at the conclusion of each rinse
Ingredient: Dexamethasone (Systemic)
Note: Depending on severity of ulceration, instructions can be tailored to include swallowing initial doses and then
tapering to every other dose eventually over 4 to 7 days to no swallowing. See Erosive Lichen Planus, Other Biopsy-
Proven Desquamative Oral Diseases, and Major Aphthae for more examples.
MILD LICHEN PLANUS

available sizes.
For additional information, see Betamethasone (Topical) on page 210, Clobetasol on page 334, Dexamethasone
(Systemic) on page 406, Fluocinonide on page 608, Triamcinolone (Topical) on page 1301
Rx:
Oralone 0.1%
Disp: 5 g tube
Sig: Apply locally as directed by coating the lesion with a thin film after each meal and at bedtime
Ingredient: Triamcinolone (Topical) 0.1%
Rx:
Fluocinonide 0.05% gel
Disp: 45 g tube
Sig: Apply locally as directed to lesion 4 times/day
Rx:
Temovate 0.05%
Disp: 45 g tube
Ingredient: Clobetasol
Note: The pharmacist can compound potent steroids, such as clobetasol with Orabase, to enhance adherence to oral
tissues.
Rx:
Betamethasone 0.1% ointment
Disp: 45 g tube
Rx:
Decadron elixir 0.5 mg per 5 mL
Disp: 500 mL
Sig: Rinse with 1 teaspoon for 4 to 5 minutes 3 to 4 times/day and expectorate at the conclusion of each rinse
Ingredient: Dexamethasone (Systemic)
Note: Depending on severity of ulceration, instructions can be tailored to include swallowing initial doses and then
tapering to every other dose eventually over 4 to 7 days to no swallowing. See Erosive Lichen Planus, Other Biopsy-
Proven Desquamative Oral Diseases, and Major Aphthae for more examples.
48
EROSIVE LICHEN PLANUS, OTHER BIOPSY-PROVEN DESQUAMATIVE ORAL

DISEASES (ie, PEMPHIGOID, PEMPHIGUS), AND MAJOR APHTHAE
Cream, gel, and ointment formulations should only be selected if the sites of the oral lesions are localized and are
accessible for applications.
Cream, gel, and ointment tube sizes may vary based on availability. Refer to individual monograph or check with
pharmacist for available sizes.
Note: Soft, thin, vacuum-formed trays can be made (similar to bleaching trays but extending slightly onto the gingiva) to
deliver steroid ointments or creams to any gingival lesions. Also, the pharmacist can compound potent steroids, such as
clobetasol with Orabase, to enhance adherence to oral tissues. For chronically recurring lesions, prednisone can be
prescribed at 40 mg/day for week 1, 30 mg/day for week 2, continue tapering dose each week to 0. Occasionally, the
clinician needs to tailor the regimen by using alternating doses every other day, such as 20 mg day 1, 10 mg day 2, then
back to 20 mg. It is important to assess patient compliance when such a regimen is considered.
For additional information, see Clobetasol on page 334, Dexamethasone (Systemic) on page 406, MethylPREDNISolone
on page 877, PredniSONE on page 1109
If a combination topical and systemic treatment is considered and the pill form followed by a rinse regimen is not
preferred:
Rx:
Decadron 0.5 mg per 5 mL elixir
Disp: 500 mL bottle
Sig: For 3 days, rinse with 1 tablespoonful (15 mL) 4 times/day and swallow; then for 3 days, rinse with 1 teaspoonful (5
mL) 4 times/day and swallow; then for 3 days, rinse with 1 teaspoonful (5 mL) 4 times/day and swallow every other time.
Then for 3 days rinse with 1 teaspoonful (5 mL) 4 times/day and expectorate. Continue the rinse and expectorate mode
for 2 minutes but discontinue medication when mouth becomes completely comfortable.
Ingredient: Dexamethasone (Systemic); the practitioner can tailor this rinse, hold expectorate and/or swallow prescription
to the severity and lesion location for each individual patient.
Rx:
Temovate 0.05% cream
Disp: 15 g tube
Sig: Apply locally as directed 4 to 5 times/day
Ingredient: Clobetasol; high potency topical steroid
Rx:
PredniSONE 5 mg tablets
Disp: 40 tablets
Sig: Take 5 tablets in the morning for 5 days, then 5 tablets in the morning every other day until gone
Rx:
PredniSONE 10 mg tablets
Disp: 50 tablets
Sig: Take 4 tablets in the morning for 5 days, then decrease by 1 tablet on each successive series of 5 days.
Note: Longer durations of a regimen (eg, 7 to 10 days) can be tailored to the severity of the oral condition.
Rx:
Medrol Dose Pak
Disp: 1 Pack
Sig: Follow package insert directions until gone
Ingredient: MethylPREDNISolone
Rx:
Protopic ointment (available in 0.03% and 0.1% strengths)
Disp: Available in 30 g, 60 g, and 100 g tubes
Sig: Apply locally as directed 2 times/day
Ingredient: Tacrolimus (Calcineurin Inhibitor; Immunosuppressant Agent)
49
ALPHABETICAL LISTING OF DRUGS
51
ABACAVIR
interferes with HIV viral RNA-dependent DNA polymer-

Abacavir (a BAK a veer) ase resulting in inhibition of viral replication.
Related Information Half-life Elimination
HIV Infection and AIDS on page 1477 Serum:
Brand Names: US Ziagen Pediatric patients ≥3 months to ≤13 years: 1 to 1.5
Brand Names: Canada Ziagen hours (Hughes 1999; Kline 1999)
Pharmacologic Category Antiretroviral, Reverse Adults: 1.54 ± 0.63 hours
Transcriptase Inhibitor, Nucleoside (Anti-HIV) Hepatic impairment (mild): Increases half-life by 58%
Use HIV-1 infection: Treatment of HIV-1 infection in Intracellular: 12 to 26 hours
combination with other antiretroviral agents Time to Peak Pediatric patients ≥3 months to ≤13
Local Anesthetic/Vasoconstrictor Precautions years: Within 1.5 hours (Hughes 1999); Adults: 0.7
No information available to require special precautions to 1.7 hours
Effects on Dental Treatment No significant effects or Pregnancy Considerations
complications reported Abacavir has a high level of transfer across the human
Effects on Bleeding No information available to placenta.
require special precautions relative to altered hemo-
No increased risk of overall birth defects has been
stasis
observed following first trimester exposure according
Adverse Reactions Rates of adverse reactions were to data collected by the antiretroviral pregnancy registry.
defined during combination therapy with other antire- Maternal antiretroviral therapy (ART) may increase the
trovirals. risk of preterm delivery, although available information
>10%: is conflicting possibly due to variability of maternal
Central nervous system: Headache (adults: ≤13%; factors (disease severity; gestational age at initiation
infants, children, & adolescents: 1%), fatigue of therapy). An increased risk of stillbirth, low birth
(≤12%), malaise (≤12%) weight, and small for gestational age infants has been
Gastrointestinal: Nausea (7% to 19%) observed in some but not all studies. Because there is
1% to 10%: clear benefit to appropriate treatment, maternal ART
Central nervous system: Abnormal dreams (≤10%), should not be withheld due to concerns for adverse
sleep disorder (≤10%), chills (≤9%), migraine neonatal outcomes. Long-term follow-up is recom-
(≤7%), depression (6%), dizziness (6%), anxi- mended for all infants exposed to antiretroviral medi-
ety (5%) cations; children who develop significant organ system
Dermatologic: Skin rash (5% to 7%) abnormalities of unknown etiology (particularly of the
Endocrine & metabolic: Hypertriglyceridemia (grades CNS or heart) should be evaluated for potential mito-
3/4: 2% to 6%) chondrial dysfunction.
Gastrointestinal: Nausea and vomiting (9% to 10%),
diarrhea (7%), abdominal pain (≤6%), gastritis Cases of lactic acidosis and hepatic steatosis related to
(≤6%), gastrointestinal signs and symptoms (≤6%), mitochondrial toxicity have been reported with use of
increased serum amylase (grades 3/4: 2% to 4%), nucleoside reverse transcriptase inhibitors (NRTIs).
vomiting (2%) These adverse events are similar to other rare but
Hematologic & oncologic: Neutropenia (grades 3/4: life-threatening syndromes which occur during preg-
2% to 5%), thrombocytopenia (grades 3/4: 1%) nancy (eg, HELLP syndrome). In general nucleoside
Hepatic: Increased serum alanine aminotransferase reverse transcriptase inhibitors are well tolerated and
(grades 3/4: 6%), increased serum aspartate amino- the benefits of use generally outweigh potential risk.
transferase (grades 3/4: 6%)
The Health and Human Services (HHS) Perinatal HIV
Hypersensitivity: Drug-induced hypersensitivity (9%),
Guidelines consider abacavir a preferred NRTI for HIV
hypersensitivity reaction (including anaphylaxis and
infected pregnant females who are antiretroviral-naive,
multiorgan failure; 8%; excluding subjects carrying
who have had ART therapy in the past but are restart-
the HLA-B*5701 allele: 1%)
ing, who require a new ART regimen (due to poor
Neuromuscular & skeletal: Increased creatine phos-
tolerance or poor virologic response of current regi-
phokinase (grades 3/4: 7% to 8%), musculoskeletal
men), and who are not yet pregnant but are trying to
pain (5% to 6%)
conceive. In addition, females who become pregnant
Respiratory: ENT infection (5%), viral respiratory tract
while taking abacavir may continue if viral suppression
infection (5%), bronchitis (4%), pneumonia (infants,
is effective and the regimen is well tolerated. The
children, & adolescents: 4%)
pharmacokinetics of abacavir are not significantly
Miscellaneous: Fever (≤9%)
changed by pregnancy and dose adjustment is not
Frequency not defined:
needed for pregnant females.
Endocrine & metabolic: Increased gamma-glutamyl
transferase The HHS Perinatal HIV Guidelines consider abacavir in
Gastrointestinal: Pancreatitis combination with lamivudine to be a preferred NRTI
<1%, postmarketing, and/or case reports: Anemia, backbone for initial therapy in antiretroviral-naive preg-
autoimmune disease, erythema multiforme, Graves nant females (do not use in females who are positive for
disease, Guillain-Barre syndrome, hepatomegaly, the HLA-B*5701 allele). This backbone is not recom-
hyperglycemia, immune reconstitution syndrome, lac- mended with atazanavir/ritonavir or efavirenz if pretreat-
tic acidosis, leukopenia, lipotrophy, liver steatosis, ment HIV RNA is >100,000 copies/mL. In addition, the
myocardial infarction, pain, polymyositis, redistribution HHS Perinatal HIV Guidelines consider abacavir in
of body fat, renal function abnormality, Stevens-John- combination with lamivudine and dolutegravir to be a
son syndrome, toxic epidermal necrolysis preferred integrase strand transfer inhibitor (INSTI)
Mechanism of Action Nucleoside reverse transcrip- regimen for initial therapy in antiretroviral-naive preg-
tase inhibitor. Abacavir is a guanosine analogue which nant females who present after the first trimester
is phosphorylated to carbovir triphosphate which (dolutegravir combinations are not recommended in
52
ABACAVIR, DOLUTEGRAVIR, AND LAMIVUDINE
pregnant females prior to 14 weeks gestation or viral RNA-dependent DNA polymerase resulting in
females trying to conceive). inhibition of viral replication.
In general, ART is recommended for all pregnant Lamivudine is a cytosine analog. After lamivudine is
females with HIV to keep the viral load below the limit triphosphorylated, the principle mode of action is inhib-
of detection and reduce the risk of perinatal transition of HIV reverse transcription via viral DNA chain
mission. Monitoring during pregnancy is more frequent termination; inhibits RNA-dependent DNA polymerase
than in non-pregnant adults. ART should be continued activities of reverse transcriptase.
postpartum for all females living with HIV and can be Pregnancy Considerations
modified after delivery. The Health and Human Services (HHS) Perinatal HIV
Health care providers are encouraged to enroll preg- Guidelines consider abacavir in combination with lam-
nant females exposed to antiretroviral medications as ivudine to be a preferred NRTI combination for HIV-
early in pregnancy as possible in the Antiretroviral infected pregnant females who are antiretroviral-naive,
Pregnancy Registry (1-800-258-4263 or http://www.- who have had antiretroviral therapy (ART) in the past
APRegistry.com). Health care providers caring for but are restarting, who require a new ART regimen (due
HIV-infected females and their infants may contact the to poor tolerance or poor virologic response of current
National Perinatal HIV Hotline (888-448-8765) for clin- regimen), and who are not yet pregnant but are trying to
ical consultation (HHS [perinatal] 2018). conceive. In addition, females who become pregnant
while taking abacavir/lamivudine may continue if viral
suppression is effective and the regimen is well toler-
Abacavir and Lamivudine ated. Do not use in females who are positive for the
(a BAK a veer & la MI vyoo deen) HLA-B*5701 allele. This backbone is not recommended
Related Information with atazanavir/ritonavir or efavirenz if pretreatment HIV
Abacavir on page 52 RNA is >100,000 copies/mL (HHS [perinatal] 2018).
LamiVUDine on page 767 Refer to individual monographs for additional infor-
Brand Names: US Epzicom mation.
Brand Names: Canada Apo-Abacavir-Lamivudine;
Kivexa; Mylan-Abacavir/Lamivudine; Teva-Abacavir/ Abacavir, Dolutegravir, and
Lamivudine
Pharmacologic Category Antiretroviral, Reverse Lamivudine
(a BAK a veer, doe loo TEG ra vir, & la MI vyoo deen)
Transcriptase Inhibitor, Nucleoside (Anti-HIV)
Use HIV-1 infection: Treatment of HIV-1 infection in Brand Names: US Triumeq
combination with other antiretroviral agents Brand Names: Canada Triumeq
Local Anesthetic/Vasoconstrictor Precautions Pharmacologic Category Antiretroviral, Integrase
No information available to require special precautions Inhibitor (Anti-HIV); Antiretroviral, Reverse Transcrip-
Effects on Dental Treatment No significant effects or tase Inhibitor, Nucleoside (Anti-HIV)
complications reported Use
Effects on Bleeding No information available to HIV infection, treatment: Treatment of HIV-1 infection
require special precautions relative to altered hemo- in adult and pediatric patients weighing ≥40 kg.
stasis Limitations of use: Not recommended for use in patients
Adverse Reactions See individual agents as well as with known or clinically suspected integrase strand
other combination products for additional information. transfer inhibitor resistance because the dose of dolu-
Rates of adverse reactions were defined during combi- tegravir is insufficient in these subpopulations.
nation therapy with other antiretrovirals. Local Anesthetic/Vasoconstrictor Precautions
1% to 10%: No information available to require special precautions
Central nervous system: Abnormal dreams, anxiety, Effects on Dental Treatment No significant effects or
depression, dizziness, fatigue, headache, insomnia, complications reported
malaise, migraine, vertigo Effects on Bleeding No information available to
Dermatologic: Skin rash require special precautions
Gastrointestinal: Abdominal pain, diarrhea, gastritis
Adverse Reactions See individual agents as well as
Hypersensitivity: Hypersensitivity (including multior-
other combination products for additional information.
gan failure and anaphylaxis; ≤9%; higher incidence
>10%:
in subjects carrying the HLA-B*5701 allele)
Endocrine & metabolic: Hyperglycemia (≥126 mg/dL)
Miscellaneous: Fever
Gastrointestinal: Increased serum lipase (>1.5 x ULN)
<1%, postmarketing, and/or case reports: Abnormal
breath sounds, alopecia, anemia (including pure red
phokinase (≥6.0 x ULN)
cell aplasia and severe anemias progressing on ther-
1% to 10%:
apy), aplastic anemia, erythema multiforme, exacer-
Central nervous system: Drowsiness (<2%), lethargy
bation of hepatitis B, hepatitis, hyperglycemia,
(<2%), nightmares (<2%), sleep disorder (<2%),
immune reconstitution syndrome, increased creatine
suicidal ideation (<2%), depression, fatigue, head-
phosphokinase, lactic acidosis, liver steatosis, lym-
ache, insomnia
phadenopathy, myasthenia, paresthesia, peripheral
Dermatologic: Pruritus (<2%)
neuropathy, redistribution of body fat, rhabdomyolysis,
Endocrine & metabolic: Hypertriglyceridemia (<2%)
seizure, splenomegaly, Stevens-Johnson syndrome,
Gastrointestinal: Abdominal distention (<2%), abdomi-
stomatitis, weakness, wheezing
nal distress (<2%), abdominal pain (<2%), anorexia
Mechanism of Action Nucleoside reverse transcrip-
(<2%), dyspepsia (<2%), flatulence (<2%), gastro-
tase inhibitor combination.
esophageal reflux disease (<2%), upper abdominal
Abacavir is a guanosine analogue which is phosphory- pain (<2%), vomiting (<2%)
lated to carbovir triphosphate which interferes with HIV Hematologic & oncologic: Decreased neutrophils
53
ABACAVIR, DOLUTEGRAVIR, AND LAMIVUDINE
Hepatic: Hepatitis (<2%), increased serum ALT (>2.5 x

ULN), increased serum AST (>2.5 x ULN) Abacavir, Lamivudine, and Zidovudine
(a BAK a veer, la MI vyoo deen, & zye DOE vyoo deen)
Neuromuscular & skeletal: Arthralgia (<2%), myosi-
tis (<2%) Related Information
Renal: Renal insufficiency (<2%) Abacavir on page 52
Miscellaneous: Fever (<2%) HIV Infection and AIDS on page 1477
<1%, postmarketing, and/or case reports: Abnormal LamiVUDine on page 767
dreams, diarrhea, dizziness, hypersensitivity reaction, Zidovudine on page 1361
immune reconstitution syndrome, nausea, skin rash Brand Names: US Trizivir
Mechanism of Action Dolutegravir inhibits HIV inte- Brand Names: Canada Trizivir
grase by binding to the integrase active site and block- Pharmacologic Category Antiretroviral, Reverse
ing the strand transfer step of retroviral DNA integration. Transcriptase Inhibitor, Nucleoside (Anti-HIV)
Abacavir is converted by cellular enzymes to the active Use
HIV infection: Treatment of HIV-1 infection in combi-
metabolite, carbovir triphosphate (CBV-TP), an ana-
nation with other antiretroviral agents.
logue of deoxyguanosine-5′-triphosphate (dGTP).
Local Anesthetic/Vasoconstrictor Precautions
CBV-TP inhibits the activity of HIV-1 reverse transcrip- No information available to require special precautions
tase (RT) both by competing with the natural substrate Effects on Dental Treatment No significant effects or
dGTP and by its incorporation into viral DNA. Intra- complications reported
cellularly, lamivudine is phosphorylated to its active 5′- Effects on Bleeding No information available to
triphosphate metabolite, lamivudine triphosphate (3TC- require special precautions relative to altered hemo-
TP). The principal mode of action of 3TC-TP is inhibition stasis
of reverse transcriptase via DNA chain termination after Adverse Reactions See individual agents as well as
incorporation of the nucleotide analogue. other combination products for additional information.
Pregnancy Considerations Frequency not always defined.
Central nervous system: Headache (13%), fatigue
Use of dolutegravir during the first trimester is not
(12%), malaise (12%), depression (6%), anxiety (5%)
recommended. Dermatologic: Skin rash (5%)
Based on available data, the Health and Human Serv- Endocrine & metabolic: Increased amylase (2%),
ices (HHS) Perinatal HIV Guidelines consider this fixed- increased serum triglycerides (grade 3-4: 2%),
increased gamma-glutamyl transferase, redistribution
dose combination a preferred regimen after the first
of body fat
trimester for HIV-infected pregnant females who are Gastrointestinal: Nausea (19%), nausea and vomiting
antiretroviral-naive. Due to the potential risk of neural (10%), diarrhea (7%), pancreatitis
tube defects, dolutegravir should not be initiated dur- Hematologic & oncologic: Neutropenia (5%)
ing the first trimester (<14 weeks [up to 13 6/7 weeks]; Hepatic: Increased serum ALT (6%)
gestational age by last menstrual period). Based on Hypersensitivity: Hypersensitivity (1% to 9%; based on
available data, the HHS Perinatal HIV Guidelines also abacavir component; higher risk in carriers of the HLA-
consider this fixed-dose combination a preferred regi- B*5701 allele)
men after the first trimester for HIV-infected pregnant Immunologic: Immune reconstitution syndrome
Infection: Viral infection (5%)
females who have had antiretroviral therapy (ART) in
Miscellaneous: Fever and chills (6%)
the past but are restarting, or who require a new ART Neuromuscular & skeletal: Increased creatine phospho-
regimen (due to poor tolerance or poor virologic kinase (7%)
response of current regimen). When pregnancy is diag- Respiratory: ENT infection (5%)
nosed during therapy with this combination, treatment <1%, postmarketing, and/or case reports: Abdominal
may be continued if the patient is in the second or third pain, abnormal breath sounds, allergic sensitization
trimester if viral suppression is effective and the regi- (including anaphylaxis), alopecia, anemia, anorexia,
men is well tolerated. When pregnancy is diagnosed aplastic anemia, arthralgia, cardiomyopathy,
during the first trimester, the risks and benefits of decreased appetite, dizziness, dyspepsia, erythema
multiforme, exacerbation of hepatitis B (posttreat-
continuing this regimen or changing ART should be
ment), gynecomastia, increased serum bilirubin,
discussed. increased serum transaminases, insomnia, lactic
The HHS Perinatal HIV Guidelines do not recommend acidosis, liver steatosis, lymphadenopathy, myalgia,
use of this combination in females who are not yet myasthenia, oral mucosa hyperpigmentation, pares-
thesia, peripheral neuropathy, rhabdomyolysis, seiz-
pregnant but are trying to conceive. Evaluate preg-
ure, sleep disorder, splenomegaly, Stevens-Johnson
nancy status in females of reproductive potential; a syndrome, stomatitis, thrombocytopenia, urticaria,
pregnancy test should be completed prior to therapy vasculitis, weakness, wheezing
with dolutegravir. Patients who wish to become preg- Mechanism of Action The combination of abacavir,
nant or who cannot use effective contraception during lamivudine, and zidovudine is believed to act synergisti-
therapy should not be prescribed dolutegravir-based cally to inhibit reverse transcriptase via DNA chain
regimens. Options for postpartum contraception should termination after incorporation of the nucleoside ana-
be evaluated when dolutegravir is continued following logue as well as to delay the emergence of mutations
delivery (HHS [perinatal] 2018). conferring resistance.
Pregnancy Considerations
Refer to individual monographs for additional infor- The Health and Human Services (HHS) Perinatal HIV
mation. Guidelines do not recommend use of this fixed-dose
54
ABATACEPT
combination regimen in pregnancy (HHS [perinatal] Use

2018). Juvenile idiopathic arthritis: Treatment of moderately
to severely active polyarticular juvenile idiopathic
Refer to individual monographs for additional infor-
arthritis (JIA); may be used as monotherapy or in
mation. combination with methotrexate
Psoriatic arthritis: Treatment of active psoriatic arthri-
Abaloparatide (a bal oh PAR a tide) tis (PsA) in adults
Rheumatoid arthritis: Treatment of moderately to
Brand Names: US Tymlos severely active adult rheumatoid arthritis (RA); may
Pharmacologic Category Parathyroid Hormone Ana- be used as monotherapy or in combination with other
log DMARDs
Use Osteoporosis in postmenopausal females: Note: Abatacept should not be used in combination
Treatment of postmenopausal females with osteoporo- with anakinra or TNF-blocking agents
sis at high risk for fracture defined as a history of Local Anesthetic/Vasoconstrictor Precautions
osteoporotic fracture, multiple risk factors for fracture, No information available to require special precautions
or patients who have failed or are intolerant to other Effects on Dental Treatment No significant effects or
available osteoporosis therapy. complications reported
Limitations of use: Use of abaloparatide and any other Effects on Bleeding No information available to
parathyroid hormone analogs (eg, teriparatide) for >2 require special precautions
years is not recommended. Adverse Reactions Frequency not always defined;
Local Anesthetic/Vasoconstrictor Precautions COPD patients experienced a higher frequency of
No information available to require special precautions COPD-related adverse reactions (COPD exacerbation,
cough, dyspnea, pneumonia, rhonchi)
Effects on Dental Treatment No significant effects or
>10%:
complications reported
Central nervous system: Headache (≤18%)
Effects on Bleeding No information available to Gastrointestinal: Nausea
require special precautions Immunologic: Antibody development (2% to 41%)
Adverse Reactions Infection: Infection (adults 54%; children 36%)
>10%: Respiratory: Nasopharyngitis (12%), upper respiratory
Endocrine & metabolic: Increased uric acid (25%) tract infection
Genitourinary: Hypercalciuria (11% to 20%) 1% to 10%:
Immunologic: Antibody development (49%; neutraliz- Cardiovascular: Hypertension (7%)
ing antibodies: 68%; antibody formation was not Central nervous system: Dizziness (9%)
found to have any clinical significance) Dermatologic: Skin rash (4%)
Local: Erythema at injection site (58%) Gastrointestinal: Dyspepsia (6%), abdominal pain,
1% to 10%: diarrhea
Cardiovascular: Palpitations (5%), orthostatic hypo- Genitourinary: Urinary tract infection (6%)
tension (1% to 4%), sinus tachycardia (≤2%), tachy- Immunologic: Immunogenicity (1% to 2%)
cardia (≤2%) Infection: Herpes simplex infection, influenza
Central nervous system: Dizziness (10%), headache Local: Injection site reaction (3% to 4%)
(8%), fatigue (3%) Neuromuscular & skeletal: Back pain (7%), limb
Endocrine & metabolic: Hypercalcemia (3%) pain (3%)
Gastrointestinal: Nausea (8%), upper abdominal Respiratory: Cough (8%), bronchitis, pneumonia, rhi-
nitis, sinusitis
pain (3%)
Miscellaneous: Infusion-related reaction (≤9%), fever
Local: Swelling at injection site (10%), pain at injection
<1%, postmarketing, and/or case reports: Acute lym-
site (9%)
phocytic leukemia, anaphylactoid reaction, anaphy-
Mechanism of Action Abaloparatide is an analog of laxis, cellulitis, diverticulitis, dyspnea, exacerbation of
human parathyroid hormone related peptide (PTHrP arthritis, exacerbation of chronic obstructive pulmo-
[1-34]), which acts as an agonist at the PTH1 receptor nary disease, flushing, hypersensitivity reaction, hypo-
(PTH1R). This results in stimulation of osteoblast func- tension, joint wear, malignant lymphoma, malignant
tion and increased bone mass (Harslof 2016; Leder melanoma, malignant neoplasm of bile duct, malig-
2017). nant neoplasm of bladder, malignant neoplasm of
Pharmacodynamics/Kinetics breast, malignant neoplasm of cervix, malignant neo-
Half-life Elimination 1.7 hours plasm of kidney, malignant neoplasm of lung, malig-
Time to Peak 0.51 hours (range: 0.25 to 0.52 hours) nant neoplasm of prostate, malignant neoplasm of
Pregnancy Considerations Abaloparatide is not indi- skin, malignant neoplasm of thyroid, malignant neo-
cated for use in women of reproductive potential. Ani- plasm of uterus, myelodysplastic syndrome, ovarian
mal reproduction studies have not been conducted. cyst, pruritus, pyelonephritis, rhonchi, urticaria, vari-
cella, vasculitis (including cutaneous vasculitis and
leukocytoclastic vasculitis), wheezing
Abatacept (ab a TA sept) Mechanism of Action Selective costimulation modu-
lator; inhibits T-cell (T-lymphocyte) activation by binding
Related Information
to CD80 and CD86 on antigen presenting cells (APC),
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis thus blocking the required CD28 interaction between
on page 1484 APCs and T cells. Activated T lymphocytes are found in
Brand Names: US Orencia; Orencia ClickJect the synovium of rheumatoid arthritis patients.
Brand Names: Canada Orencia Pharmacodynamics/Kinetics
Pharmacologic Category Antirheumatic, Disease Half-life Elimination
Modifying; Selective T-Cell Costimulation Blocker RA: 13.1 days (range: 8 to 25 days)
55
ABATACEPT
Clearance: 0.22 to 0.23 mL/hour/kg; Children 6 to 17 <1%, postmarketing, and/or case reports: Acute hepatic
years: JIA: 0.4 mL/hour/kg (increases with baseline failure, adrenocortical insufficiency, fulminant hepati-
body weight) tis, myopathy, pneumonitis, rhabdomyolysis
Pregnancy Considerations Information related to the Mechanism of Action Abiraterone selectively and
use of abatacept in pregnancy is limited (Kumar 2015). irreversibly inhibits CYP17 (17 alpha-hydroxylase/
Until additional data are available, it is recommended to C17,20-lyase), an enzyme required for androgen bio-
discontinue use and switch to a safer medication prior synthesis which is expressed in testicular, adrenal, and
to conception unless no other pregnancy compatible prostatic tumor tissues. Inhibits the formation of the
medication is able to control maternal disease (Götes- testosterone precursors dehydroepiandrosterone
tam Skorpen 2016). (DHEA) and androstenedione.
A pregnancy registry has been established to monitor
Half-life Elimination 14.4 to 16.5 hours (Acharya
outcomes of women exposed to abatacept during preg-
2012)
nancy (1-877-311-8972).
Time to Peak 2 hours (Acharya 2012)
Abiraterone Acetate (a bir A ter one AS e tate) Based on the mechanism of action and adverse effects
observed in animal reproduction studies, abiraterone
Brand Names: US Yonsa; Zytiga may cause fetal harm or fetal loss if administered during
Brand Names: Canada Zytiga pregnancy. Abiraterone is not indicated for use in
Pharmacologic Category Antiandrogen; Antineoplas- females and is specifically contraindicated in females
tic Agent, Antiandrogen who are or may become pregnant. Abiraterone is avail-
Use able in uncoated and film-coated tablets and in micron-
Prostate cancer, metastatic: ized tablets; the manufacturer recommends females
Treatment of metastatic, castration-resistant prostate who are or may become pregnant wear gloves if han-
cancer (in combination with prednisone [Zytiga] or dling uncoated tablets, micronized tablets, or tablets
methylprednisolone [Yonsa]) that are broken, crushed, or damaged. NIOSH recom-
Treatment of metastatic, high-risk castration-sensitive mends single gloving for administration of hazardous
prostate cancer (in combination with prednisone intact oral tablets (NIOSH 2016).
[Zytiga])
Local Anesthetic/Vasoconstrictor Precautions Male patients with female partners of reproductive
No information available to require special precautions potential should use effective contraception during
Effects on Dental Treatment No significant effects or treatment and for 3 weeks after the last abiraterone
complications reported dose. Abiraterone may impair reproductive function and
Effects on Bleeding No information available to fertility in males of reproductive potential.
require special precautions
Adverse Reactions Adverse reactions reported for AbobotulinumtoxinA
use in combination with a corticosteroid. (aye bo BOT yoo lin num TOKS in aye)
>10%:
Brand Names: US Dysport
Cardiovascular: Hypertension (9% to 37%), edema
(25% to 27%) Brand Names: Canada Dysport Aesthetic; Dysport
Central nervous system: Fatigue (39%), insom- Therapeutic
nia (14%) Pharmacologic Category Neuromuscular Blocker
Endocrine & metabolic: Hypertriglyceridemia (63%), Agent, Toxin
hyperglycemia (57%), hypernatremia (33%), hypo- Use
kalemia (17% to 30%), hypophosphatemia (24%), Cervical dystonia: Treatment of adults with cervical
hot flash (15% to 22%) dystonia.
Gastrointestinal: Constipation (23%), diarrhea (18% to Glabellar lines: Temporary improvement in the appear-
22%), dyspepsia (6% to 11%) ance of moderate to severe glabellar lines associated
Genitourinary: Urinary tract infection (7% to 12%) with corrugator and procerus muscle activity in adults
Hematologic & oncologic: Lymphocytopenia (20% to <65 years.
38%; grades 3/4: 4% to 9%), bruise (13%) Lower limb spasticity: Treatment of lower limb spas-
Hepatic: Increased serum alanine aminotransferase ticity in pediatric patients ≥2 years.
(11% to 46%), increased serum aspartate amino- Spasticity: Treatment of spasticity in adults.
transferase (15% to 37%), increased serum bilirubin Local Anesthetic/Vasoconstrictor Precautions
(7% to 16%) No information available to require special precautions
Neuromuscular & skeletal: Arthralgia (≤30%), joint Effects on Dental Treatment Key adverse event(s)
swelling (≤30%), myalgia (26%) related to dental treatment: Xerostomia (normal salivary
Respiratory: Cough (7% to 17%), upper respiratory flow resumes upon discontinuation) and facial paresis.
infection (5% to 13%), dyspnea (12%), nasopharyng- Effects on Bleeding No information available to
itis (11%) require special precautions
1% to 10%: Adverse Reactions
Cardiovascular: Cardiac arrhythmia (7%), chest dis- Cervical dystonia: Frequency not always defined.
comfort (≤4%), chest pain (≤4%), cardiac failure (2%) Cardiovascular: Decreased heart rate
Central nervous system: Headache (8%), falling (6%) Central nervous system: Voice disorder (6% to 28%),
Dermatologic: Skin rash (8%) fatigue (12%), headache (11%), facial paresis (5% to
Genitourinary: Hematuria (10%), groin pain (7%), uri- 11%), dizziness (4%)
nary frequency (7%), nocturia (6%) Endocrine & metabolic: Increased serum glucose
Neuromuscular & skeletal: Bone fracture (6%) Gastrointestinal: Dysphagia (15% to 39%), xerostomia
Miscellaneous: Fever (9%) (13% to 39%)
56
ACALABRUTINIB
Immunologic: Antibody development (binding or neu- to 5%), viral gastroenteritis (children & adolescents:
tralizing; 3%) 2% to 4%), constipation (adults: 2%), dysphagia
Infection: Infection (13%) (adults: 2%)
Local: Discomfort at injection site (13% to 22%), pain Hematologic & oncologic: Bruise (adults: 2%)
at injection site (5%) Hepatic: Increased serum alanine aminotransferase
Neuromuscular & skeletal: Myasthenia (11% to 56%), (adults: 2%)
musculoskeletal pain (7%), amyotrophy (1%) Immunologic: Antibody development (4%; neutraliz-
Ophthalmic: Eye disease (6% to 17%) ing: ≤2%)
Respiratory: Dyspnea (3%; onset: ~1 week; duration: Infection: Varicella (children & adolescents: 5%)
~3 weeks) Neuromuscular & skeletal: Limb pain (6% to 7%),
Glabellar lines: arthralgia (adults: 2% to 4%), back pain (adults:
Central nervous system: Headache (9%) 3%), bone fracture (adults: 2%, wrist), asthenia
Dermatologic: Contact dermatitis (2% to 3%) (adults: 2%)
Gastrointestinal: Nausea (2%) Otic: Otic infection (children & adolescents: 4%)
Genitourinary: Hematuria (2%) Respiratory: Bronchitis (children & adolescents: 7%
Immunologic: Antibody development (<1%) to 8%), rhinitis (children & adolescents: 5%), viral
Infection: Influenza (2% to 3%) respiratory tract infection (children & adolescents:
Local: Pain at injection site (3%), discomfort at injec- 2% to 5%), oropharyngeal pain (children & adoles-
tion site (2% to 3%), injection site reaction (2% to cents: 2% to 4%), flu-like symptoms (adults: 2%)
3%), swelling at injection site (2% to 3%)
Ophthalmic: Blepharoptosis (2%), eyelid edema (2%) Any indication: <1%, postmarketing and/or case
Respiratory: Nasopharyngitis (10%), upper respiratory reports: Anaphylaxis, blurred vision, burning sensa-
tract infection (3%), bronchitis (2% to 3%), cough tion, connective tissue disease (excessive granulation
(2% to 3%), pharyngolaryngeal pain (2% to 3%), tissue), corneal disease, decreased lacrimation, dip-
sinusitis (2%) lopia, disturbance in attention, dysarthria, dyspnea,
edema (soft tissue), erythema, feeling abnormal,
Upper limb spasticity: Frequency not always defined. hypersensitivity reaction, photophobia, reduced blink-
Cardiovascular: Hypertension (1% to 2%), syncope ing, respiratory failure, serum sickness, urinary incon-
(1% to 2%)
tinence, urticaria, xerophthalmia, vertigo
Central nervous system: Epilepsy (≤4%), seizure
(≤4%), status epilepticus (≤4%), myasthenia (2% to Mechanism of Action AbobotulinumtoxinA (previously
4%), dizziness (3%), falling (3%), depression (2% to known as botulinum toxin type A) is a neurotoxin
3%), fatigue (2%), headache (2%), hypoesthesia produced by Clostridium botulinum, spore-forming
(2%), abnormal gait (<1%), feeling of heaviness anaerobic bacillus, which appears to affect only the
(<1%), hypertonia (<1%) presynaptic membrane of the neuromuscular junction
Endocrine & metabolic: Increased serum triglycerides in humans, where it prevents calcium-dependent
(1% to 2%) release of acetylcholine and produces a state of dener-
Gastrointestinal: Constipation (2%), nausea (2%), vation. Muscle inactivation persists until new fibrils grow
diarrhea (1% to 2%), dysphagia (<1%) from the nerve and form junction plates on new areas of
Genitourinary: Urinary tract infection (3%) the muscle-cell walls.
Hematologic & oncologic: Bruise (1% to 2%) Pharmacodynamics/Kinetics
Immunologic Antibody development (7%; neutraliz- Onset of Action Peak effect: Cervical dystonia: 2 to 4
ing: ≤4%) weeks; Upper limb spasticity: 1 week
Infection: Infection (2%), influenza (2%) Duration of Action Cervical dystonia, glabellar lines:
Local: Injection site reaction ≥4 months; Lower limb spasticity: ≥5 ½ months; Upper
Neuromuscular & skeletal: Musculoskeletal pain (3%), limb spasticity: ≥5 months
back pain (2%), limb pain (2%), asthenia (1% to 2%) Pregnancy Considerations Adverse events have
Respiratory: Nasopharyngitis (4%), cough (2%) been observed in animal reproduction studies.
Miscellaneous: Accidental injury (2%)
Lower limb spasticity: Acalabrutinib (a KAL a broo ti nib)
>10%:
Infection: Influenza (children & adolescents: 10% Brand Names: US Calquence
to 14%) Pharmacologic Category Antineoplastic Agent; Anti-
Respiratory: Upper respiratory tract infection (chil- neoplastic Agent, Bruton Tyrosine Kinase Inhibitor;
dren & adolescents: 20%; adults: 2%), nasophar- Antineoplastic Agent, Tyrosine Kinase Inhibitor
yngitis (children & adolescents: 9% to 16%), cough Use Mantle cell lymphoma (previously treated):
(children & adolescents: 7% to 14%), pharyngitis Treatment of mantle cell lymphoma (MCL) in patients
(children & adolescents: 11%) who have received at least 1 prior therapy.
Miscellaneous: Fever (children & adolescents: 7%
to 12%)
No information available to require special precautions
1% to 10%:
Cardiovascular: Hypertension (adults: 2%), periph- Effects on Dental Treatment No significant effects or
eral edema (adults: 2%) complications reported
Central nervous system: Falling (adults: 6% to 9%), Effects on Bleeding Chemotherapy may result in
epilepsy (≤7%), seizure (≤7%), myasthenia (5% to significant myelosuppression, potentially including sig-
7%), fatigue (adults: 1% to 4%), headache (adults: nificant reduction in platelet counts (thrombocytopenia
3%), depression (adults: 2% to 3%), insomnia grades 3 or 4: 8%), neutropenia (grade 3 or 4: 23%) and
(adults: 2%) altered hemostasis. Hematoma ~8% and hemorrhage
Gastrointestinal: Vomiting (children & adolescents: ~8% of patients. In patients who are under active treat-
6% to 8%), nausea (children & adolescents: 2% ment with these agents, medical consult is suggested.
57
ACALABRUTINIB
Adverse Reactions salivation (normal salivary flow resumes upon discon-

>10%: tinuation) and taste perversion.
Central nervous system: Headache (39%), Effects on Bleeding No information available to
fatigue (28%) require special precautions
Dermatologic: Skin rash (18%) Adverse Reactions Many adverse effects associated
Gastrointestinal: Diarrhea (31%), nausea (19%), with treatment may be related to alcohol abstinence;
abdominal pain (15%), constipation (15%), vomit- reported frequency range may overlap with placebo.
ing (13%)
Hematologic & oncologic: Neutropenia (grade 3 or 4: >10%: Gastrointestinal: Diarrhea (10% to 17%)
23%), bruise (21%; grade 1: 19%), anemia (grade 3 1% to 10%:
or 4: 11%), malignant neoplasm (11%) Cardiovascular: Chest pain, hypertension, palpita-
Neuromuscular & skeletal: Myalgia (21%) tions, peripheral edema, syncope, vasodilatation
1% to 10%: Central nervous system: Insomnia (6% to 9%), anxiety
Cardiovascular: Atrial fibrillation (≤3%), atrial flut- (5% to 8%), depression (4% to 8%), dizziness (3% to
ter (≤3%) 4%), pain (2% to 4%), paresthesia (2% to 3%),
Hematologic & oncologic: Thrombocytopenia (grade 3 abnormality in thinking, amnesia, attempted suicide,
or 4: 8%), hematoma (≤8%; grade ≥3: ≤1%), hemor- chills, drowsiness, headache
rhage (≤8%; grade ≥3: ≤1%), skin carcinoma (7%) Dermatologic: Pruritus (3% to 4%), diaphoresis (2% to
Renal: Increased serum creatinine (grade 2: 5%) 3%), skin rash
Respiratory: Epistaxis (6%) Endocrine & metabolic: Decreased libido, weight gain
Frequency not defined: Gastrointestinal: Anorexia (2% to 5%), nausea (3% to
Central nervous system: Progressive multifocal leu- 4%), flatulence (1% to 4%), xerostomia (1% to 3%),
koencephalopathy abdominal pain, constipation, dysgeusia, dyspepsia,
Infection: Opportunistic infection, reactivation of HBV, increased appetite, vomiting
serious infection Genitourinary: Impotence
Respiratory: Pneumonia Infection: Infection
Mechanism of Action Acalabrutinib is a selective and Neuromuscular & skeletal: Weakness (5% to 7%),
irreversible second-generation Bruton’s tyrosine kinase arthralgia, back pain, myalgia, tremor
(BTK) inhibitor (Byrd 2016). Acalabrutinib and the active Ophthalmic: Visual disturbance
metabolite (ACP-5862) form a bond (covalent) with a Respiratory: Bronchitis, dyspnea, flu-like symptoms,
cysteine residue in the active BTK site to inhibit BTK increased cough, pharyngitis, rhinitis
enzyme activity. BTK is an integral component of the B- <1%, postmarketing, and/or case reports: Abnormal
cell receptor (BCR) and cytokine receptor pathways. hepatic function tests, agitation, alopecia, anemia,
BTK signals activation of the pathways necessary for B- angina pectoris, asthma, brain disease, colitis, con-
cell proliferation, trafficking, chemotaxis and adhesion. fusion, deafness, diabetes mellitus, duodenal ulcer,
BTK inhibition results in decreased malignant B-cell eosinophilia, epistaxis, exfoliative dermatitis, fever,
proliferation and survival. gastrointestinal hemorrhage, gout, hallucination, hem-
Pharmacodynamics/Kinetics orrhage, hepatic cirrhosis, hepatitis, hostility, hyper-
Half-life Elimination Acalabrutinib: 0.9 hours (range: bilirubinemia, hyperesthesia, hyperglycemia,
0.6 to 2.8 hours); ACP-5862 (active metabolite): 6.9 hypersensitivity reaction, hyperuricemia, hyponatre-
hours mia, hypotension, hypothyroidism, increased serum
Time to Peak 0.75 hours creatinine, increased serum transaminases, leukope-
Pregnancy Considerations Adverse events were nia, lymphadenopathy, lymphocytosis, myocardial
observed in some animal reproduction studies. infarction, nephrolithiasis, neuralgia, ophthalmic
Prescribing and Access Restrictions inflammation, orthostatic hypotension, pancreatitis,
Available through specialty pharmacy distributors. Infor- pneumonia, psychoneurosis, psychosis, pulmonary
mation regarding distribution is available from the man- embolism, rectal hemorrhage, renal failure, seizure,
ufacturer at www.calquence.com. skin photosensitivity, suicidal ideation, tachycardia,
thrombocytopenia, urticaria, withdrawal syndrome
Acamprosate (a kam PROE sate)
Mechanism of Action Mechanism not fully defined.
Structurally similar to gamma-amino butyric acid
Brand Names: Canada Campral® (GABA), acamprosate appears to increase the activity
Pharmacologic Category GABA Agonist/Glutamate of the GABA-ergic system, and decreases activity of
Antagonist glutamate within the CNS, including a decrease in
Use activity at N-methyl D-aspartate (NMDA) receptors;
Alcohol use disorder: Maintenance of abstinence may also affect CNS calcium channels. Restores bal-
from alcohol in patients with alcohol use disorder ance to GABA and glutamate activities which appear to
who are abstinent at treatment initiation, as part of a be disrupted in alcohol use disorder. During therapeutic
comprehensive management program use, reduces alcohol intake, but does not cause a
Limitations of use: Efficacy has not been demonstrated disulfiram-like reaction following alcohol ingestion.
in subjects who have not undergone detoxification and Insignificant CNS activity, outside its effect on alcohol
not achieved alcohol abstinence prior to beginning use disorder, was observed including no anxiolytic,
treatment. Efficacy in promoting abstinence from alco- anticonvulsant, or antidepressant activity.
hol in polysubstance abusers has not been adequately Pharmacodynamics/Kinetics
assessed. Half-life Elimination 20 to 33 hours
Local Anesthetic/Vasoconstrictor Precautions Time to Peak Plasma: 3 to 8 hours
No information available to require special precautions Pregnancy Risk Factor C
Effects on Dental Treatment Key adverse event(s) Pregnancy Considerations Adverse events were
related to dental treatment: Xerostomia and changes in observed in animal reproduction studies.
58
ACEBUTOLOL
Pharmacological agents should not be used for the

treatment of alcohol use disorder in pregnant women Acebutolol (a se BYOO toe lole)
unless needed for the treatment of acute alcohol with-
drawal or a coexisting disorder; agents other than Related Information
acamprosate are recommended for acute alcohol with- Cardiovascular Diseases on page 1442
drawal (APA [Reus 2018]). Brand Names: US Sectral [DSC]
Brand Names: Canada Rhotral; Sectral
Pharmacologic Category Antiarrhythmic Agent,
Acarbose (AY car bose) Class II; Antihypertensive; Beta-Blocker With Intrinsic
Sympathomimetic Activity
Related Information
Use
Endocrine Disorders and Pregnancy on page 1471
Hypertension: Management of hypertension. Note:
Brand Names: US Precose Beta-blockers are not recommended as first-line ther-
Brand Names: Canada Glucobay apy (ACC/AHA [Whelton 2017]).
Pharmacologic Category Antidiabetic Agent, Alpha- Ventricular premature beats: Management of ventric-
Glucosidase Inhibitor ular premature beats
Use Local Anesthetic/Vasoconstrictor Precautions
Diabetes mellitus, type 2: Adjunct to diet and exercise No information available to require special precautions.
to improve glycemic control in adults with type 2 Local anesthetic with vasoconstrictor can be safely
diabetes mellitus (noninsulin dependent, NIDDM) used in patients medicated with acebutolol.
Guideline recommendations: Alpha-glucosidase inhib- Effects on Dental Treatment Acebutolol is a cardio-
itors (eg, acarbose) are generally not used in patients selective beta-blocker. Local anesthetic with vasocon-
with type 2 diabetes, but may be tried in specific strictor can be safely used in patients medicated with
situations ADA 2017a. acebutolol. Nonselective beta-blockers (ie, propranolol,
Local Anesthetic/Vasoconstrictor Precautions nadolol) enhance the pressor response to epinephrine,
No information available to require special precautions or levonordefrin resulting in hypertension and bradycar-
Effects on Dental Treatment No significant effects or dia; this has not been reported for acebutolol. Many
complications reported nonsteroidal anti-inflammatory drugs, such as ibuprofen
Effects on Bleeding No information available to and indomethacin, can reduce the hypotensive effect of
require special precautions beta-blockers after 3 or more weeks of therapy with the
NSAID. Short-term NSAID use (ie, 3 days) requires no
Adverse Reactions
special precautions in patients taking beta-blockers.
>10%: Gastrointestinal: Frequency and intensity of flat-
Effects on Bleeding No information available to
ulence (74%) tend to abate with time; diarrhea (31%)
and abdominal pain (19%) tend to return to pretreat-
Adverse Reactions
ment levels over time
>10%: Central nervous system: Fatigue (11%)
1% to 10%: Hepatic: Increased serum transami-
1% to 10%:
nases (≤4%)
Cardiovascular: Chest pain (2%), edema (2%), brady-
<1%, postmarketing, and/or case reports: Edema, cardia (≤2%), cardiac failure (≤2%), hypoten-
erythema, hepatic injury, hepatitis, intestinal obstruc- sion (≤2%)
tion, jaundice, pneumatosis cystoides intestinalis, skin Central nervous system: Dizziness (6%), headache
rash, thrombocytopenia, urticaria (6%), insomnia (3%), abnormal dreams (2%),
Mechanism of Action Competitive inhibitor of pancre- depression (2%), anxiety (≤2%), hyperesthesia
atic α-amylase and intestinal brush border α-glucosi- (≤2%), hypoesthesia (≤2%)
dases, resulting in delayed hydrolysis of ingested Dermatologic: Skin rash (2%), pruritus (≤2%)
complex carbohydrates and disaccharides and absorp- Gastrointestinal: Constipation (4%), diarrhea (4%),
tion of glucose; dose-dependent reduction in postpran- dyspepsia (4%), nausea (4%), flatulence (3%),
dial serum insulin and glucose peaks; inhibits the abdominal pain (≤2%), vomiting (≤2%)
metabolism of sucrose to glucose and fructose Genitourinary: Urinary frequency (3%), dysuria (≤2%),
Pharmacodynamics/Kinetics impotence (≤2%), nocturia (≤2%)
Half-life Elimination ~2 hours Hepatic: Hepatic abnormality (≤2%)
Time to Peak Active drug: ~1 hour Neuromuscular & skeletal: Myalgia (2%), arthralgia
Pregnancy Risk Factor B (≤2%), back pain (≤2%)
Pregnancy Considerations Ophthalmic: Visual disturbance (2%), conjunctivitis
Adverse events have not been observed in animal (≤2%), dry eye syndrome (≤2%), eye pain (≤2%)
reproduction studies. Less than 2% of an oral dose of Respiratory: Dyspnea (4%), rhinitis (2%), cough (1%),
acarbose is absorbed systemically, which should limit pharyngitis (≤2%), wheezing (≤2%)
<1%, postmarketing, and/or case reports: Increased
fetal exposure.
ANA titer, systemic lupus erythematosus
In women with diabetes, maternal hyperglycemia can Mechanism of Action Competitively blocks beta1-
be associated with congenital malformations as well as adrenergic receptors with little or no effect on beta2-
adverse effects in the fetus, neonate, and the mother receptors except at high doses; exhibits membrane
(ACOG 2005; ADA 2018c; Metzger 2007). To prevent stabilizing and intrinsic sympathomimetic activity
adverse outcomes, prior to conception and throughout Pharmacodynamics/Kinetics
pregnancy, maternal blood glucose and HbA1c should Onset of Action 1 to 2 hours
be kept as close to target goals as possible but without Duration of Action 12 to 24 hours
causing significant hypoglycemia (ADA 2018c; Blumer Half-life Elimination Parent drug: 3 to 4 hours;
2013). Agents other than acarbose are currently rec- Metabolite: 8 to 13 hours
ommended to treat diabetes in pregnant women (ADA Time to Peak 2 to 4 hours
2018c). Pregnancy Risk Factor B
59
ACEBUTOLOL
Pregnancy Considerations Effects on Bleeding As a single agent, acetamino-

Adverse effects were observed in some animal repro- phen does not appear to affect bleeding or platelet
duction studies. Acebutolol and diacetolol (active aggregation. Acetaminophen may prolong the INR
metabolite) cross the placenta. Decreases in birth and increase bleeding in patients taking warfarin (Cou-
weight, blood pressure, and heart rate have been madin). For patients taking warfarin, single acetamino-
observed in neonates following maternal use of acebu- phen doses or acetaminophen therapy of short duration
tolol during pregnancy. Hypoglycemia has also been should be safe, but if large (>1.3 g/day) doses are
found following in utero exposure to beta-blockers as administered for longer than 10 to 14 days, then the
a class. The half-life of acebutolol is 6 to 14 hours in the INR should be monitored (see Dental Health Professio-
newborn. The half-life of diacetolol is 24 to 30 hours for nal Considerations).
the first 24 hours of life, then 12 to 16 hours. Adequate Adverse Reactions
facilities for monitoring infants at birth should be avail- Oral, Rectal: Frequency not defined:
able. The plasma elimination half-life of acebutolol is Dermatologic: Skin rash
longer in pregnant women at term (Bianchetti 1981a; Endocrine & metabolic: Decreased serum bicarbon-
Boutroy 1982). ate, decreased serum calcium, decreased serum
Untreated chronic maternal hypertension and pree- sodium, hyperchloremia, hyperuricemia, increased
clampsia are also associated with adverse events in serum glucose
the fetus, infant, and mother (ACOG 2015; Magee Genitourinary: Nephrotoxicity (with chronic overdose)
2014). When treatment of hypertension in pregnancy Hematologic & oncologic: Anemia, leukopenia, neu-
is indicated, beta-blockers may be used. Specific rec- tropenia, pancytopenia
ommendations vary by guideline. Although other agents Hepatic: Increased serum alkaline phosphatase,
are preferred (ACOG 2013), use of acebutolol may be increased serum bilirubin
considered (Magee 2014). Hypersensitivity: Hypersensitivity reaction (rare)
Renal: Hyperammonemia, renal disease (analgesic)
IV:
Acetaminophen (a seet a MIN oh fen)
>10%: Gastrointestinal: Nausea (adults: 34%; neo-
Related Information nates, infants, children, and adolescents: ≥5%), vom-
Oral Pain on page 1520 iting (adults: 15%; neonates, infants, children, and
Related Sample Prescriptions adolescents: ≥5%)
Oral Pain - Sample Prescriptions on page 32 1% to 10%:
Brand Names: US Acephen [OTC]; Aspirin Free Ana- Cardiovascular: Hypertension (≥1%), hypotension
cin Extra Strength [OTC]; Cetafen Extra [OTC]; Cetafen (≥1%), peripheral edema (adults: ≥1%), tachycardia
[OTC]; FeverAll Adult [OTC]; FeverAll Children's [OTC]; Central nervous system: Headache (adults: 10%;
FeverAll Infants' [OTC]; FeverAll Junior Strength [OTC]; neonates, infants, children, and adolescents:
Little Fevers [OTC]; Mapap Arthritis Pain [OTC]; Mapap ≥1%), insomnia (adults: 7%), agitation (neonates,
Children's [OTC]; Mapap Extra Strength [OTC]; Mapap infants, children, and adolescents: ≥1%), anxiety
[OTC]; Midol Long Lasting Relief [OTC]; Non-Aspirin (adults: ≥1%), fatigue (adults: ≥1%), trismus
Pain Reliever [OTC]; Nortemp Children's [OTC]; Ofir- (adults: ≥1%)
mev; Pain & Fever Children's [OTC]; Pain Eze [OTC]; Dermatologic: Pruritus (neonates, infants, children,
Pain Relief Extra Strength [OTC]; Pharbetol Extra and adolescents: ≥5%), skin rash
Strength [OTC]; Pharbetol [OTC]; Q-Pap Children's Endocrine & metabolic: Hypoalbuminemia (neo-
[OTC] [DSC]; Q-Pap Extra Strength [OTC] [DSC]; Q- nates, infants, children, and adolescents: ≥1%),
Pap Infants' [OTC] [DSC]; Q-Pap [OTC] [DSC]; Silapap hypokalemia (≥1%), hypomagnesemia (neonates,
Children's [OTC]; Silapap Infants' [OTC] [DSC]; Tria- infants, children, and adolescents: ≥1%), hypo-
minic Children's Fever Reducer Pain Reliever [OTC]; phosphatemia (neonates, infants, children, and
Tylenol 8 HR Arthritis Pain [OTC]; Tylenol 8 HR [OTC] adolescents: ≥1%), hypervolemia
[DSC]; Tylenol Children's [OTC]; Tylenol Extra Strength Gastrointestinal: Constipation (neonates, infants,
[OTC]; Tylenol Infants' [OTC]; Tylenol [OTC]; Valorin children, and adolescents: ≥5%), diarrhea (neo-
Extra [OTC]; Valorin [OTC] nates, infants, children, and adolescents: ≥1%),
Brand Names: Canada Abenol; Apo-Acetaminophen; abdominal pain
Atasol; Novo-Gesic; Pediatrix; Tempra; Tylenol Genitourinary: Oliguria (neonates, infants, children,
Generic Availability (US) Yes: Excludes extended and adolescents: ≥1%)
release products; injectable formulation Hematologic & oncologic: Anemia (≥1%)
Pharmacologic Category Analgesic, Nonopioid Hepatic: Increased serum transaminases
Dental Use Treatment of postoperative pain Local: Pain at injection site (≥1%)
Use Neuromuscular & skeletal: Limb pain, muscle
Pain: spasm (≥1%)
Injection: Management of mild to moderate pain in Ophthalmic: Periorbital edema
patients ≥2 years of age; management of moderate Respiratory: Abnormal breath sounds (adults: ≥1%),
to severe pain when combined with opioid analgesia atelectasis (neonates, infants, children, and adoles-
in patients ≥2 years cents: ≥1%), dyspnea (adults: ≥1%), hypoxia, pleu-
Oral, Rectal: Temporary relief of minor aches, pains, ral effusion (neonates, infants, children, and
and headache adolescents: ≥1%), pulmonary edema (neonates,
Fever: Temporary reduction of fever infants, children, and adolescents: ≥1%), stridor
Local Anesthetic/Vasoconstrictor Precautions (adults: ≥1%), wheezing (adults: ≥1%)
No information available to require special precautions Miscellaneous: Fever (neonates, infants, children,
Effects on Dental Treatment No significant effects or and adolescents: ≥1%)
complications reported (see Dental Health Professional All formulations: <1%, postmarketing, and/or case
Considerations) reports: Anaphylaxis, hypersensitivity reaction
60
ACETAMINOPHEN
Dental Usual Dosage Postoperative pain: Oral, rectal: IV:

Children <12 years: 10 to 15 mg/kg/dose every 4 to 6 CrCl >30 mL/minute: There are no dosage adjust-
hours as needed; do not exceed 5 doses (2.6 g) in 24 ments provided in the manufacturer's labeling.
hours CrCl ≤30 mL/minute: There are no dosage adjust-
Adults: 325 to 650 mg every 4 to 6 hours or 1000 mg 3 ments provided in the manufacturer's labeling. Use
to 4 times/day; do not exceed 4 g/day with caution; consider decreasing daily dose and
Dosing extending dosing interval.
Adult Note: In 2011, McNeil Consumer Healthcare Hepatic Impairment: Adult
reduced the maximum doses and increased the dos- Oral: Use with extreme caution. Although limited data
ing interval on the labeling of some of their acetami- exist, low-dose (≤2 to 3 g/day) therapy is usually well
nophen OTC products used in older pediatric patients tolerated in hepatic disease/cirrhosis; however, fac-
(usually children ≥12 years and adolescents) and tors such as alcohol use, nutritional status, and renal
adults in an attempt to protect consumers from inad- function must also be taken into consideration (Bosil-
vertent overdoses. For example, the maximum daily kovska 2012; Chandok 2010; Dwyer 2014; Hayward
dose of Tylenol Extra Strength and Tylenol Regular 2015, Imani 2014). In patients with hepatic impair-
Strength was decreased and the dosing interval for ment/cirrhosis and active alcohol use, most experts
Tylenol Extra Strength was increased. Health care recommend avoiding use as much as possible, and if
professionals may still prescribe or recommend the used, limiting therapy to short-term use only at doses
4 g daily maximum to patients (but are advised to use ≤2 g/day (Bosilkovska 2012; Chandok 2010).
their own discretion and clinical judgment) (McNeil IV:
Consumer Healthcare, 2014). Mild to moderate impairment: There are no dosage
adjustments provided in the manufacturer's label-
Pain or fever: ing. Use with caution; a reduced total daily dosage
Oral: Note: OTC dosing recommendations may vary may be warranted.
by product and/or manufacturer. When calculating Severe impairment: Use is contraindicated.
the maximum daily dose, consider all sources of Pediatric Note: In 2011, McNeil Consumer Healthcare
acetaminophen (prescription and OTC) and all reduced the maximum daily doses and increased the
routes of administration. Do not exceed the max- dosing interval on the labeling of some of their acet-
imum recommended daily dose. No dose adjustment aminophen OTC products used in older pediatric
required when converting between different acetami- patients (usually children ≥12 years and adolescents)
nophen formulations. and adults in an attempt to protect consumers from
Immediate-release: inadvertent overdoses. For example, the maximum
Regular strength: 650 mg every 4 to 6 hours; daily dose of Extra Strength Tylenol OTC and Regular
maximum daily dose: 3250 mg daily unless S t r e n g t h Ty l e n o l O T C w e r e d e c r e a s e d t o
directed by health care provider; under health 3,000 mg/day and 3,250 mg/day respectively, and
care provider supervision, daily doses ≤4 g may the dosing interval for Extra Strength Tylenol OTC
be used was increased. Health care professionals may still
Extra strength: 1000 mg every 6 hours; maximum prescribe or recommend the 4 g adult daily maximum
daily dose: 3000 mg daily unless directed by a to patients ≥12 years of age (but are advised to use
health care provider; under health care provider their own discretion and clinical judgment) (McNeil
supervision, daily doses ≤4 g may be used Consumer Healthcare 2014).
Extended-release: 1300 mg every 8 hours; maxi- Note: Oral liquids are available in multiple concen-
mum daily dose: 3900 mg daily trations (eg, 160 mg/5 mL, 500 mg/5 mL and
Rectal: 650 mg every 4 to 6 hours; maximum daily 500 mg/15 mL); precautions should be taken to
dose: 3900 mg daily verify and avoid confusion between the different
IV: concentrations; dose should be clearly presented
<50 kg: 12.5 mg/kg every 4 hours or 15 mg/kg every as "mg"
6 hours; maximum single dose: 15 mg/kg/dose Pain (mild to moderate) or fever: Note: Limit
acetaminophen dose from all sources (prescription
(≤750 mg/dose); maximum daily dose: 75 mg/kg/
and OTC); maximum daily dose of acetaminophen
day (≤3.75 g/day)
should be limited to ≤75 mg/kg/day in ≤5 divided
≥50 kg: 650 mg every 4 hours or 1,000 mg every 6
doses and not to exceed 4,000 mg/day for most
hours; maximum single dose: 1,000 mg/dose; max-
products although some formulations suggest lower
imum daily dose: 4 g/day
maximum daily dosing (see dosing information for
Geriatric Pain (acute) or fever: Oral, IV: Refer to further detail):
adult dosing. Oral: Note: With OTC use, should not exceed
Persistent pain (off-label): Adults ≥75 years: Oral: recommended treatment duration unless directed
Initial: 325 to 500 mg every 4 hours or 500 to by health care provider; for fever: 3 days (all
1,000 mg every 6 hours ages); pain (excluding sore throat): Children ≥12
Maximum: ≤4,000 mg/day. In older adults with hep- years and Adolescents: 10 days, children: 5 days,
atic impairment or history of alcohol abuse being or infants: 3 days; sore throat in children: 2 days
treated for persistent pain, do not exceed a max- Weight-directed dosing: Infants, Children, and
imum of 2,000 to 3,000 mg/day (AGS 2009) Adolescents: 10 to 15 mg/kg/dose every 4 to 6
Renal Impairment: Adult hours as needed (American Pain Society 2008;
Oral (Aronoff 2007): Kliegman 2011; Sullivan 2011); do not exceed 5
GFR ≥50 mL/minute: No dosage adjustment nec- doses in 24 hours; maximum daily dose:
essary. 75 mg/kg/day not to exceed 4,000 mg/day
GFR 10 to 50 mL/minute: Administer every 6 hours. Fixed dosing:
GFR <10 mL/minute: Administer every 8 hours. Oral suspension, chewable tablets: Infants and
CRRT: Administer every 6 hours. Children <12 years: Consult specific product
61
ACETAMINOPHEN
formulations for appropriate age groups. See 20 mg/kg/dose every 4 to 6 hours as needed;
table; use of weight to select dose is preferred; do not exceed 5 doses in 24 hours (Kliegman
if weight is not available, then use age; doses 2011; Vernon 1979); maximum daily dose:
may be repeated every 4 hours; maximum: 5 75 mg/kg/day
doses/day Fixed dosing:
Infants 6 to 11 months: 80 mg every 6 hours;
Acetaminophen Dosing (Oral) maximum daily dose: 320 mg/day
Weight (preferred)A Dosage
Infants and Children 12 to 36 months: 80 mg
Age every 4 to 6 hours; maximum daily dose:
kg lbs (mg)
400 mg/day
2.7 to 5.3 6 to 11 0 to 3 mo 40
Children >3 to 6 years: 120 mg every 4 to 6
5.4 to 8.1 12 to 17 4 to 11 mo 80
hours; maximum daily dose: 600 mg/day
8.2 to 10.8 18 to 23 1 to 2 y 120 Children >6 up to 12 years: 325 mg every 4 to 6
10.9 to 24 to 35 2 to 3 y 160 hours; maximum daily dose: 1,625 mg/day
16.3
Children ≥12 years and Adolescents: 650 mg
16.4 to every 4 to 6 hours; maximum daily dose:
21.7 36 to 47 4 to 5 y 240
3,900 mg/day
21.8 to
48 to 59 6 to 8 y 320 Pain; peri-/postoperative management; adjunct
27.2
27.3 to to opioid therapy:
60 to 71 9 to 10 y 400 IV:
32.6
32.7 to Infants and Children <2 years: Limited data avail-
72 to 95 11 y 480
43.2 able: 7.5 to 15 mg/kg/dose every 6 hours; max-
A
Manufacturer’s recommendations are based on weight imum daily dose: 60 mg/kg/day (Wilson-
in pounds (OTC labeling); weight in kg listed here is Smith, 2009)
derived from pounds and rounded; kg weight listed also is
adjusted to allow for continuous weight ranges in kg. OTC Children ≥2 years and Adolescents:
labeling instructs consumer to consult with physician for <50 kg: 15 mg/kg/dose every 6 hours or
dosing instructions in infants and children under 2 years
of age. 12.5 mg/kg/dose every 4 hours; maximum sin-
Immediate release solid dosage formulations: gle dose: 15 mg/kg up to 750 mg; maximum
Note: Actual OTC dosing recommendations daily dose: 75 mg/kg/day not to exceed
may vary by product and/or manufacturer: 3,750 mg/day
Children 6 to 11 years: 325 mg every 4 to 6 ≥50 kg: 1,000 mg every 6 hours or 650 mg every
hours; maximum daily dose: 1,625 mg/day; 4 hours; maximum single dose: 1,000 mg;
Note: Do not use more than 5 days unless maximum daily dose: 4,000 mg/day
directed by a physician Rectal: Limited data available: Children and Ado-
Children ≥12 years and Adolescents: lescents:
Regular strength: 650 mg every 4 to 6 hours; Loading dose: 40 mg/kg for 1 dose, in most trials,
maximum daily dose: 3,250 mg/day unless the dose was administered postoperatively (Bir-
directed by a physician; under physician mingham 2001; Capici 2008; Hahn 2000; Mir-
supervision daily doses ≤4,000 mg may
eskandari 2011; Prins 2008; Riad 2007; Viitanen
be used
2003); a maximum dose of 1,000 mg was most
Extra strength: 1,000 mg every 6 hours; max-
frequently reported. However, in one trial evalu-
imum daily dose: 3,000 mg/day unless
directed by a physician; under physician ating 24 older pediatric patients (all patients ≥25
supervision daily doses ≤4,000 mg may kg; mean age: ~13 years), the data suggested
be used that a dose of 1,000 mg does not produce ther-
Extended release: Children ≥12 years and Ado- apeutic serum concentrations (target for study:
lescents: 1,300 mg every 8 hours; maximum >10 mcg/mL) compared to a 40 mg/kg dose (up
daily dose: 3,900 mg/day to ~2,000 mg); the resultant C max was: 7.8
IV: mcg/mL (1,000 mg dose group) vs 15.9 mcg/mL
Infants and Children <2 years: (40 mg/kg dose group). Note: Therapeutic
Manufacturer’s labeling: Fever: 15 mg/kg/dose serum concentrations for analgesia have not
every 6 hours; maximum daily dose: been well-established (Howell 2003).
60 mg/kg/day Maintenance dose: 20 to 25 mg/kg/dose every 6
Alternate dosing: Limited data available: Pain hours as needed for 2 to 3 days has been
and fever: 7.5 to 15 mg/kg/dose every 6 hours; suggested if further pain control is needed post-
maximum daily dose: 60 mg/kg/day (Wilson- operatively; maximum daily dose: 100 mg/kg/
Smith 2009) day; therapy longer than 5 days has not been
Children ≥2 years and Adolescents: evaluated (Birmingham 2001; Hahn 2000;
<50 kg: 15 mg/kg/dose every 6 hours or
Prins 2008).
12.5 mg/kg/dose every 4 hours; maximum sin-
Note: In the majority of trials, suppositories were
gle dose: 15 mg/kg up to 750 mg; maximum
not divided due to unequal distribution of drug
daily dose: 75 mg/kg/day not to exceed
3,750 mg/day within suppository; doses were rounded to the
≥50 kg: 1,000 mg every 6 hours or 650 mg nearest mg amount using 1 or 2 suppositories of
every 4 hours; maximum single dose: available product strengths.
1,000 mg; maximum daily dose: 4,000 mg/day Renal Impairment: Pediatric
Rectal: IV: Children ≥2 years and Adolescents: CrCl ≤30 mL/
Weight-directed dosing: Limited data available: minute: Use with caution; consider decreasing daily
I nf a n ts a nd C h il d r en < 1 2 y e a r s : 1 0 to dose and extending dosing interval
62
ACETAMINOPHEN
Oral (Aronoff 2007): benzyl alcohol; large amounts of benzyl alcohol

Infants, Children, and Adolescents: (≥99 mg/kg/day) have been associated with a poten-
GFR ≥10 mL/minute/1.73 m2 : No adjustment tially fatal toxicity ("gasping syndrome") in neonates; the
required "gasping syndrome" consists of metabolic acidosis,
GFR <10 mL/minute/1.73 m2: Administer every 8 respiratory distress, gasping respirations, CNS dysfunc-
hours tion (including convulsions, intracranial hemorrhage),
Intermittent hemodialysis or peritoneal dialysis: hypotension and cardiovascular collapse (AAP ["Inac-
Administer every 8 hours tive" 1997]; CDC, 1982); some data suggests that
CRRT: No adjustments necessary benzoate displaces bilirubin from protein binding sites
Hepatic Impairment: Pediatric Use with caution. (Ahlfors, 2001); avoid or use dosage forms containing
Limited, low-dose therapy is usually well-tolerated in benzyl alcohol and/or benzyl alcohol derivative with
hepatic disease/cirrhosis; however, cases of hepato- caution in neonates. See manufacturer’s labeling.
toxicity at daily acetaminophen dosages Polysorbate 80: Some dosage forms may contain poly-
<4,000 mg/day have been reported. Avoid chronic sorbate 80 (also known as Tweens). Hypersensitivity
use in hepatic impairment. reactions, usually a delayed reaction, have been
Mechanism of Action Although not fully elucidated, reported following exposure to pharmaceutical products
the analgesic effects are believed to be due to activa- containing polysorbate 80 in certain individuals (Isaks-
tion of descending serotonergic inhibitory pathways in son, 2002; Lucente 2000; Shelley, 1995). Thrombocy-
the CNS. Interactions with other nociceptive systems topenia, ascites, pulmonary deterioration, and renal and
may be involved as well (Smith 2009). Antipyresis is hepatic failure have been reported in premature neo-
produced from inhibition of the hypothalamic heat-reg- nates after receiving parenteral products containing
ulating center. polysorbate 80 (Alade, 1986; CDC, 1984). See manu-
Contraindications facturer’s labeling. Some products may contain aspar-
Injection: Hypersensitivity to acetaminophen or any tame which is metabolized to phenylalanine and must
component of the formulation; severe hepatic impair- be avoided (or used with caution) in patients with
ment or severe active liver disease phenylketonuria.
OTC labeling: When used for self-medication, do not
use with other drug products containing acetamino- Propylene glycol: Some dosage forms may contain
phen or if allergic to acetaminophen or any of the propylene glycol; large amounts are potentially toxic
inactive ingredients and have been associated hyperosmolality, lactic acido-
Warnings/Precautions [Injection: US Boxed Warn- sis, seizures, and respiratory depression; use caution
ing]: Acetaminophen has been associated with (AAP ["Inactive" 1997]; Zar, 2007).
acute liver failure, at times resulting in liver trans- When used for self-medication (OTC), patients should
plant and death. Hepatotoxicity is usually associ- be instructed to contact healthcare provider if symp-
ated with excessive acetaminophen intake and toms get worse or new symptoms appear, redness or
often involves more than one product that contains swelling is present in the painful area, fever lasts >3
acetaminophen. Do not exceed the maximum recom- days (all ages), or pain (excluding sore throat) lasts
mended daily dose (>4 g daily in adults). In addition, longer than: Adults: 10 days, Children and Adolescents:
chronic daily dosing may also result in liver damage in 5 days, Infants: 3 days. When treating children with sore
some patients. Limit acetaminophen dose from all throat, if sore throat is severe, persists for >2 days, or is
sources (prescription, OTC, combination products) followed by fever, rash, headache, nausea, or vomiting,
and all routes of administration (IV, oral, rectal) to consult health care provider immediately.
≤4 g/day (adults). Use with caution in patients with
alcoholic liver disease; consuming ≥3 alcoholic drinks/ Use with caution in patients with chronic malnutrition or
day may increase the risk of liver damage. Use caution severe renal impairment; use intravenous formulation
in patients with hepatic impairment or active liver dis- with caution in patients with severe hypovolemia. Use
ease; use of IV formulation is contraindicated in patients with caution in patients with known G6PD deficiency.
with severe hepatic impairment or severe active liver Warnings: Additional Pediatric Considerations
disease. Prophylactic use of acetaminophen to reduce fever
and discomfort associated vaccination is not recom-
[Injection: US Boxed Warning]: Take care to avoid mended by the Advisory Committee on Immunization
dosing errors with acetaminophen injection, which Practices (ACIP). Additionally, the ACIP does not rec-
could result in accidental overdose and death; ommend prophylactic acetaminophen to reduce risk of
ensure that the dose in mg is not confused with febrile seizure in infants and children with or without a
mL, dosing in patients <50 kg is based on body history of febrile seizures. Antipyretics have not been
weight, infusion pumps are properly programmed, shown to prevent febrile seizures (NCIRD/ACIP 2011).
and total daily dose of acetaminophen from all One study reported that routine prophylactic adminis-
sources does not exceed the maximum daily limits. tration of acetaminophen to prevent fever prior to vac-
Hypersensitivity and anaphylactic reactions have been cination decreased the immune response of some
reported including life-threatening anaphylaxis; discon- vaccines; in the trial evaluating 459 infants (including
tinue immediately if symptoms occur. Serious and 226 who received acetaminophen), antibody geometric
mean concentrations (GMCs) for targeted vaccine
potentially fatal skin reactions, including acute general-
immune response markers were lower in significantly
ized exanthematous pustulosis (AGEP), Stevens-John-
more infants in the acetaminophen group compared
son syndrome (SJS), and toxic epidermal necrolysis
with control. Before the booster dose, children who
(TEN), have occurred rarely with acetaminophen use.
received prophylactic acetaminophen had lower anti-
Discontinue therapy at the first appearance of skin rash.
body GMCs for all vaccine serotypes than children in
Benzyl alcohol and derivatives: Some dosage forms the control group; this effect persisted after boosting
may contain benzyl alcohol and/or sodium benzoate/ even in the absence of additional acetaminophen
benzoic acid; benzoic acid (benzoate) is a metabolite of doses. The clinical significance of this reduction in
63
ACETAMINOPHEN
immune response has not been established (Prymula noted in case reports following maternal use during
2009). Antipyretics may be used to treat fever or dis- the third trimester (Suhag 2008; Wood 2005). The use
comfort following vaccination (NCIRD/ACIP 2011). of acetaminophen in normal doses during pregnancy is
not associated with an increased risk of miscarriage or
Some dosage forms may contain propylene glycol; in
still birth; however, an increase in fetal death or sponta-
neonates large amounts of propylene glycol delivered
neous abortion may be seen following maternal over-
orally, intravenously (eg, >3,000 mg/day), or topically
dose if treatment is delayed (Li 2003; Rebordosa 2009;
have been associated with potentially fatal toxicities
Riggs 1989). Frequent maternal use of acetaminophen
which can include metabolic acidosis, seizures, renal
during pregnancy may be associated with wheezing
failure, and CNS depression; toxicities have also been
and asthma in early childhood (Perzanowki 2010).
reported in children and adults including hyperosmolal-
ity, lactic acidosis, seizures and respiratory depression; Breastfeeding Considerations Acetaminophen is
use caution (AAP, 1997; Shehab, 2009). excreted in breast milk (Notarianni 1987).
Drug Interactions The relative infant dose (RID) of acetaminophen is
Metabolism/Transport Effects Substrate of 3.98% when calculated using the highest breast milk
CYP1A2 (minor), CYP2A6 (minor), CYP2C9 (minor), concentration located and compared to an infant ther-
CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); apeutic dose of 60 mg/kg/day. In general, breastfeeding
Note: Assignment of Major/Minor substrate status is considered acceptable when the RID is <10%; when
based on clinically relevant drug interaction potential an RID is >25% breastfeeding should generally be
Avoid Concomitant Use There are no known inter- avoided (Anderson 2016; Ito 2000). Using the highest
actions where it is recommended to avoid concomitant milk concentration (15.9 mcg/mL), the estimated daily
use. infant dose via breast milk is 2.385 mg/kg/day. This milk
Increased Effect/Toxicity concentration was obtained following a single maternal
Acetaminophen may increase the levels/effects of: dose of oral acetaminophen 1,000 mg (Hurden 1980).
Busulfan; Dasatinib; Imatinib; Local Anesthetics;
Mipomersen; Phenylephrine (Systemic); Prilocaine; Following a single oral maternal dose of acetaminophen
Sodium Nitrite; SORAfenib; Vitamin K Antagonists 650 mg, the half-life of acetaminophen is 1.35 to 3.5
hours in breast milk (Berlin 1980). Acetaminophen can
The levels/effects of Acetaminophen may be be detected in the urine of nursing infants (Notarianni
increased by: Alcohol (Ethyl); Dapsone (Topical); 1987). Except for a single case report of a rash (Math-
Dasatinib; Flucloxacillin; Isoniazid; MetyraPONE; eson 1985), adverse reactions have generally not been
Nitric Oxide; Probenecid; SORAfenib observed in nursing infants (Ito 1993).
Decreased Effect
Acetaminophen may decrease the levels/effects of: Current guidelines note that nonopioid analgesics are
LamoTRIgine preferred for the treatment of pain in breastfeeding
women and acetaminophen is one of the preferred
The levels/effects of Acetaminophen may be nonopioid agents (Montgomery 2012; Sachs 2013).
decreased by: Barbiturates; CarBAMazepine; Fosphe- Acetaminophen is considered compatible with breast-
nytoin-Phenytoin feeding when used in usual recommended doses
Food Interactions Rate of absorption may be (WHO 2002).
decreased when given with food. Management: Admin- Dosage Forms: US
ister without regard to food. Caplet, oral: 500 mg
Dietary Considerations Some products may contain Cetafen Extra [OTC]: 500 mg
phenylalanine and/or sodium. Mapap Extra Strength [OTC]: 500 mg
Pharmacodynamics/Kinetics Pain Eze [OTC]: 650 mg
Onset of Action Tylenol [OTC]: 325 mg
Oral: <1 hour Tylenol Extra Strength [OTC]: 500 mg
IV: Analgesia: 5 to 10 minutes; Antipyretic: Within 30 Caplet, extended release, oral:
minutes Mapap Arthritis Pain [OTC]: 650 mg
Peak effect: IV: Analgesic: 1 hour Midol Long Lasting Relief [OTC]: 650 mg
Duration of Action Tylenol 8 HR Arthritis Pain [OTC]: 650 mg
IV, Oral: Analgesia: 4 to 6 hours Capsule, oral:
IV: Antipyretic: ≥6 hours Mapap Extra Strength [OTC]: 500 mg
Half-life Elimination Prolonged following toxic doses Tylenol [OTC]: 325 mg
Neonates: 7 hours (range: 4 to 10 hours) Tylenol Extra Strength [OTC]: 500 mg
Infants: ~4 hours (range: 1 to 7 hours) Injection, solution [preservative free]:
Children: 3 hours (range: 2 to 5 hours) Ofirmev: 10 mg/mL (100 mL)
Adolescents: ~3 hours (range: 2 to 4 hours) Liquid, oral: 160 mg/5 mL (120 mL, 473 mL)
Adults: ~2 hours (range: 2 to 3 hours); may be slightly Silapap Children's [OTC]: 160 mg/5 mL (118 mL, 237
prolonged in severe renal insufficiency (CrCl <30 mL/ mL, 473 mL)
minute): 2 to 5.3 hours Solution, oral: 160 mg/5 mL (5 mL, 10 mL, 20 mL, 118
Time to Peak Serum: Oral: Immediate release: 10 to mL, 473 mL); 325 mg/10.15 mL (10.15 mL); 650 mg/
60 minutes (may be delayed in acute overdoses); IV: 20.3 mL (20.3 mL)
15 minutes Pain & Fever Children's [OTC]: 160 mg/5 mL (118 mL,
Pregnancy Considerations Acetaminophen crosses 473 mL)
the placenta and can be detected in cord blood, new- Suppository, rectal: 120 mg (12s, 50s, 100s); 325 mg
born serum, and urine immediately after delivery (Levy (12s); 650 mg (12s, 50s, 100s)
1975; Naga Rani 1989; Wang 1997). An increased risk Acephen [OTC]: 120 mg (12s, 50s, 100s); 325 mg
of teratogenic effects has not been observed following (6s, 12s, 50s, 100s); 650 mg (12s, 50s, 100s)
maternal use of acetaminophen during pregnancy. Pre- Feverall [OTC]: 80 mg (6s, 50s); 120 mg (6s, 50s);
natal constriction of the ductus arteriosus has been 325 mg (6s, 50s); 650 mg (50s)
64
ACETAMINOPHEN AND CODEINE
Suspension, oral: 160 mg/5 mL (5 mL, 10 mL, 10.15 (Caldeira 2015), acetaminophen was associated with
mL, 20 mL, 20.3 mL) a mean 0.62 INR increase compared to placebo. Spe-
Mapap Children's [OTC]: 160 mg/5 mL (118 mL) cifically, there was 0.17 mean increase of the INR per
Nortemp Children's [OTC]: 160 mg/5 mL (118 mL) each daily gram of acetaminophen. Statistically, this
Pain & Fever Children's [OTC]: 160 mg/5 mL (60 mL) was significant; however, the clinical relevance was
Tylenol Children's [OTC]: 160 mg/5 mL (60 mL, questionable since the reviewed studies did not report
120 mL) any major bleeding event.
Tylenol Infants' [OTC]: 160 mg/5 mL (60 mL)
Syrup, oral: There are no reports of acetaminophen interacting with
Triaminic Children's Fever Reducer Pain Reliever antiplatelet drugs such as aspirin, clopidogrel (Plavix),
[OTC]: 160 mg/5 mL (118 mL) ticagrelor (Brilinta), or prasugrel (Effient). Also, there
Tablet, oral: 325 mg, 500 mg are no reports of acetaminophen in combination with
Aspirin Free Anacin Extra Strength [OTC]: 500 mg hydrocodone, codeine, or oxycodone interacting with
Cetafen [OTC]: 325 mg warfarin (Coumadin).
Mapap [OTC]: 325 mg
Mapap Extra Strength [OTC]: 500 mg Acetaminophen and Codeine
Non-Aspirin Pain Reliever [OTC]: 325 mg (a seet a MIN oh fen & KOE deen)
Pain Relief Extra Strength [OTC]: 500 mg
Pharbetol [OTC]: 325 mg Related Information
Pharbetol Extra Strength [OTC]: 500 mg Acetaminophen on page 60
Tylenol [OTC]: 325 mg Codeine on page 357
Tylenol Extra Strength [OTC]: 500 mg Related Sample Prescriptions
Valorin [OTC]: 325 mg Oral Pain - Sample Prescriptions on page 32
Valorin Extra [OTC]: 500 mg Brand Names: US Capital/Codeine [DSC]; Tylenol with
Tablet, chewable, oral: 80 mg Codeine #3; Tylenol with Codeine #4
Mapap Children's [OTC]: 80 mg Brand Names: Canada Procet-30; Tylenol with
Tablet, dispersible, oral: 80 mg, 160 mg Codeine #4
Mapap Children's [OTC]: 80 mg
Generic Availability (US) May be product dependent
Dental Health Professional Considerations
Pharmacologic Category Analgesic Combination
Although the OTC product labeling for acetaminophen
(Opioid); Analgesic, Opioid
products state to limit the maximum dose to 3,000 mg
daily (for extra strength) or 3,250 mg (for regular Dental Use Treatment of postoperative pain
strength) (see this site for details: http://www.- Use
tylenolprofessional.com/products-and-dosages.html), it Pain management: Management of mild to moderate
is still appropriate for patients to take up to 4,000 mg pain where treatment with an opioid is appropriate and
daily "under the direction of a health care provider" for which alternative treatments are inadequate.
(http://www.tylenolprofessional.com/dosage.html). Limitations of use: Reserve for use in patients for whom
alternative treatment options (eg, nonopioid analge-
The acetaminophen component requires use with cau- sics) are ineffective, not tolerated, or would be other-
tion in patients who use alcohol, with preexisting liver wise inadequate.
disease, and those receiving more than one source of Local Anesthetic/Vasoconstrictor Precautions
acetaminophen-containing medication. No information available to require special precautions
Hepatotoxicity caused by acetaminophen is potentiated Effects on Dental Treatment No significant effects or
by chronic alcohol consumption. People who are taking complications reported (see Dental Health Professional
acetaminophen, even at therapeutic doses, and con- Considerations)
sume alcohol are at risk of developing hepatotoxicity. Effects on Bleeding As a single agent, acetamino-
phen does not appear to affect bleeding or platelet
Acetaminophen may increase the levels and enhance
aggregation. Acetaminophen may prolong the INR
the anticoagulant effects of vitamin K antagonists ace-
and increase bleeding in patients taking warfarin (Cou-
nocoumarol and warfarin (Coumadin). Studies have
reported that acetaminophen has increased the INR in madin). For patients taking warfarin, single acetamino-
warfarin-treated patients with daily acetaminophen phen doses or acetaminophen therapy of short duration
doses as low as 2 g, particularly when taking acetami- should be safe, but if large (>1.3 g/day) doses are
nophen for >1 week (Gebauer 2003; Hylek 1998). In administered for longer than 10-14 days, then the INR
addition, case reports of bleeding as a result of should be monitored (see Dental Health Professional
increased INR have been published (Bagheri 1999). Considerations).
There is no known mechanism of the interaction; fur- Adverse Reactions Also see individual agents.
thermore, some studies have failed to demonstrate this Frequency not defined:
interaction (Gadisseur 2003; Kwan 1995; van den Bemt Central nervous system: Dizziness, drowsiness, dys-
2002). In terms of risk, the data suggest that acetami- phoria, euphoria, sedation, serotonin syndrome
nophen and warfarin could interact in some clinically Dermatologic: Pruritus, skin rash
significant manner but that the benefits of concomitant Endocrine & metabolic: Adrenocortical insufficiency
use of acetaminophen for pain control in dental patients Gastrointestinal: Abdominal pain, constipation, nau-
taking warfarin usually outweigh the risks. An appropri- sea, vomiting
ate monitoring plan should be in place to identify Hematologic & oncologic: Agranulocytosis, thrombo-
potential negative effects and dosage adjustments cytopenia
may be necessary in a minority of patients. The inter- Hypersensitivity: Hypersensitivity reaction
action may be more likely to occur with daily acetami- Respiratory: Dyspnea
nophen doses of >1.3 g for >1 week. In a review of <1%, postmarketing, and/or case reports: Hypogonad-
seven random controlled trials comparing acetamino- ism (Brennan 2013; Debono 2011), respiratory
phen versus placebo in warfarin-treated patients depression
65
Dental Usual Dosage Postoperative pain: Adults: patients 12 to 18 years of age who have undergone
Analgesic: Based on codeine (30-60 mg/dose) every tonsillectomy and/or adenoidectomy. Avoid codeine
4-6 hours (maximum: 4000 mg/24 hours based on use in all pediatric patient populations in which it is
acetaminophen component) contraindicated and in pediatric patients 12 to 18
Dosing years of age who have other risk factors that
Adult Note: Adult doses ≥60 mg codeine fail to give increase risk for respiratory depression associated
commensurate relief of pain but merely prolong anal- with codeine (eg, conditions associated with hypo-
gesia and are associated with an appreciably ventilation like postoperative status, obstructive
increased incidence of side effects. sleep apnea, obesity, severe pulmonary disease,
Pain management: Oral: neuromuscular disease, use of other medications
Solution or suspension: known to depress respiratory drive); in rare cases
Acetaminophen 120 mg/codeine 12 mg per 5 mL: in which codeine-containing product is the only
15 mL every 4 hours as needed; adjust dose option, consider genotype testing prior to use; use
according to severity of pain and response of extra precaution; monitor closely for adverse effects.
patient (maximum: acetaminophen 4,000 mg per Codeine has been associated with reports of life-
24 hours). threatening or fatal respiratory depression in children
Acetaminophen 160 mg/codeine 8 mg per 5 mL and adolescents; multifactorial causes have been
[Canadian product]: 10 to 20 mL every 4 hours identified; of primary concern are unrecognized ultra-
as needed; adjust dose according to severity of rapid metabolizers of CYP2D6 who may have exten-
pain and response of patient (maximum: 100 mL sive conversion of codeine (prodrug) to morphine
per 24 hours) and thus increased opioid-mediated effects (AAP
Tablets: Acetaminophen (300 to 1,000 mg/dose)/ [Tobias 2016]; Dancel 2017; Gammal 2016; Gold-
codeine (15 to 60 mg/dose) every 4 hours as schneider 2017; Poonai 2015).
needed; adjust dose according to severity of pain Children and Adolescents: Limited data available in
and response of patient (maximum: acetaminophen ages <12 years and in postoperative tonsillectomy
4,000 mg/codeine 360 mg per 24 hours). and/or adenoidectomy patients: Not a preferred
Discontinuation of therapy: When discontinuing agent; use only when determined codeine is only
chronic opioid therapy, the dose should be gradu- option
ally tapered down. An optimal universal tapering Weight-directed dosing: Dosage for individual com-
schedule for all patients has not been established ponents:
(CDC [Dowell 2016]). Proposed schedules range Codeine: Oral: 0.5 to 1 mg/kg/dose every 4 to 6
from slow (eg, 10% reductions per week) to rapid hours; maximum dose: 60 mg/dose (APS 2016).
(eg, 25% to 50% reduction every few days) (CDC Note: Do not use for postoperative tonsillectomy
2015). Tapering schedules should be individualized and/or adenoidectomy pain management
to minimize opioid withdrawal while considering Acetaminophen: Oral: 10 to 15 mg/kg/dose every
patient-specific goals and concerns as well as the 4 to 6 hours; do not exceed 5 doses in 24 hours;
pharmacokinetics of the opioid being tapered. An maximum daily dose: 75 mg/kg/day not to
even slower taper may be appropriate in patients exceed 4,000 mg/day
who have been receiving opioids for a long duration Acetaminophen 160 mg/codeine 8 mg per 5 mL
(eg, years), particularly in the final stage of taper- [Canadian product]: Children ≥12 years and Ado-
ing, whereas more rapid tapers may be appropriate lescents: Oral: 10 to 20 mL every 4 to 6 hours as
in patients experiencing severe adverse events needed; adjust dose according to severity of pain
(CDC [Dowell 2016]). Monitor carefully for signs/ and response of patient; maximum daily dose: 100
symptoms of withdrawal. If the patient displays mL/24 hours
withdrawal symptoms, consider slowing the taper Renal Impairment: Pediatric Children and Adoles-
schedule; alterations may include increasing the cents: There are no specific dosage adjustments
interval between dose reductions, decreasing provided in the manufacturer's labeling; however,
amount of daily dose reduction, pausing the taper clearance may be reduced; active metabolites may
and restarting when the patient is ready, and/or accumulate. Use with caution; initiate at lower doses
coadministration of an alpha2 agonist (eg, cloni- or longer dosing intervals followed by careful titration.
dine) to blunt withdrawal symptoms (Berna 2015; See individual monographs for specific adjustments.
CDC [Dowell 2016]). Continue to offer nonopioid Hepatic Impairment: Pediatric Children and Ado-
analgesics as needed for pain management during lescents: There are no dosage adjustments provided
the taper; consider nonopioid adjunctive treatments in the manufacturer’s labeling; however, product con-
for withdrawal symptoms (eg,GI complaints, muscle tains acetaminophen; use with caution. Cases of hep-
spasm) as needed (Berna 2015; Sevarino 2018). atotoxicity at daily acetaminophen dosages <4 g/day
Geriatric Refer to adult dosing. Use with caution and have been reported. See individual monographs.
consider initiation at the low end of the dosing range; Mechanism of Action
titrate slowly. Acetaminophen: Although not fully elucidated, the anal-
Renal Impairment: Adult There are no specific gesic effects are believed to be due to activation of
dosage adjustments provided in the manufacturer's descending serotonergic inhibitory pathways in the
labeling; use with caution. Also see individual agents. CNS. Interactions with other nociceptive systems
Hepatic Impairment: Adult There are no specific may be involved as well (Smith 2009). Antipyresis is
dosage adjustments provided in the manufacturer's produced from inhibition of the hypothalamic heat-
labeling; use with caution. Also see individual agents. regulating center.
Pediatric Note: Doses should be titrated to appropri- Codeine: Binds to opiate receptors in the CNS, causing
ate analgesic effect: inhibition of ascending pain pathways, altering the
Pain management, mild to moderate: Note: Use is perception of and response to pain; causes cough
contraindicated in pediatric patients <12 years of age suppression by direct central action in the medulla;
and for postoperative management in pediatric produces generalized CNS depression.
66
Contraindications Avoid use of codeine in patients with impaired con-

Hypersensitivity (eg, anaphylaxis) to acetaminophen, sciousness or coma as these patients are susceptible
codeine, or any component of the formulation; pedia- to intracranial effects of CO2 retention. Some products
tric patients <12 years of age; postoperative manage- may contain metabisulfite which may cause allergic
ment in pediatric patients <18 years of age who have reactions. Use caution in patients with two or more
undergone tonsillectomy and/or adenoidectomy; sig- copies of the variant CYP2D6*2 allele; may have exten-
nificant respiratory depression; acute or severe bron- sive conversion to morphine and thus increased opioid-
chial asthma in an unmonitored setting or in the mediated effects. Avoid the use of codeine in these
absence of resuscitative equipment; GI obstruction, patients; consider alternative analgesics such as mor-
including paralytic ileus (known or suspected); con- phine or a nonopioid agent (Crews 2012). The occur-
current use with or within 14 days following mono- rence of this phenotype is seen in 0.5% to 1% of
amine oxidase inhibitors (MAOIs) therapy. Chinese and Japanese, 0.5% to 1% of Hispanics, 1%
Canadian labeling: Additional contraindications (not in to 10% of Caucasians, 3% of African-Americans, and
US labeling): Hypersensitivity to other opioid analge- 16% to 28% of North Africans, Ethiopians, and Arabs.
sics; mechanical GI obstruction (eg, bowel obstruc- Serious and potentially fatal skin reactions, including
tion, strictures) or any disease/condition that affects acute generalized exanthematous pustulosis (AGEP),
bowel transit (known or suspected); suspected surgi- Stevens-Johnson syndrome (SJS), and toxic epidermal
cal abdomen (eg, acute appendicitis, pancreatitis); necrolysis (TEN) have occurred rarely with acetamino-
mild pain that can be managed with other pain med- phen use. Discontinue therapy at the first appearance
ications; severe hepatic or renal impairment; acute or of skin rash or any other sign of hypersensitivity. Limit
severe bronchial asthma, chronic obstructive airway acetaminophen dose from all sources (prescription,
disease; status asthmaticus; hypercapnia; cor pulmo- OTC, combination products) to <4 g/day in adults. Do
nale; acute alcoholism; delirium tremens; seizure dis- not use acetaminophen/codeine concomitantly with
order; severe CNS depression; increased other acetaminophen-containing products.
cerebrospinal or intracranial pressure; head injury;
pregnancy; use during labor and delivery; CYP2D6 [US Boxed Warning]: Acetaminophen has been
ultra-rapid metabolizers. Some products may contra- associated with cases of acute liver failure, at times
indicate use in patients <18 years (refer to specific resulting in liver transplant and death. Most of the
product labeling). cases of liver injury are associated with the use of
acetaminophen at dosages that exceed 4 g/day, and
Documentation of allergenic cross-reactivity for opioids often involve more than one acetaminophen-con-
is limited. However, because of similarities in chemical taining product. Risk is increased with alcohol use,
structure and/or pharmacologic actions, the possibility preexisting liver disease, and intake of more than one
of cross-sensitivity cannot be ruled out with certainty. source of acetaminophen-containing medications.
Warnings/Precautions [US Boxed Warning]: Life- Chronic daily dosing in adults has also resulted in liver
threatening respiratory depression and death have damage in some patients. Hypersensitivity and anaphy-
occurred in children who received codeine. Most of lactic reactions have been reported with acetaminophen
the reported cases occurred following tonsillec- use; discontinue immediately if symptoms of allergic or
tomy and/or adenoidectomy, and many of the chil- hypersensitivity reactions occur. Use with caution in
dren had evidence of being ultrarapid metabolizers patients with hypersensitivity reactions to other phenan-
of codeine due to a CYP2D6 polymorphism. Acet- threne-derivative opioid agonists (hydrocodone, hydro-
aminophen/codeine is contraindicated in pediatric morphone, levorphanol, oxycodone, oxymorphone).
patients <12 years of age and pediatric patients <18 Use acetaminophen with caution in patients with known
years of age following tonsillectomy and/or adenoi- G6PD deficiency. Use with caution in patients with
dectomy. Avoid the use of acetaminophen/codeine alcoholic liver disease; consuming ≥3 alcoholic drinks/
in pediatric patients 12 to 18 years of age who have day may increase the risk of liver damage.
other risk factors that may increase their sensitivity May cause CNS depression, which may impair physical
to the respiratory depressant effects of codeine. or mental abilities; patients must be cautioned about
Risk factors include conditions associated with hypo- performing tasks which require mental alertness (eg,
ventilation, such as postoperative status, obstructive operating machinery or driving). [US Boxed Warning]:
sleep apnea, obesity, severe pulmonary disease, neu- Use exposes patients and other users to the risks of
romuscular disease, and concomitant use of other opioid addiction, abuse, and misuse, which can
medications that cause respiratory depression. Deaths lead to overdose and death. Assess each patient's
have also occurred in breastfeeding infants after being risk prior to prescribing acetaminophen/codeine,
exposed to high concentrations of morphine because and monitor all patients regularly for the develop-
the mothers were ultrarapid metabolizers. [US Boxed ment of these behaviors or conditions. Use with
Warning]: Prolonged use during pregnancy can caution in patients with a history of drug abuse or acute
cause neonatal opioid withdrawal syndrome, which alcoholism; potential for drug dependency exists. Other
may be life-threatening if not recognized and factors associated with increased risk for misuse
treated according to protocols developed by neo- include younger age, concomitant depression (major),
natology experts. If opioid use is required for a and psychotropic medication use. Consider offering
prolonged period in a pregnant woman, advise the naloxone prescriptions in patients with factors associ-
patient of the risk of neonatal opioid withdrawal ated with an increased risk for overdose, such as
syndrome and ensure that appropriate treatment history of overdose or substance use disorder, higher
will be available. Signs and symptoms include irrita- opioid dosages (≥50 morphine milligram equivalents/
bility, hyperactivity and abnormal sleep pattern, high day orally), and concomitant benzodiazepine use (Dow-
pitched cry, tremor, vomiting, diarrhea and failure to ell [CDC 2016]). Abuse or misuse of ER tablets by
gain weight. Onset, duration, and severity depend on crushing, chewing, snorting, or injecting the dissolved
the drug used, duration of use, maternal dose, and rate product will result in the uncontrolled delivery of the
of drug elimination by the newborn. oxycodone and can result in overdose and death.
67
Chronic pain (outside of end-of-life or palliative care, in patients with unstable angina and patients post-
active cancer treatment, sickle cell disease, or medi- myocardial infarction. Consider preventive measures
cation-assisted treatment for opioid use disorder) in (eg, stool softener, increased fiber) to reduce the poten-
outpatient setting in adults: Opioids should not be used tial for constipation. [US Boxed Warning]: Serious,
as first-line therapy for chronic pain management (pain life-threatening, or fatal respiratory depression
>3-month duration or beyond time of normal tissue may occur with use. Monitor for respiratory depres-
healing) due to limited short-term benefits, undeter- sion, especially during initiation of therapy or fol-
mined long-term benefits, and association with serious lowing a dose increase. Carbon dioxide retention from
risks (eg, overdose, MI, auto accidents, risk of devel- opioid-induced respiratory depression can exacerbate
oping opioid use disorder). Preferred management the sedating effects of opioids. Use with caution and
includes nonpharmacologic therapy and nonopioid ther- monitor for respiratory depression in patients with sig-
apy (eg, NSAIDs, acetaminophen, certain anticonvul- nificant chronic obstructive pulmonary disease or cor
sants and antidepressants). If opioid therapy is initiated,
pulmonale, and those with a substantially decreased
it should be combined with nonpharmacologic and non-
respiratory reserve, hypoxia, hypercapnia, or preexist-
opioid therapy, as appropriate. Prior to initiation, known
ing respiratory depression, particularly when initiating
risks of opioid therapy should be discussed and realistic
treatment goals for pain/function should be established, and titrating therapy; critical respiratory depression may
including consideration for discontinuation if benefits do occur, even at therapeutic dosages. Consider the use of
not outweigh risks. Therapy should be continued only if alternative nonopioid analgesics in these patients. May
clinically meaningful improvement in pain/function out- obscure diagnosis or clinical course of patients with
weighs risks. Therapy should be initiated at the lowest acute abdominal conditions. Use with caution in the
effective dosage using immediate-release opioids elderly; may be more sensitive to adverse effects, such
(instead of extended-release/long-acting opioids). Risk as respiratory depression. Use opioids for chronic pain
associated with use increases with higher opioid dos- with caution in this age group; monitor closely due to an
ages. Risks and benefits should be re-evaluated when increased potential for risks, including certain risks such
increasing dosage to ≥50 morphine milligram equiva- as falls/fracture, cognitive impairment, and constipation.
lents (MME)/day orally; dosages ≥90 MME/day orally Clearance may also be reduced in older adults (with or
should be avoided unless carefully justified (Dowell without renal impairment) resulting in a narrow thera-
[CDC 2016]). peutic window and increasing the risk for respiratory
depression or overdose (Dowell [CDC 2016]).
Concurrent use of mixed agonist/antagonist (eg, penta-
zocine, nalbuphine, butorphanol) or partial agonist (eg, [US Boxed Warning]: Accidental ingestion of acet-
buprenorphine) analgesics may precipitate withdrawal aminophen/codeine, especially by children, can
symptoms and/or reduced analgesic efficacy in patients result in a fatal overdose of codeine. [US Boxed
following prolonged therapy with mu opioid agonists. Warning]: Ensure accuracy when prescribing, dis-
Abrupt discontinuation following prolonged use may pensing, and administering acetaminophen/
also lead to withdrawal symptoms. Taper dose gradu- codeine oral solution or suspension. Dosing errors
ally when discontinuing. Potentially significant drug- due to confusion between mg and mL and other
drug interactions may exist, requiring dose or frequency codeine containing oral products of different con-
adjustment, additional monitoring, and/or selection of centrations can result in accidental overdose and
alternative therapy. [US Boxed Warning]: Concomi-
death. May cause severe hypotension (including ortho-
tant use of opioids with benzodiazepines or other
static hypotension and syncope); use with caution in
CNS depressants, including alcohol, may result in
patients with hypovolemia, cardiovascular disease
profound sedation, respiratory depression, coma,
and death. Reserve concomitant prescribing of (including acute MI), or drugs which may exaggerate
acetaminophen/codeine and benzodiazepines or hypotensive effects (including phenothiazines or gen-
other CNS depressants for use in patients for whom eral anesthetics). Monitor for symptoms of hypotension
alternative treatment options are inadequate. Limit following initiation or dose titration. Avoid use in patients
dosages and durations to the minimum required. with circulatory shock. Use opioids with caution for
Follow patients for signs and symptoms of respira- chronic pain in patients with mental health conditions
tory depression and sedation. [US Boxed Warning]: (eg, depression, anxiety disorders, post-traumatic
The effects of concomitant use or discontinuation stress disorder) due to increased risk for opioid use
of CYP450 3A4 inducers, 3A4 inhibitors, or 2D6 disorder and overdose; more frequent monitoring is
inhibitors with codeine are complex. Use of recommended (Dowell [CDC 2016]). Use opioids with
CYP450 3A4 inducers, 3A4 inhibitors, or 2D6 inhib- caution for chronic pain and titrate dosage cautiously in
itors with acetaminophen/codeine requires careful patients with risk factors for sleep-disordered breathing,
consideration of the effects on the parent drug, including HF and obesity. Avoid opioids in patients with
codeine, and the active metabolite, morphine. moderate to severe sleep-disordered breathing (Dowell
Use with caution in cachectic or debilitated patients, or [CDC 2016]). An opioid-containing analgesic regimen
in morbidly obese patients; adrenal insufficiency should be tailored to each patient's needs and based
(including Addison disease); biliary tract impairment upon the type of pain being treated (acute versus
(including acute pancreatitis); renal or severe hepatic chronic), the route of administration, degree of toler-
impairment; toxic psychosis; delirium tremens; thyroid ance for opioids (naive versus chronic user), age,
disorders; prostatic hyperplasia and/or urethral stric- weight, and medical condition. The optimal analgesic
ture; seizure disorder; head injury, intracranial lesions dose varies widely among patients; doses should be
or increased intracranial pressure. May cause or aggra- titrated to pain relief/prevention. Opioids decrease
vate constipation; chronic use may result in obstructive bowel motility; monitor for decreased bowel motility in
bowel disease, particularly in those with underlying postop patients receiving opioids. Use with caution in
intestinal motility disorders. May also be problematic the perioperative setting; individualize treatment when
transitioning from parenteral to oral analgesics.
68
[US Boxed Warning]: To ensure that the benefits of each also has unique therapeutic challenges and con-
opioid analgesics outweigh the risks of addiction, cerns; refer to individual monographs for detailed infor-
abuse, and misuse, the FDA has required a Risk mation (AAP [Tobias 2016]; Dancel 2017; Gammal
Evaluation and Mitigation Strategy (REMS) for these 2016; Goldschneider 2017; Poonai 2015).
products. Under the requirements of the REMS,
drug companies with approved opioid analgesic
products must make REMS-compliant education
programs available to health care providers. Health
care providers are strongly encouraged to complete
a REMS-compliant education program; counsel
patients and/or their caregivers, with every pre-
scription, on safe use, serious risks, storage, and
ity, lactic acidosis, seizures, and respiratory depression;
disposal of these products; emphasize to patients
use caution (AAP 1997; Shehab 2009).
and their caregivers the importance of reading the
Drug Interactions
Medication Guide every time it is provided by their
pharmacist; and consider other tools to improve
Metabolism/Transport Effects Refer to individual
components.
patient, household, and community safety.
Avoid Concomitant Use
Some dosage forms may contain propylene glycol; Avoid concomitant use of Acetaminophen and
large amounts are potentially toxic and have been Codeine with any of the following: Azelastine (Nasal);
associated hyperosmolality, lactic acidosis, seizures Bromperidol; Eluxadoline; Opioids (Mixed Agonist /
and respiratory depression; use caution (AAP ["Inac- Antagonist); Orphenadrine; Oxomemazine; Paralde-
tive" 1997]; Zar 2007). hyde; Thalidomide
Some dosage forms may contain sodium benzoate/ Increased Effect/Toxicity
benzoic acid; benzoic acid (benzoate) is a metabolite Acetaminophen and Codeine may increase the levels/
of benzyl alcohol; large amounts of benzyl alcohol effects of: Alvimopan; Azelastine (Nasal); Blonanserin;
(≥99 mg/kg/day) have been associated with a poten- Busulfan; Dasatinib; Desmopressin; Diuretics; Eluxa-
tially fatal toxicity ("gasping syndrome") in neonates; the doline; Flunitrazepam; HYDROcodone; Imatinib; Local
"gasping syndrome" consists of metabolic acidosis, Anesthetics; Methotrimeprazine; MetyroSINE; Mipo-
respiratory distress, gasping respirations, CNS dysfunc- mersen; Opioid Agonists; Orphenadrine; OxyCO-
tion (including convulsions, intracranial hemorrhage), DONE; Paraldehyde; Perhexiline; Phenylephrine
hypotension, and cardiovascular collapse (AAP ["Inac- (Systemic); Piribedil; Pramipexole; Prilocaine; Ramo-
tive" 1997]; CDC 1982); some data suggests that setron; ROPINIRole; Rotigotine; Selective Serotonin
benzoate displaces bilirubin from protein binding sites Reuptake Inhibitors; Serotonin Modulators; Sodium
(Ahlfors 2001); avoid or use dosage forms containing Nitrite; SORAfenib; Suvorexant; Thalidomide; Vitamin
benzyl alcohol derivative with caution in neonates. See K Antagonists; Zolpidem
manufacturer's labeling. The levels/effects of Acetaminophen and Codeine
Warnings: Additional Pediatric Considerations may be increased by: Abiraterone Acetate; Ajmaline;
Use is contraindicated in pediatric patients <12 years Alizapride; Amphetamines; Anticholinergic Agents;
of age and for postoperative management in pediatric Asunaprevir; Brimonidine (Topical); Bromopride;
patients 12 to 18 years of age who have undergone Bromperidol; Cannabidiol; Cannabis; Chlormethia-
tonsillectomy and/or adenoidectomy. Avoid codeine use zole; Chlorphenesin Carbamate; CNS Depressants;
in all pediatric patient populations in which it is contra- Cobicistat; CYP3A4 Inhibitors (Strong); Dacomitinib;
indicated and in pediatric patients 12 to 18 years of age Dapsone (Topical); Darunavir; Dasatinib; Dimethin-
who have other risk factors that increase risk for respi- dene (Topical); Dronabinol; Droperidol; Flucloxacillin;
ratory depression associated with codeine (eg, condi- Isoniazid; Kava Kava; Lofexidine; Lumefantrine; Mag-
tions associated with hypoventilation like postoperative nesium Sulfate; Methotrimeprazine; MetyraPONE;
status, obstructive sleep apnea, obesity, severe pulmo- Minocycline; Monoamine Oxidase Inhibitors; Nabi-
nary disease, neuromuscular disease, use of other lone; Nitric Oxide; Oxomemazine; Panobinostat;
medications known to depress respiratory drive); in rare Peginterferon Alfa-2b; Perampanel; Perhexiline; PHE-
cases in which codeine-containing product is the only Nobarbital; Primidone; Probenecid; QuiNINE; Rufina-
option, consider genotype testing prior to use; use extra mide; Sodium Oxybate; Somatostatin Analogs;
precaution; monitor closely for adverse effects. Prior to SORAfenib; Succinylcholine; Tapentadol; Tetrahydro-
2017, acetaminophen/codeine was approved for use in cannabinol; Tetrahydrocannabinol and Cannabidiol
children as young as 3 years of age. Codeine has also Decreased Effect
been removed from the WHO List of Essential Medi- Acetaminophen and Codeine may decrease the lev-
cations in Children since 2011. Codeine has been els/effects of: Diuretics; Gastrointestinal Agents (Pro-
associated with reports of life-threatening or fatal respi- kinetic); Pegvisomant; Sincalide
ratory depression in children and adolescents; a review
of FDA adverse events data and the literature includes The levels/effects of Acetaminophen and Codeine
reports of at least 21 deaths in infants or children may be decreased by: CarBAMazepine; CYP2D6
(1965-2015). Multifactorial causes for the respiratory Inhibitors (Moderate); CYP2D6 Inhibitors (Strong);
depression have been identified; of primary concern CYP3A4 Inducers (Moderate); CYP3A4 Inducers
are unrecognized ultrarapid metabolizers of CYP2D6 (Strong); CYP3A4 Inhibitors (Moderate); Fospheny-
who may have extensive conversion of codeine (pro- toin-Phenytoin; Nalmefene; Naltrexone; Opioids
drug) to morphine and thus increased opioid-mediated (Mixed Agonist / Antagonist); Peginterferon Alfa-2b;
effects (ie, respiratory depression). Other oral opioid PHENobarbital; Primidone
and nonopioid analgesics are alternate options depend- Pregnancy Risk Factor C
ing upon severity of pain and other patient specific Pregnancy Considerations Animal reproduction
factors (eg, age, route of administration, etc); however, studies have not been conducted with this combination.
69
[US Boxed Warning]: Prolonged use of opioids There is no known mechanism of the interaction; fur-
during pregnancy can cause neonatal opioid with- thermore, some studies have failed to demonstrate this
drawal syndrome, which may be life-threatening if interaction (Gadisseur, 2003; Kwan, 1995; van den
not recognized and treated according to protocols Bemt, 2002). In terms of risk, the data suggest that
developed by neonatology experts. If opioid use is acetaminophen and warfarin could interact in some
required for a prolonged period in a pregnant clinically significant manner but that the benefits of
woman, advise the patient of the risk of neonatal concomitant use of acetaminophen for pain control in
opioid withdrawal syndrome and ensure that appro- dental patients taking warfarin usually outweigh the
priate treatment will be available. Refer to individual risks. An appropriate monitoring plan should be in place
agents. to identify potential negative effects and dosage adjust-
Breastfeeding Considerations Acetaminophen and ments may be necessary in a minority of patients. The
codeine are present in breast milk. Due to the potential interaction may be more likely to occur with daily
for serious adverse reactions in the breastfed infant, acetaminophen doses of >1.3 g for >1 week.
breastfeeding is not recommended by the manufac- There are no reports of acetaminophen interacting with
turer. Refer to individual agents. antiplatelet drugs such as aspirin, clopidogrel (Plavix),
Controlled Substance Liquid products: C-V; Tablet: ticagrelor (Brilinta), or prasugrel (Effient). Also, there
C-III are no reports of acetaminophen in combination with
Dosage Forms: US hydrocodone, codeine, or oxycodone interacting with
Solution, Oral: warfarin (Coumadin).
Generic: Acetaminophen 120 mg and codeine phos-
phate 12 mg per 5 mL (5 mL, 12.5 mL, 118 mL, 120
mL, 473 mL) Acetaminophen and Tramadol
(a seet a MIN oh fen & TRA ma dole)
Tablet, Oral:
Tylenol with Codeine #3: Acetaminophen 300 mg and Related Information
codeine phosphate 30 mg Acetaminophen on page 60
Tylenol with Codeine #4: Acetaminophen 300 mg and Oral Pain on page 1520
codeine phosphate 60 mg TraMADol on page 1281
Generic: Acetaminophen 300 mg and codeine phos- Related Sample Prescriptions
phate 15 mg, Acetaminophen 300 mg and codeine
Oral Pain - Sample Prescriptions on page 32
phosphate 30 mg, Acetaminophen 300 mg and
Brand Names: US Ultracet
codeine phosphate 60 mg
Brand Names: Canada Tramacet
Dosage Forms: Canada
Solution, Oral: Generic Availability (US) Yes
pms-Acetaminophen with Codeine Elixir: Acetamino- Pharmacologic Category Analgesic Combination
phen 160 mg and codeine phosphate 8 mg per 5 mL (Opioid); Analgesic, Opioid
Tablet: Dental Use Treatment of postoperative pain (≤5 days)
Acet-Codeine, Procet-30, ratio-Emtec-30, Triatec-30: Use
Acetaminophen 300 mg and codeine phos- Pain management: Short-term (≤5 days) management
phate 30 mg of acute pain severe enough to require an opioid
Acet-Codeine, ratio-Lenoltec No. 4: Acetaminophen analgesic and for which alternative treatments are
300 mg and codeine phosphate 60 mg inadequate.
Dental Health Professional Considerations Limitations of use: Reserve tramadol/acetaminophen
Although the OTC product labeling for acetaminophen for use in patients for whom alternative treatment
products state to limit the maximum dose to 3,000 mg options (eg, nonopioid analgesics) are ineffective,
daily (for extra strength) or 3,250 mg (for regular not tolerated, or would be otherwise inadequate to
strength) (see this site for details: http://www.- provide sufficient management of pain.
tylenolprofessional.com/products-and-dosages.html), it Local Anesthetic/Vasoconstrictor Precautions
is still appropriate for patients to take up to 4,000 mg No information available to require special precautions
daily "under the direction of a health care provider" Effects on Dental Treatment Key adverse event(s)
(http://www.tylenolprofessional.com/dosage.html). related to dental treatment: Xerostomia and changes in
salivation (normal salivary flow resumes upon discon-
The acetaminophen component requires use with cau- tinuation) (see Dental Health Professional Considera-
tion in patients who use alcohol, with preexisting liver tions).
disease, and those receiving more than one source of Effects on Bleeding As a single agent, acetamino-
acetaminophen-containing medication. phen does not appear to affect bleeding or platelet
Hepatotoxicity caused by acetaminophen is potentiated aggregation. Acetaminophen may prolong the INR
by chronic alcohol consumption. People who are taking and increase bleeding in patients taking warfarin (Cou-
acetaminophen, even at therapeutic doses, and con- madin). For patients taking warfarin, single acetamino-
sume alcohol are at risk of developing hepatotoxicity. phen doses or acetaminophen therapy of short duration
should be safe, but if large (>1.3 g/day) doses are
Acetaminophen may increase the levels and enhance administered for longer than 10-14 days, then the INR
the anticoagulant effects of vitamin K antagonists ace- should be monitored (see Dental Health Professional
nocoumarol and warfarin (Coumadin). Studies have Considerations).
reported that acetaminophen has increased the INR in Adverse Reactions Also see individual agents.
warfarin treated patients with daily acetaminophen 1% to 10%:
doses as low as 2 g, particularly when taking acetami- Central nervous system: Drowsiness (6%), dizziness
nophen for >1 week (Antlitz, 1968; Boeijinga, 1982; (3%), insomnia (2%), anxiety, confusion, euphoria,
Gebauer, 2003; Hylek, 1998; Rubin, 1984). In addition, fatigue, headache, nervousness
case reports of bleeding as a result of increased INR Dermatologic: Diaphoresis (4%), pruritus (2%),
have been published (Bagheri, 1999; Bartle, 1991). skin rash
70
ACETAMINOPHEN AND TRAMADOL
Endocrine & metabolic: Hot flash Canadian labeling: Additional contraindications (not in
Gastrointestinal: Constipation (6%), anorexia (3%), US labeling): Known or suspected mechanical GI
diarrhea (3%), nausea (3%), xerostomia (2%), obstruction (eg, bowel obstruction, strictures) or any
abdominal pain, dyspepsia, flatulence, vomiting disease/condition that affects bowel transit; suspected
Genitourinary: Prostatic disease (2%) surgical abdomen (eg, acute appendicitis, pancreati-
Neuromuscular & skeletal: Tremor, weakness tis); severe renal impairment (creatinine clearance
<1%, postmarketing, and/or case reports: Abnormality <30 mL/minute); severe hepatic impairment (Child-
in thinking, albuminuria, amnesia, anemia, ataxia, Pugh class C); mild pain that can be managed with
cardiac arrhythmia, changes in liver function, chest other pain medications; acute or severe bronchial
pain, convulsions, depersonalization, depression, asthma, chronic obstructive airway, or status asthma-
drug abuse, dysphagia, dyspnea, emotional lability, ticus; acute respiratory depression, hypercapnia, or
exacerbation of migraine headache, exacerbation of cor pulmonale; acute alcoholism, delirium tremens,
hypertension, hallucination, hypertension, hypertonia, or seizure disorder; severe CNS depression,
hypotension, impotence, melena, migraine, muscle increased cerebrospinal or intracranial pressure, or
spasm, nightmares, oliguria, palpitations, paresthesia, head injury; any situation where opioids are contra-
rigors, stupor, syncope, tachycardia, tinnitus, tongue indicated (eg, acute intoxication with alcohol, hyp-
edema, urinary retention, urination disorder, vertigo, notics, centrally acting analgesics, opioids or
visual disturbance, weight loss, withdrawal syndrome psychotropic drugs); breastfeeding; pregnancy; use
(with abrupt discontinuation; includes anxiety, diar- during labor and delivery.
rhea, hallucinations [rare], nausea, pain, piloerection, Warnings/Precautions See individual agents.
rigors, sweating, and tremor; uncommon discontinua- Drug Interactions
tion symptoms may include severe anxiety, panic Metabolism/Transport Effects Refer to individual
attacks, or paresthesia) components.
Dental Usual Dosage Acute postoperative pain (≤5 Avoid Concomitant Use
days): Adults: Oral: Two tablets every 4-6 hours as Avoid concomitant use of Acetaminophen and Trama-
needed for pain relief (maximum: 8 tablets/day); treat- dol with any of the following: Azelastine (Nasal);
ment should not exceed 5 days Bromperidol; CarBAMazepine; Dapoxetine; Eluxado-
Dosing line; Iobenguane Radiopharmaceutical Products;
Adult Pain management: Oral: Acetaminophen Methylene Blue; Moclobemide; Opioids (Mixed Ago-
325 mg/tramadol 37.5 mg: Two tablets every 4 to 6 nist / Antagonist); Orphenadrine; Oxomemazine;
hours as needed for pain relief (maximum: 8 tablets/ Paraldehyde; Thalidomide
day [acetaminophen 2,600 mg/tramadol 300 mg per Increased Effect/Toxicity
day]); do not exceed 5 days of therapy
Acetaminophen and Tramadol may increase the lev-
Geriatric Refer to adult dosing. Use with caution. els/effects of: Alvimopan; Amifampridine; Azelastine
Renal Impairment: Adult (Nasal); Blonanserin; Busulfan; CarBAMazepine;
CrCl ≥30 mL/minute: No dosage adjustment neces- Dasatinib; Desmopressin; Diuretics; Eluxadoline; Flu-
sary. nitrazepam; HYDROcodone; Imatinib; Iohexol; Iome-
CrCl <30 mL/minute: Maximum: Two tablets every 12 prol; Iopamidol; Local Anesthetics;
hours Methotrimeprazine; Metoclopramide; MetyroSINE;
Hepatic Impairment: Adult Use is not recom- Mipomersen; Moclobemide; Orphenadrine; OxyCO-
mended (acetaminophen and tramadol undergo DONE; Paraldehyde; Phenylephrine (Systemic); Pir-
extensive hepatic metabolism). ibedil; Pramipexole; Prilocaine; Ramosetron;
Mechanism of Action ROPINIRole; Rotigotine; Serotonin Modulators;
Acetaminophen: Although not fully elucidated, the anal- Sodium Nitrite; SORAfenib; Suvorexant; Thalidomide;
gesic effects are believed to be due to activation of Vitamin K Antagonists; Zolpidem
descending serotonergic inhibitory pathways in the
CNS. Interactions with other nociceptive systems The levels/effects of Acetaminophen and Tramadol
may be involved as well (Smith 2009). Antipyresis is may be increased by: Alizapride; Amphetamines; Anti-
produced from inhibition of the hypothalamic heat- cholinergic Agents; Anti-Parkinson Agents (Mono-
regulating center. amine Oxidase Inhibitor); Brimonidine (Topical);
Tramadol: Binds to μ-opiate receptors in the CNS Bromopride; Bromperidol; BuPROPion; Cannabidiol;
causing inhibition of ascending pain pathways, altering Cannabis; Chlormethiazole; Chlorphenesin Carba-
the perception of and response to pain; also inhibits mate; CNS Depressants; CYP2D6 Inhibitors (Strong);
the reuptake of norepinephrine and serotonin, which CYP3A4 Inhibitors (Strong); Dapoxetine; Dapsone
also modifies the ascending pain pathway (Topical); Dasatinib; Dimethindene (Topical); Dronabi-
Contraindications nol; Droperidol; Flucloxacillin; Isoniazid; Kava Kava;
Hypersensitivity to acetaminophen, tramadol, or any Linezolid; Lofexidine; Magnesium Sulfate; Methotri-
component of the formulation; pediatric patients <12 meprazine; Methylene Blue; Methylphenidate; Metyr-
years; postoperative management in pediatric patients aPONE; Minocycline; Nabilone; Nitric Oxide;
<18 years who have undergone tonsillectomy and/or Oxomemazine; Perampanel; PHENobarbital; Primi-
adenoidectomy; significant respiratory depression; done; Probenecid; Ritonavir; Rufinamide; Serotonin
acute or severe bronchial asthma in an unmonitored Modulators; Sodium Oxybate; SORAfenib; Succinyl-
setting or in the absence of resuscitative equipment; choline; Tapentadol; Tedizolid; Tetrahydrocannabinol;
GI obstruction, including paralytic ileus (known or Tetrahydrocannabinol and Cannabidiol
suspected); concomitant use with or within 14 days Decreased Effect
following MAO inhibitor therapy. Acetaminophen and Tramadol may decrease the lev-
Documentation of allergenic cross-reactivity for opioids els/effects of: CarBAMazepine; Diuretics; Gastrointes-
is limited. However, because of similarities in chemical tinal Agents (Prokinetic); Iobenguane
structure and/or pharmacologic actions, the possibility Radiopharmaceutical Products; Pegvisomant; Sinca-
of cross-sensitivity cannot be ruled out with certainty. lide
71
ACETAMINOPHEN AND TRAMADOL
The levels/effects of Acetaminophen and Tramadol case reports of bleeding as a result of increased INR
may be decreased by: Antiemetics (5HT3 Antago- have been published (Bagheri, 1999; Bartle, 1991).
nists); Bosentan; CarBAMazepine; CYP2D6 Inhibitors There is no known mechanism of the interaction; fur-
(Moderate); CYP2D6 Inhibitors (Strong); CYP3A4 thermore, some studies have failed to demonstrate this
Inducers (Moderate); CYP3A4 Inducers (Strong); interaction (Gadisseur, 2003; Kwan, 1995; van den
Dabrafenib; Deferasirox; Enzalutamide; Fospheny- Bemt, 2002). In terms of risk, the data suggest that
toin-Phenytoin; Ivosidenib; Lorlatinib; Mitotane; Nal- acetaminophen and warfarin could interact in some
mefene; Naltrexone; Opioids (Mixed Agonist / clinically significant manner but that the benefits of
Antagonist); PHENobarbital; Pitolisant; Primidone; concomitant use of acetaminophen for pain control in
Ritonavir; Sarilumab; Siltuximab; St John's Wort; Toci- dental patients taking warfarin usually outweigh the
lizumab risks. An appropriate monitoring plan should be in place
Food Interactions Food may delay time to peak to identify potential negative effects and dosage adjust-
plasma levels, however, the extent of absorption is not ments may be necessary in a minority of patients. The
affected. Management: Administer without regard to interaction may be more likely to occur with daily
meals. acetaminophen doses of >1.3 g for >1 week.
Pregnancy Considerations Acetaminophen and tra- There are no reports of acetaminophen interacting with
madol cross the placenta. Use is not recommended antiplatelet drugs such as aspirin, clopidogrel (Plavix®),
prior to or during labor and delivery. [US Boxed Warn- or prasugrel (Effient™). Also, there are no reports of
ing]: Prolonged use of opioids during pregnancy acetaminophen in combination with hydrocodone,
can cause neonatal withdrawal syndrome, which codeine, or oxycodone interacting with warfarin (Cou-
may be life-threatening if not recognized and madin®).
treated according to protocols developed by neo-
natology experts. If opioid use is required for a
prolonged period in a pregnant woman, advise the AcetaZOLAMIDE (a set a ZOLE a mide)
patient of the risk of neonatal opioid withdrawal
syndrome and ensure that appropriate treatment Brand Names: US Diamox Sequels [DSC]
will be available. Refer to individual monographs. Brand Names: Canada Acetazolam; Diamox
Breastfeeding Considerations Acetaminophen and Pharmacologic Category Anticonvulsant, Miscella-
tramadol are present in breast milk. Due to the potential neous; Carbonic Anhydrase Inhibitor; Diuretic, Carbonic
for serious adverse reactions in the breastfed infant, Anhydrase Inhibitor; Ophthalmic Agent, Antiglaucoma
breastfeeding is not recommended by the manufac- Use
turer. Refer to individual monographs. Altitude illness: Prevention or amelioration of symp-
Controlled Substance C-IV toms associated with acute mountain sickness (imme-
Dosage Forms: US diate and extended release dosage forms)
Tablet, Oral: Edema: Adjunctive treatment of drug-induced edema or
Ultracet: Acetaminophen 325 mg and tramadol hydro- edema due to congestive heart failure (IV and imme-
chloride 37.5 mg diate release dosage forms)
Generic: Acetaminophen 325 mg and tramadol hydro- Elevated intraocular pressure: Treatment of elevated
chloride 37.5 mg intraocular pressure (IOP) in patients with chronic
open-angle glaucoma or acute angle-closure glau-
coma prior to surgery or as part of a 4-drug medical
Tablet, Oral:
management regimen when a patient cannot be seen
Tramacet: Acetaminophen 325 mg and tramadol
by an ophthalmologist for ≥1 hour
hydrochloride 37.5 mg
Epilepsy: Adjunctive treatment of centrencephalic epi-
Dental Health Professional Considerations lepsies (IV and immediate release dosage forms)
Although the OTC product labeling for acetaminophen
products state to limit the maximum dose to 3,000 mg
daily (for extra strength) or 3,250 mg (for regular
Effects on Dental Treatment Key adverse event(s)
strength) (see this site for details: http://www.-
related to dental treatment: Metallic taste (resolves
tylenolprofessional.com/products-and-dosages.html), it
upon discontinuation)
is still appropriate for patients to take up to 4,000 mg
daily "under the direction of a health care provider" Effects on Bleeding No information available to
(http://www.tylenolprofessional.com/dosage.html). require special precautions
Adverse Reactions Frequency not defined.
The acetaminophen component requires use with cau- Cardiovascular: Flushing
tion in patients who use alcohol, with preexisting liver Central nervous system: Ataxia, confusion, convul-
disease, and those receiving more than one source of sions, depression, dizziness, drowsiness, excitement,
acetaminophen-containing medication. fatigue, flaccid paralysis, headache, malaise, pares-
Hepatotoxicity caused by acetaminophen is potentiated thesia
Dermatologic: Allergic skin reaction, skin photosensitiv-
by chronic alcohol consumption. People who are taking
ity, Stevens-Johnson syndrome, toxic epidermal nec-
acetaminophen, even at therapeutic doses, and con-
rolysis, urticaria
sume alcohol are at risk of developing hepatotoxicity.
Endocrine & metabolic: Electrolyte imbalance, growth
Acetaminophen may increase the levels and enhance retardation (children), hyperglycemia, hypoglycemia,
the anticoagulant effects of vitamin K antagonists ace- hypokalemia, hyponatremia, metabolic acidosis
nocoumarol and warfarin (Coumadin®). Studies have Gastrointestinal: Decreased appetite, diarrhea, dysgeu-
reported that acetaminophen has increased the INR in sia, glycosuria, melena, nausea, vomiting
warfarin treated patients with daily acetaminophen Genitourinary: Crystalluria, hematuria
doses as low as 2 g, particularly when taking acetami- Hematologic and oncologic: Agranulocytosis, aplastic
nophen for >1 week (Antlitz, 1968; Boeijinga, 1982; anemia, leukopenia, thrombocytopenia, thrombocyto-
Gebauer, 2003; Hylek, 1998; Rubin, 1984). In addition, penic purpura
72
ACYCLOVIR (SYSTEMIC)
Hepatic: Abnormal hepatic function tests, cholestatic cardiopulmonary arrest, diabetes mellitus, dizziness,
jaundice, fulminant hepatic necrosis, hepatic insuffi- dyspnea, dysuria, first degree atrioventricular block,
ciency hypersensitivity reaction (immediate), nausea, osteo-
Hypersensitivity: Anaphylaxis arthritis, palpitations, pruritus, skin rash, tachycardia,
Local: Pain at injection site urinary retention, urticaria, xerostomia
Ophthalmic: Myopia Mechanism of Action Competitively and reversibly
Otic: Auditory disturbance, tinnitus inhibits the action of acetylcholine at type 3 muscarinic
Renal: Polyuria, renal failure (M3) receptors in bronchial smooth muscle causing
Miscellaneous: Fever bronchodilation
Mechanism of Action Reversible inhibition of the Pharmacodynamics/Kinetics
enzyme carbonic anhydrase resulting in reduction of Half-life Elimination 5 to 8 hours (following inhala-
hydrogen ion secretion at renal tubule and an increased tion)
renal excretion of sodium, potassium, bicarbonate, and Time to Peak Plasma: Within 10 minutes (steady
water. Decreases production of aqueous humor and state, following inhalation)
inhibits carbonic anhydrase in central nervous system Pregnancy Considerations Adverse events have
to retard abnormal and excessive discharge from CNS been observed in animal reproduction studies.
neurons.
Onset of Action Acyclovir (Systemic) (ay SYE kloe veer)
Capsule (extended release): 2 hours; Tablet (immedi-
Related Information
ate release): 1 to 1.5 hours; IV: 2 to 10 minutes
Systemic Viral Diseases on page 1496
Peak effect: Capsule (extended release): 8 to 18
hours; IV: 15 minutes; Tablet: 2 to 4 hours ValACYclovir on page 1316
Duration of Action Inhibition of aqueous humor Viral Infections on page 1540
secretion: Capsule (extended release): 18 to 24 hours; Related Sample Prescriptions
IV: 4 to 5 hours; Tablet: 8 to 12 hours Viral Infections - Sample Prescriptions on page 44
Half-life Elimination 2.4 to 5.8 hours Brand Names: US Zovirax
Time to Peak Plasma: Capsule (extended release): 3 Brand Names: Canada Zovirax
to 6 hours; Tablet: 1 to 4 hours; IV: 15 minutes Generic Availability (US) Yes
Pregnancy Considerations Pharmacologic Category Antiviral Agent
Adverse events have been observed in animal repro- Dental Use Treatment of initial and prophylaxis of
duction studies. Limited data is available following the recurrent mucosal and cutaneous herpes simplex
use of acetazolamide in pregnant women for the treat- (HSV-1 and HSV-2) infections in immunocompromised
ment of idiopathic intracranial hypertension (Falardeau patients
2013; Kesler 2013). Use
Oral:
Pregnant women exposed to acetazolamide during
Herpes simplex virus (HSV), genital: Treatment of
pregnancy for the treatment of seizure disorders are
initial episodes and the management of recurrent
encouraged to enroll themselves into the AED Preg-
episodes of genital herpes.
nancy Registry by calling 1-888-233-2334. Additional
Herpes zoster (shingles): Acute treatment of herpes
information is available at aedpregnancyregistry.org
zoster (shingles).
Varicella (chickenpox): Treatment of varicella (chick-
Aclidinium (a kli DIN ee um) enpox).
Injection:
Related Information Herpes simplex encephalitis: Treatment of herpes
Respiratory Diseases on page 1467 simplex encephalitis.
Brand Names: US Tudorza Pressair Herpes simplex virus (HSV), genital infection (severe):
Brand Names: Canada Tudorza Genuair Treatment of severe initial clinical episodes of genital
Pharmacologic Category Anticholinergic Agent; Anti- herpes in immunocompetent patients.
cholinergic Agent, Long-Acting Herpes simplex virus (HSV), mucocutaneous infection
Use Chronic obstructive pulmonary disease: Main- in immunocompromised patients: Treatment of initial
tenance treatment of patients with chronic obstructive and recurrent mucosal and cutaneous herpes sim-
pulmonary disease (COPD). plex (HSV-1 and HSV-2) in immunocompromised
Local Anesthetic/Vasoconstrictor Precautions patients.
No information available to require special precautions Herpes simplex virus (HSV), neonatal: Treatment of
Effects on Dental Treatment Key adverse event(s) neonatal herpes infections.
related to dental treatment: Cough, nasopharyngitis, Herpes zoster (shingles) in immunocompromised
rhinitis, sinusitis, and toothache have been reported. patients: Treatment of herpes zoster (shingles) in
Effects on Bleeding No information available to immunocompromised patients.
require special precautions Local Anesthetic/Vasoconstrictor Precautions
Adverse Reactions No information available to require special precautions
1% to 10%: Effects on Dental Treatment No significant effects or
Central nervous system: Headache (7%), falling (1%) complications reported (see Dental Health Professional
Gastrointestinal: Diarrhea (3%), toothache (1%), vom- Considerations)
iting (1%) Effects on Bleeding No information available to
Respiratory: Nasopharyngitis (6%), cough (3%), rhini- require special precautions
tis (2%), sinusitis (2%) Adverse Reactions As reported with IV administration,
<1%, postmarketing, and/or case reports: Anaphylaxis, unless otherwise noted.
angioedema (including swelling of the lips, tongue, or >10%:
throat), bronchospasm, cardiac failure, Central nervous system: Malaise (oral: 12%)
73
Hematologic & oncologic: Decrease in absolute neu- Herpes simplex virus (HSV), central nervous sys-
trophil count (neonates: 3% to 16%), decreased tem infection (encephalitis or meningitis): IV:
hemoglobin (neonates: 13%) 10 mg/kg/dose every 8 hours. Duration for encepha-
1% to 10%: litis is 14 to 21 days and for meningitis is 10 to 14
Central nervous system: Headache (oral: ≤2%) days; treatment of encephalitis requires IV therapy
Dermatologic: Pruritus (2%), skin rash (2%), urtica- while treatment of meningitis may include step-down
ria (2%) oral antiviral therapy. Note: Empiric HSV therapy
Gastrointestinal: Nausea (oral and IV: ≤7%), vomiting should be initiated in all patients with suspected
(oral and IV: ≤7%), diarrhea (oral: 2% to 3%; encephalitis (IDSA [Tunkel 2008]; Tunkel 2018; Wilck
IV: <1%) 2013).
Hematologic & oncologic: Thrombocytopenia (neo- Herpes simplex virus, mucocutaneous infection:
nates: 5% to 10%; children, adolescents, and adults: Esophagitis (off-label use):
<1%) Immunocompetent patients: Oral: 400 mg 3 times
Hepatic: Increased serum bilirubin (neonates, grades daily or 200 mg 5 times daily for 7 to 10 days
3/4: 4%), increased serum transaminases (1% (Bonis 2018; Canalejo Castrillero 2010)
to 2%) Immunocompromised patients: Oral: 400 mg 5
Local: Inflammation at injection site (≤9%), injection times daily for 14 to 21 days (Bonis 2018)
site phlebitis (≤9%) Patients with severe odynophagia or dysphagia: IV:
Renal: Increased blood urea nitrogen (5% to 10%), 5 mg/kg/dose every 8 hours; patients who rapidly
increased serum creatinine (5% to 10%) improve can be switched to an oral antiviral to
<1%, postmarketing, and/or case reports (all routes): complete a total of 7 to 14 days of therapy (Bonis
Abdominal pain, aggressive behavior, agitation, alo- 2018; Canalejo Castrillero 2010).
pecia, anaphylaxis, anemia, angioedema, anorexia, Genital:
ataxia, coma, confusion, delirium, disseminated intra- Immunocompetent patients:
vascular coagulation, dizziness, drowsiness, dysarth- Treatment, initial episode:
ria, encephalopathy, erythema multiforme, fatigue, Oral: 400 mg 3 times daily or 200 mg 5 times
fever, gastrointestinal distress, hallucination, hematu- daily for 7 to 10 days; extend duration if lesions
ria, hemolysis, hepatitis, hyperbilirubinemia, hyper- have not healed completely after 10 days (CDC
sensitivity angiitis, hypotension, impaired [Workowski 2015]).
consciousness, increased liver enzymes, jaundice, IV (for severe disease): 5 to 10 mg/kg/dose
leukocytosis, leukopenia, lymphadenopathy, myalgia, every 8 hours for 2 to 7 days, followed by oral
neutropenia, neutrophilia, obtundation, pain, paresthe- acyclovir (or similar antiviral) to complete ≥10
sia, peripheral edema, psychosis, renal failure syn- days of therapy total (CDC [Workowski 2015])
drome, renal pain, seizure, skin photosensitivity, Treatment, recurrent episode: Oral: 400 mg 3
Stevens-Johnson syndrome, thrombocythemia, toxic times daily for 5 days or 800 mg twice daily for
epidermal necrolysis, tremor, visual disturbance 5 days or 800 mg 3 times daily for 2 days. Note:
Dental Usual Dosage Treatment is most effective when initiated during
Mucocutaneous HSV: Adults: the prodrome or within 1 day of lesion onset
Immunocompromised (off-label use): Oral: 400 mg 5 (CDC [Workowski 2015]).
times a day for 7-14 days Suppressive therapy (eg, for severe and/or fre-
Chronic suppression of recurrent herpes labialis (cold quent recurrences): Oral: 400 mg twice daily.
sores) (off-label use): Immunocompetent adults: oral: Note: Reassess need periodically (eg, annually)
400 mg twice daily (Rooney 1993) (CDC [Workowski 2015]).
Dosing Immunocompromised patients (including HIV-
Adult infected):
Bell palsy, new onset (adjunctive therapy) (alter- Treatment, initial or recurrent episode:
native agent) (off-label use): Oral: 400 mg 5 times Oral: 400 mg 3 times daily for 5 to 10 days;
daily for 10 days in combination with corticosteroids; extend treatment duration if lesions have not
begin within 3 days of symptom onset. Note: Anti- healed completely after 10 days (CDC [Work-
viral therapy alone is not recommended (AAN [Gron- owski 2015]; HHS [OI adult 2018]; Wilck 2013).
seth 2012]; AAO-HNSF [Baugh 2013]; Ronthal IV (for severe disease): 5 to 10 mg/kg/dose
2018); some experts only recommend addition of every 8 hours for 2 to 7 days, followed by oral
an antiviral to steroid therapy in patients with severe acyclovir (or similar antiviral) once lesions
Bell palsy (de Almeida 2014). begin to regress and continue for ≥10 days of
Cytomegalovirus (CMV), prevention in low-risk therapy and until complete resolution (CDC
allogeneic hematopoietic cell transplant (HCT) [Workowski 2015]; HHS [OI adult 2018]).
recipients (alternative agent) (off-label use): Suppressive therapy (eg, for severe and/or fre-
Note: Begin at engraftment and continue to day quent recurrences): Oral: 400 to 800 mg 2 to 3
100; requires close monitoring for CMV reactivation times daily. Note: Reassess need periodically
(due to weak activity); not for use in patients at high (eg, annually) (CDC [Workowski 2015]; HHS
risk for CMV disease (ASBMT/IDSA [Tomblyn [OI adult 2018]).
2009]): Pregnant females:
IV: 500 mg/m2/dose every 8 hours for up to 4 weeks Treatment, initial episode: Oral: 400 mg 3 times
or until hospital discharge, followed by oral therapy daily for 7 to 10 days; extend treatment duration
(ASBMT/IDSA [Tomblyn 2009]; Boeckh 2009; if lesion has not healed completely after 10 days
Ljungman 2002) (ACOG 2007).
Oral: Following initial IV therapy: 800 mg 4 times Treatment, recurrent episode (symptomatic): Oral:
daily (ASBMT/IDSA [Tomblyn 2009]; Boeckh 400 mg 3 times daily or 800 mg twice daily for 5
2009; Ljungman 2002) days (ACOG 2007). Note: Some experts reserve
74
treatment of recurrent episodes for patients with formation of new lesions has ceased and signs/
severe and/or frequent symptoms (Riley 2018). symptoms of visceral infection are improving,
Suppressive therapy, for patients with a genital switch to an oral antiviral to complete a total of
HSV lesion anytime during pregnancy: Oral: 10 to 14 days of therapy (HHS [OI adult 2018]).
400 mg 3 times daily, beginning at 36 weeks' Herpes zoster ophthalmicus (off-label use): Immu-
gestation and continued until the onset of labor nocompromised patients or patients who require
(ACOG 2007; CDC [Workowski 2015]; Riley hospitalization for sight-threatening disease: IV:
2018). Note: Some experts offer suppressive 10 mg/kg/dose every 8 hours for 7 days (Albrecht
therapy earlier than 36 weeks' gestation for 2018a)
women who have a first-episode lesion during Varicella (chickenpox), treatment: Ideally initiate
the third trimester (Riley 2018).
therapy within 24 hours of symptom onset, but may
Orolabial: Note: Initiate therapy at earliest
start later if the patient still has active lesions:
symptom.
Immunocompetent patients with uncomplicated
Immunocompetent and immunocompromised
infection: Oral: 800 mg 5 times daily for ≥5 to 7
patients (including HIV-infected):
Treatment, initial orrecurrent episode: days and until all lesions have crusted (Albrecht
Oral: 400 mg 3 times daily for 5 to 10 days and 2018b; Arvin 1996; Wallace 1992)
until complete lesion resolution in immunocom- Immunocompromised patients (including HIV-
promised patients (HHS [OI adult 2018]; Klein infected):
2018; Wilck 2013) Severe or complicated infection: IV: 10 mg/kg/dose
IV (for severe disease in immunocompromised every 8 hours for 7 to 10 days (HHS [OI adult
patients): 5 mg/kg/dose every 8 hours; switch 2018]; Pergam 2013); some experts recommend
to oral acyclovir (or similar antiviral) once up to 15 mg/kg/dose every 8 hours (HHS [OI adult
lesions begin to regress and continue until 2018]). May switch to oral antiviral after deferves-
complete resolution (HHS [OI adult 2018]; cence if no evidence of visceral involvement;
Wilck 2013). continue until all lesions have crusted (HHS [OI
Suppressive therapy (eg, for severe and/or fre- adult 2018]; Pergam 2013).
quent recurrences): Oral: 400 mg twice daily Uncomplicated infection: Oral: 800 mg 5 times daily
(HHS [OI adult 2018]; Rooney 1993). Note: for 5 to 7 days (HHS [OI adult 2018]); some
Reassess need periodically (eg, annually) experts recommend a minimum duration of 7
(HHS [adult OI 2018]). days, extending the course until all lesions have
Herpes simplex virus, prevention in immunocom- crusted (Albrecht 2018b; Pergam 2013).
promised patients (off-label use): Varicella zoster virus (VZV), acute retinal necrosis
Seropositive HCT recipients (allogeneic or autolo- (off-label use): IV: 10 to 15 mg/kg/dose every 8
gous) or seropositive patients undergoing leukemia
hours for 10 to 14 days, followed by ~6 weeks of
induction chemotherapy:
valacyclovir (Albrecht 2018a; HHS [OI adult 2018]);
IV: 250 mg/m2/dose every 12 hours (ASBMT/IDSA
in HIV-infected patients, intravitreal ganciclovir
[Tomblyn 2009])
should be added (HHS [OI adult 2018]).
Oral: 400 to 800 mg twice daily (ASBMT/IDSA
[Tomblyn 2009]) Varicella zoster virus, encephalitis (off-label use):
Note: Initiate with the chemotherapeutic or condi- IV: 10 to 15 mg/kg/dose every 8 hours for 10 to 14
tioning regimen and continue until recovery of days (IDSA [Tunkel 2008])
WBC count and resolution of mucositis; duration Varicella zoster virus, prevention in immunocom-
may be extended in patients with frequent recur- promised patients (off-label use):
rences or graft-vs-host disease (ASBMT/IDSA Seropositive HCT recipients (allogeneic and autolo-
[Tomblyn 2009]; ASCO/IDSA [Taplitz 2018]). gous): Oral: 800 mg twice daily (ASBMT/IDSA
Solid organ transplant recipients (HSV-seropositive [Tomblyn 2009]; Boeckh 2006). Note: Initiate with
patients who do not require CMV prophylaxis): the chemotherapeutic or conditioning regimen and
Oral: 400 to 800 mg twice daily for ≥1 month (Wilck continue for 1 year; may extend duration in patients
2013); some experts recommend continuing for 3 to requiring ongoing immunosuppression (some
6 months after transplantation and during periods of experts continue prophylaxis in these patients until
lymphodepletion associated with treatment of rejec- 6 months after discontinuation of all systemic
tion (Fishman 2018). immunosuppression) (ASBMT/IDSA [Tomb-
Herpes zoster (shingles), treatment: lyn 2009]).
Immunocompetent patients: Oral: 800 mg 5 times Solid organ transplant recipients (VZV-seropositive
daily for 7 days (Pott Junior 2018; Shafran 2004). patients who do not require CMV prophylaxis):
Initiate at earliest sign or symptom; treatment is Oral: 200 mg 3 to 5 times daily for 3 to 6 months
most effective when initiated ≤72 hours after rash after transplantation and during periods of lympho-
onset, but may initiate treatment >72 hours after
depletion associated with treatment of rejection
rash onset if new lesions are continuing to appear
(Fishman 2018; Pergam 2013)
(Cohen 1999).
Immunocompromised patients (including HIV- Geriatric Refer to adult dosing; use with caution.
infected): Renal Impairment: Adult Note: Monitor closely for
Acute localized dermatomal: Oral: 800 mg 5 times neurotoxicity (Chowdhury 2016)
daily for 7 to 10 days; consider longer duration if Oral:
lesions resolve slowly (HHS [OI adult 2018]; Per- CrCl >25 mL/minute/1.73 m2: No dosage adjustment
gam 2013). necessary.
Extensive cutaneous lesions or visceral involve- CrCl 10 to 25 mL/minute/1.73 m2: If the usual rec-
ment: IV: 10 to 15 mg/kg/dose every 8 hours ommended dose is 800 mg 5 times daily: Adminis-
(HHS [OI adult 2018]; Pergam 2013). When ter 800 mg every 8 hours
75
CrCl <10 mL/minute/1.73 m2: CVVHD/CVVHDF: 5 to 10 mg/kg/dose every 12 to

If the usual recommended dose is 200 mg 5 times 24 hours
daily or 400 mg every 12 hours: Administer Note: The higher end of dosage range is recom-
200 mg every 12 hours mended for viral meningoencephalitis and vari-
If the usual recommended dose is 800 mg 5 times cella-zoster virus infections.
daily: Administer 200 mg every 12 hours (IDSA Hepatic Impairment: Adult Oral, IV: There are no
[Gupta 2005]) dosage adjustments provided in the manufacturer's
Intermittent hemodialysis (IHD): Dialyzable (60% labeling; use caution in patients with severe impair-
reduction following a 6-hour session): ment.
Note: Dosing dependent on the assumption of 3- Obesity: Adult IV: In obese patients, acyclovir IV has
times-weekly, complete IHD sessions. Administer been dosed using ideal body weight (IBW) to avoid
after hemodialysis on dialysis days. overdosing and subsequent toxicity. However, in a
If the usual recommended dose is 200 mg 5 times pharmacokinetic study using a single acyclovir IV
daily or 400 mg every 12 hours: Administer dose, morbidly obese patients (BMI ≥ 40 kg/m2) dosed
200 mg every 12 hours using IBW had lower systemic exposures compared to
If the usual recommended dose is 800 mg 5 times normal weight subjects dosed using actual body
daily: Administer a loading dose of 400 mg and a weight (exposure based on AUC, Cmax, and T >IC50
maintenance dose of 200 mg twice daily plus a [time the drug concentration remains above the 50%
single 400 mg dose after each dialysis (Almond inhibitory concentration]) (Turner 2016). Therefore, to
1995). Note: Dose based on pharmacokinetic avoid potentially underdosing obese patients who are
data and computer modeling. severely ill (eg, HSV encephalitis), some clinicians use
Continuous ambulatory peritoneal dialysis (CAPD): adjusted body weight (AjBW) to determine the IV dose
600 to 800 mg daily (Stathoulopoulou 1996) (AjBW=IBW + [0.4 x (actual body weight-IBW)]) (Wong
IV: 2017), although this approach has not been evaluated
If the usual recommended dose is 10 mg/kg/dose in clinical studies.
every 8 hours: Pediatric Note: Obese patients should be dosed using
CrCl >50 mL/minute/1.73 m2: No dosage adjust- ideal body weight. Parenteral IV doses >15 mg/kg/
ment necessary. dose or 500 mg/m 2 may be associated with an
CrCl 25 to 50 mL/minute/1.73 m2: 10 mg/kg/dose increased risk of nephrotoxicity; close monitoring of
every 12 hours renal function is recommended (Rao 2015).
CrCl 10 to <25 mL/minute/1.73 m2: 10 mg/kg/dose CMV prophylaxis: Low-risk allogeneic hemato-
every 24 hours poietic stem cell transplant (HSCT) in seropositive
CrCl <10 mL/minute/1.73 m2: 5 mg/kg/dose every recipient. Note: Begin at engraftment and continue
24 hours to day 100; requires close monitoring for CMV
If the usual recommended dose is 5 mg/kg/dose reactivation (due to weak activity); not for use in
patients at high risk for CMV disease (Tomblyn
every 8 hours:
2009):
CrCl >50 mL/minute/1.73 m2: No dosage adjust-
Oral:
ment necessary.
Infants, Children, and Adolescents <40 kg:
CrCl 25 to 50 mL/minute/1.73 m2: 5 mg/kg/dose
600 mg/m2/dose 4 times daily; maximum dose:
every 12 hours
800 mg/dose
CrCl 10 to <25 mL/minute/1.73 m2: 5 mg/kg/dose
Children and Adolescents ≥40 kg: 800 mg 4 times
every 24 hours
daily
CrCl <10 mL/minute/1.73 m2: 2.5 mg/kg/dose every
IV: Infants, Children, and Adolescents: 500 mg/m2/
24 hours dose every 8 hours
Intermittent hemodialysis (IHD): Dialyzable (60% Herpes zoster, acute retinal necrosis, treatment
reduction following a 6-hour session): 2.5 to (HIV-exposed/-positive):
5 mg/kg/dose every 24 hours (Heintz 2009). Note: Initial treatment: IV: Note: Follow up IV therapy with
Use higher end of dosing range for viral menin- oral acyclovir or valacyclovir maintenance
goencephalitis and varicella-zoster infections. Dos- therapy.
ing dependent on the assumption of 3-times- Infants: 10 to 15 mg/kg/dose every 8 hours for 10
weekly, complete IHD sessions. Administer after to 14 days (DHHS [pediatric] 2013)
hemodialysis on dialysis days Children: 10 to 15 mg/kg/dose every 8 hours for
Peritoneal dialysis (PD): 2.5 to 5 mg/kg/dose every 10 to 14 days (DHHS [pediatric] 2013)
24 hours; no supplemental dose needed (Aronoff Adolescents: 10 to 15 mg/kg/dose every 8 hours
2007). Note: Use higher end of dosing range for for 10 to 14 days (DHHS [adult] 2015)
viral meningoencephalitis and varicella-zoster Maintenance treatment; begin after 10- to 14-day
infections. course of IV acyclovir: Oral: Infants and Children:
Continuous renal replacement therapy (CRRT) 20 mg/kg/dose 4 times daily for 4 to 6 weeks
(Heintz 2009): Drug clearance is highly dependent (DHHS [pediatric] 2013)
on the method of renal replacement, filter type, and Herpes zoster (shingles), treatment:
flow rate. Appropriate dosing requires close mon- Immunocompetent host:
itoring of pharmacologic response, signs of adverse Ambulatory therapy: Oral: Children ≥12 years and
reactions due to drug accumulation, as well as drug Adolescents: 800 mg every 4 hours (5 doses per
concentrations in relation to target trough (if appro- day) for 5 to 7 days (Red Book [AAP 2015])
priate). The following are general recommendations Hospitalized patient: IV:
only (based on dialysate flow/ultrafiltration rates of Infants: 10 mg/kg/dose every 8 hours for 7 to 10
1 to 2 L/hour and minimal residual renal function) days (Red Book [AAP 2015])
and should not supersede clinical judgment: Children and Adolescents: 500 mg/m 2 /dose
CVVH: 5 to 10 mg/kg/dose every 24 hours every 8 hours for 7 to 10 days; some experts
76
recommend 10 mg/kg/dose every 8 hours (Red 70%; no untoward effects were reported during
Book [AAP 2015]) the study duration.
Immunocompromised host (non-HIV-exposed/-pos- Initial dosing: 400 mg twice daily; approximate
itive): IV: Infants, Children, and Adolescents: dose: 1,200 to 1,600 mg/m2/dose twice daily
10 mg/kg/dose every 8 hours for 7 to 10 days Maintenance dosing: Note: Approximate doses
(Red Book [AAP 2015]) for patients born at term:
HIV-exposed/-positive: Infants 1 to <5 months: 400 mg twice daily
Mild, uncomplicated disease and no or moderate Infants 5 to <9 months: 600 mg twice daily
immune suppression: Oral: Infants and Children 9 to <15 months: 800 mg
Infants and Children: 20 mg/kg/dose 4 times twice daily
daily for 7 to 10 days; maximum dose: Children 15 to 24 months: 1,000 mg twice daily
800 mg/dose; consider longer course if resolu- Note: In the trial, serum acyclovir concentra-
tion of lesions is slow (DHHS [pediatric] 2013) tions were evaluated to assess adequacy of
Adolescents: 800 mg 5 times daily for 7 to 10 dosing to maintain serum concentrations
days, longer if lesions resolve slowly (DHHS above the target of 2 to 3 mcg/mL. Samples
[adult] 2015) were collected 1 hour after a witnessed dose;
Severe immune suppression or complicated dis- if the acyclovir serum concentration
ease; trigeminal nerve involvement, extensive approached or was below the target, the dose
multidermatomal zoster or extensive cutaneous was increased to the next greater 200 mg
lesions or visceral involvement: IV: increment. Maximum dose: 1,200 mg. Serum
Infants: 10 mg/kg/dose every 8 hours until reso- concentrations were evaluated every 3
lution of cutaneous lesions and visceral dis- months; in order to limit the phlebotomy
ease clearly begins, then convert to oral losses, follow-up serum concentrations were
therapy to complete a 10- to 14-day total not evaluated outside of routine monitoring.
course of therapy (DHHS [pediatric] 2013) HSV encephalitis, treatment:
Children: 10 mg/kg/dose or 500 mg/m2/dose Infants and Children 3 months to <12 years:
every 8 hours until resolution of cutaneous Non-HIV-exposed/-positive: IV: 10 to 15 mg/kg/
lesions and visceral disease clearly begins, dose every 8 hours for 14 to 21 days. Note:
then convert to oral therapy to complete a 10- Due to increased risk of neurotoxicity and neph-
to 14-day total course of therapy (DHHS [pedia-
rotoxicity, higher doses (20 mg/kg) are not rec-
tric] 2013)
ommended (Red Book [AAP 2015]).
Adolescents: 10 to 15 mg/kg/dose every 8 hours
HIV-exposed/-positive: IV: 10 mg/kg/dose every 8
until clinical improvement is evident, then con-
hours for 21 days; higher doses (up to 20 mg/kg)
vert to oral therapy to complete a 10- to 14-day
may be necessary (DHHS [pediatric] 2013)
total course of therapy (DHHS [adult] 2015)
Children ≥12 years and Adolescents (independent
HSV neonatal infection, treatment and suppres-
of HIV status): IV: 10 mg/kg/dose every 8 hours
sive therapy in very young infants (independent
for 14 to 21 days (Red Book [AAP 2015)]
of HIV status):
HSV genital infection:
Treatment (disseminated, CNS, or skin, eye, or
First infection, mild to moderate:
mouth disease): Infants 1 to 3 months: IV:
20 mg/kg/dose every 8 hours; treatment duration: Non-HIV-exposed/-positive:
For cutaneous and mucous membrane infections Children <12 years: Oral: 40 to 80 mg/kg/day
(skin, eye, or mouth): 14 days; for CNS or dis- divided in 3 to 4 doses per day for 5 to 10 days;
seminated infection: 21 days (AAP [Kimberlin maximum daily dose: 1,200 mg/day (Bradley
2013]; Bradley 2015; CDC [Workowski 2015]; 2015; Red Book [AAP 2015])
DHHS [pediatric] 2013; Red Book [AAP 2015]) Children and Adolescents ≥12 years: Oral:
Chronic suppressive therapy following any neonatal 200 mg every 4 hours while awake (5 times
HSV infection: daily) or 400 mg 3 times daily for 7 to 10 days;
AAP Recommendation (low dose, 6-month treatment can be extended beyond 10 days if
course): Infants: Oral: 300 mg/m2/dose every 8 healing is not complete (CDC [Workowski
hours for 6 months; begin after completion of a 2015]; Red Book [AAP 2015])
14- to 21-day-course of IV therapy dependent HIV-exposed/-positive:
upon type of infection (AAP [Kimberlin 2013]; Children: Oral: 20 mg/kg/dose 3 times daily for 7
Kimberlin 2011; Red Book [AAP 2015]) to 10 days; maximum dose: 400 mg/dose
Alternate dosing (high dose, 2-year course) in (DHHS [pediatric] 2013)
infants with disseminated or CNS infection (Tif- Adolescents: Oral: 400 mg 3 times daily for 5 to
fany 2005): Limited data available: Infants and 14 days (DHHS [adult] 2015)
Children <3 years: Oral: Begin after completion First infection, severe (independent of HIV status):
of a 21-day course of IV therapy; dosing based IV: Children and Adolescents ≥12 years: 5 mg/kg/
on a prospective trial of 16 consecutive neonates dose every 8 hours for 5 to 7 days or 5 to
(GA: Premature: n=4; term=12; age at treat- 10 mg/kg/dose every 8 hours for 2 to 7 days,
ment: Neonate: n=14; PNA >30 days: n=1) followed with oral therapy to complete at least
following disseminated or CNS infection; phar- 10 days of therapy (CDC [Workowski 2015]; Red
macokinetic data were used to determine dosing Book [AAP 2015])
regimen to maintain serum acyclovir concentra- Recurrent infection:
tion above target of 2 to 3 mcg/mL; treatment Children <12 years (independent of HIV status):
was continued for 2 years in 14 of 16 patients; Oral: 20 mg/kg/dose 3 times daily for 5 days;
results showed normal neurodevelopmental out- maximum dose: 400 mg/dose (Bradley 2015;
comes in 69% and normal motor development in DHHS [pediatric] 2013)
77
Children and Adolescents ≥12 years: Suppression, chronic: Limited data available; no
Non-HIV-exposed/-positive: Oral: 200 mg every pediatric data; some experts recommend oral
4 hours while awake (5 times daily) for 5 days, 20 mg/kg/dose 2 to 3 times daily for 6 to 12
or 400 mg 3 times daily for 5 days, or 800 mg months, then reevaluate need; maximum dose:
twice daily for 5 days or 800 mg 3 times daily 400 mg/dose (Bradley 2015)
for 2 days (CDC [Workowski 2015]; Red Book Immunocompromised host:
[AAP 2015]) Treatment:
HIV-exposed/-positive: Adolescents: Oral: IV:
400 mg 3 times daily for 5 to 14 days (DHHS Infants and Children: 10 mg/kg/dose every 8
[adult] 2015) hours for 7 to 14 days (Red Book [AAP 2015])
Suppression, chronic: Adolescents: 5 to 10 mg/kg/dose every 8
Non-HIV-exposed/-positive: hours; change to oral therapy after lesions
Children <12 years: Limited data available: Oral: begin to regress (DHHS [adult] 2015; Red
20 mg/kg/dose twice daily; maximum dose: Book [AAP 2015])
400 mg/dose (Bradley 2015) Oral: Children ≥2 years and Adolescents:
Children and Adolescents ≥12 years: Oral: 1,000 mg/day in 3 to 5 divided doses for 7 to
400 mg twice daily; reassess therapy after 12 14 days; some suggest the maximum daily
months (CDC [Workowski 2015]; Red Book dose should not exceed 80 mg/kg/day (Red
[AAP 2015]) Book 2009; Red Book [AAP 2015])
HIV-exposed/-positive: Suppression, chronic (cutaneous, ocular) epi-
Infants and Children: Oral: 20 mg/kg/dose twice sodes:
daily; maximum dose: 800 mg/dose (DHHS Infants and Children (HIV-exposed/-positive):
[pediatric] 2013) Oral: 20 mg/kg/dose twice daily; maximum
Adolescents: Oral: 400 mg twice daily (DHHS dose: 800 mg/dose; reassess after 12 months
[adult] 2015) (DHHS [pediatric] 2013)
HSV gingivostomatitis: Children 12 years of age (non-HIV-exposed/-
Non-HIV-exposed/-positive: Primary infection: positive): Prevention of ocular episodes: Oral:
AAP recommendations: Children and Adoles- 400 mg twice daily; reassess at 12 months
cents: Oral: 20 mg/kg/dose 4 times daily for 5 (Red Book [AAP 2015])
to 7 days; usual maximum dose: 200 mg/dose, Adolescents (independent of HIV status): Oral:
others have reported higher (400 mg/dose) 400 mg twice daily; reassess at 12 months
(Bradley 2015; Cernik 2008; Red Book (DHHS [adult] 2015; Red Book [AAP 2015])
[AAP 2015]) HSV progressive or disseminated infection, treat-
Alternate dosing: Infants ≥10 months, Children, ment (immunocompromised host):
and Adolescents: Oral: 15 mg/kg/dose five times Non-HIV-exposed/-positive: Infants, Children, and
daily for 7 days; maximum dose: 200 mg/dose Adolescents: IV: 10 mg/kg/dose every 8 hours
(Amir 1997; Balfour 1999); dosing based on a for 7 to 14 days (Red Book [AAP 2015])
placebo controlled trial in children 1 to 6 years of HIV-exposed/-positive: Infants, Children, and Ado-
age (n=72, treatment group: n=31); results lescents: IV: 10 mg/kg/dose every 8 hours for 21
showed when treatment started within 72 hours days; higher doses (up to 20 mg/kg/dose) may be
of symptom onset a shorter duration of symp- used in children <12 years of age (DHHS [pedia-
toms and viral shedding was observed tric] 2013; Red Book [AAP 2015])
(Amir 1997) HSV, acute retinal necrosis, treatment (HIV-
HIV-exposed/-positive (DHHS [pediatric] 2013): exposed/-positive): Children (DHHS [pediatric]
Mild, symptomatic: Oral: Infants and Children: 2013):
20 mg/kg/dose 4 times daily for 7 to 10 days; Initial treatment: IV: 10 to 15 mg/kg/dose every 8
maximum dose: 400 mg/dose hours for 10 to 14 days. Note: Follow up IV
Moderate to severe, symptomatic: IV: Infants and therapy with oral acyclovir or valacyclovir main-
Children: 5 to 10 mg/kg/dose every 8 hours; tenance therapy.
switch to oral therapy once lesions begin to Maintenance treatment: Begin after 10- to 14-day
regress course of IV acyclovir: Oral: 20 mg/kg/dose 4
HSV, herpes labialis (cold sore) (HIV-exposed/- times daily for 4 to 6 weeks
positive): Treatment: HSV prophylaxis; immunocompromised hosts,
Infants and Children: Oral: 20 mg/kg/dose 4 times seropositive:
daily for 5 days; maximum dose: 400 mg/dose Hematopoietic stem cell transplant (HSCT) in sero-
(DHHS [pediatric] 2013) positive recipient (Tomblyn 2009):
Adolescents: Oral: 400 mg 3 times daily for 5 to 10 Prevention of early reactivation: Note: Begin at
days (DHHS [adult] 2015) conditioning and continue until engraftment or
HSV, herpes labialis (cold sore) recurrent, resolution of mucositis; whichever is longer
chronic suppressive therapy: Immunocompetent (~30 days post-HSCT)
Children and Adolescents: Oral: 10 mg/kg/dose 3 Infants, Children, and Adolescents <40 kg:
times daily; maximum daily dose: 1,000 mg/day; IV: 250 mg/m2/dose every 8 hours or 125 mg/
reevaluate after 12 months (Red Book [AAP 2015]) m2/dose every 6 hours; maximum daily dose:
HSV mucocutaneous infection: 80 mg/kg/day
Immunocompetent host: Infants, Children, and Oral: 60 to 90 mg/kg/day in 2 to 3 divided
Adolescents: doses; maximum dose: 800 mg/dose twice
Treatment (Bradley 2015): daily
IV: 5 mg/kg/dose every 8 hours Children and Adolescents ≥40 kg:
Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; IV: 250 mg/m2/dose every 12 hours
maximum dose: 800 mg/dose Oral: 400 to 800 mg twice daily
78
Prevention of late reactivation: Note: Treatment Adolescents: 800 mg 5 times daily for 5 to 7
during first year after HSCT. days (DHHS [adult] 2015)
Infants, Children, and Adolescents <40 kg: Oral: Severe, complicated disease or severe immune
60 to 90 mg/kg/day in 2 to 3 divided doses; suppression: IV:
maximum daily dose: 800 mg twice daily Infants: 10 mg/kg/dose every 8 hours for 7 to 10
Children and Adolescents ≥40 kg: Oral: 800 mg days and until no new lesions for 48 hours
twice daily (DHHS [pediatric] 2013)
Other immunocompromised hosts who are HSV Children: 10 mg/kg/dose or 500 mg/m2/dose
seropositive: every 8 hours for 7 to 10 days or until no new
IV: Infants, Children, and Adolescents: 5 mg/kg/ lesions for 48 hours (DHHS [pediatric] 2013)
dose every 8 hours during period of risk (Red Adolescents: 10 to 15 mg/kg/dose every 8 hours
Book [AAP 2015]) for 7 to 10 days; may convert to oral therapy
Oral: Children ≥2 years and Adolescents: 200 mg after defervescence and if no evidence of vis-
every 4 hours while awake (5 doses daily) or ceral involvement is evident (DHHS
200 mg every 8 hours; administer during periods [adult] 2015)
of risk (Red Book [AAP 2015]) Renal Impairment: Pediatric
Varicella (chickenpox) or Herpes zoster (shin- Monitor closely for neurotoxicity (Chowdhury 2016).
gles), prophylaxis Infants, Children and Adolescents: IV:
Hematopoietic stem cell transplant (HSCT): Pro- CrCl >50 mL/minute/1.73 m2: No dosage adjust-
phylaxis of disease reactivation: Note: Continue ment necessary
therapy for 1 year after HSCT (Tomblyn 2009): CrCl 25 to 50 mL/minute/1.73 m2: Administer the
Infants, Children, and Adolescents <40 kg: Oral: usual recommended dose every 12 hours
60 to 80 mg/kg/day in 2 to 3 divided doses CrCl 10 to <25 mL/minute/1.73 m2: Administer the
Children and Adolescents ≥40 kg: Oral: 800 mg usual recommended dose every 24 hours
twice daily CrCl <10 mL/minute/1.73 m2: Administer 50% of
HIV-exposed/-positive: Limited data available: the usual recommended dose every 24 hours (eg,
Note: Consider use if >96 hours postexposure if the usual recommended dose is 10 mg/kg/dose
or if VZV-immune globulin is not available; begin every 8 hours, then administer 5 mg/kg/dose
therapy 7 to 10 days after exposure; some experts every 24 hours)
begin therapy at first appearance of rash (DHHS Intermittent hemodialysis (IHD): Dialyzable (60%
[pediatric] 2013). reduction following a 6-hour session): 5 mg/kg/
Infants and Children: Oral: 20 mg/kg/dose 4 times dose every 24 hours; administer after hemodial-
daily for 7 days; maximum dose: 800 mg/dose ysis on dialysis days (Aronoff 2007)
(DHHS [pediatric] 2013) Peritoneal dialysis (PD): 5 mg/kg/dose every 24
Adolescents: Oral: 800 mg 5 times daily for 5 to 7 hours; no supplemental dose needed (Aron-
days (DHHS [adult] 2015) off 2007)
Other immunocompromised hosts: Infants, Chil- Continuous renal replacement therapy (CRRT):
dren, and Adolescents: Oral: 20 mg/kg/dose 4 10 mg/kg/dose every 12 hours (Aronoff 2007)
times daily for 7 days; maximum dose: 800 mg/ Hepatic Impairment: Pediatric There are no dos-
dose. Note: Consider use if VZV-immune globulin age adjustments provided in the manufacturer's label-
or IVIG is not available; begin therapy 7 to 10 days ing.
after exposure (Red Book [AAP] 2015). Mechanism of Action Acyclovir is converted to acy-
Varicella (chickenpox), treatment: Begin treatment clovir monophosphate by virus-specific thymidine kin-
within the first 24 hours of rash onset: ase then further converted to acyclovir triphosphate by
Immunocompetent host: other cellular enzymes. Acyclovir triphosphate inhibits
Ambulatory therapy: Oral: Children ≥2 years and DNA synthesis and viral replication by competing with
Adolescents: 20 mg/kg/dose 4 times daily for 5 deoxyguanosine triphosphate for viral DNA polymerase
days; maximum daily dose: 3,200 mg/day (Red and being incorporated into viral DNA.
Book [AAP 2015]) Contraindications Hypersensitivity to acyclovir, vala-
Hospitalized patient: IV: Infants, Children, and cyclovir, or any component of the formulation
Adolescents: 10 mg/kg/dose or 500 mg/m 2 / Warnings/Precautions Neurotoxicity (eg, tremor/myo-
dose every 8 hours for 7 to 14 days (Bradley clonus, confusion, agitation, lethargy, hallucination,
2015; Red Book [AAP 2015]); some experts impaired consciousness) has been reported; risk may
recommend 15 to 20 mg/kg/dose for severe be increased with higher doses and in patients with
disseminated or CNS infection (Bradley 2015) renal failure. Monitor patients for signs/symptoms of
Immunocompromised host (non-HIV-exposed/-pos- neurotoxicity; ensure appropriate dosage reductions in
itive): IV: patients with renal impairment (Chowdhury 2016). Use
Infants: 10 mg/kg/dose every 8 hours for 7 to 10 with caution in immunocompromised patients; throm-
days (Red Book [AAP 2015]) botic microangiopathy has been reported. Use caution
Children and Adolescents: 500 mg/m2/dose every in the elderly or preexisting renal disease (may require
8 hours for 7 to 10 days; some experts recom- dosage modification). Renal failure (sometimes fatal)
mend 10 mg/kg/dose every 8 hours (Red Book has been reported. Maintain adequate hydration during
[AAP 2015]) oral or IV therapy. Use IV preparation with caution in
HIV-exposed/-positive: patients with underlying neurologic abnormalities, seri-
Mild, uncomplicated disease and no or moderate ous hepatic or electrolyte abnormalities, or substantial
immune suppression: Oral: hypoxia. Encephalopathic changes characterized by
Infants and Children: 20 mg/kg/dose 4 times lethargy, obtundation, confusion, hallucination, tremors,
daily for 7 to 10 days and until no new lesions agitation, seizure, or coma have been observed in
for 48 hours; maximum dose: 800 mg/dose patients receiving IV acyclovir. Acyclovir IV is an irritant
(DHHS [pediatric] 2013) (depending on concentration); avoid extravasation.
79
Potentially significant drug-drug interactions may exist, Pregnancy Considerations Acyclovir has been
requiring dose or frequency adjustment, additional mon- shown to cross the human placenta (Henderson 1992).
itoring, and/or selection of alternative therapy.
Results from a pregnancy registry, established in 1984
Varicella: For maximum benefit, treatment should begin and closed in 1999, did not find an increase in the
within 24 hours of appearance of rash; oral route not number of birth defects with exposure to acyclovir when
recommended for routine use in otherwise healthy compared to those expected in the general population.
children with varicella but may be effective in patients However, due to the small size of the registry and lack
at increased risk of moderate to severe infection (>12 of long-term data, the manufacturer recommends using
years of age, chronic cutaneous or pulmonary disor- during pregnancy with caution and only when clearly
ders, long-term salicylate therapy, corticosteroid needed. Acyclovir is recommended for the treatment of
therapy). genital herpes in pregnant patients (ACOG 2007; CDC
Warnings: Additional Pediatric Considerations [Workowski 2015]).
Acyclovir can cause intrarenal obstructive nephropathy, Breastfeeding Considerations
interstitial nephritis, and tubular necrosis resulting in Acyclovir is present in breast milk.
significant renal insufficiency. In one study, 35% The relative infant dose (RID) of acyclovir is 1.83% to
(131/373 courses) in 371 pediatric patients treated with 3.65% when calculated using the highest breast milk
IV acyclovir mostly for meningoencephalitis were concentration located and compared to an IV infant
observed to have renal dysfunction. Renal dysfunction therapeutic dose of 30 to 60 mg/kg/day.
typically occurred within 48 hours of initiation and was In general, breastfeeding is considered acceptable
reversible in most cases after dosage reduction or when the RID of a medication is <10% (Anderson
discontinuation, although in some instances, return to 2016; Ito 2000).
baseline was not observed. Analysis of the degree of The RID of acyclovir was calculated using a milk
dysfunction based on percent reduction of estimated concentration of 7.3 mcg/mL, providing an estimated
GFR (eGFR) showed that of the 373 acyclovir courses, daily infant dose via breast milk of 1.095 mg/kg/day.
22% (81/373) had an eGFR reduction of 25% to 49%, This milk concentration was obtained following mater-
renal injury (defined as a 50% to 75% reduction in nal administration acyclovir 900 mg IV daily for 5 days
eGFR) in 9.7% (36/373), and renal failure (eGFR (Bork 1995). The mean half-life of acyclovir in breast
reduction >75%) in 3.8% (14/373). Doses >500 mg/m2 milk was 3.2 hours in one study (Lau 1987); acyclovir
were significantly associated with all levels of nephro- was measurable in breast milk for up to 88 hours after
toxicity and acyclovir doses >15 mg/kg were signifi- the last maternal dose in another (Bork 1995). Acy-
cantly associated with a 25% to 49% reduction in clovir has been detected in the urine of a breastfeed-
eGFR. Statistically significant risk factors for renal failing infant (Lau 1987).
ure identified through univariate analysis were age >8 In one case report, the mother reported no adverse
years, weight >20 kg, BMI >19 kg/m2, and concurrent events in her exclusively breastfed infant following a
ceftriaxone with or without gadolinium. Associations of maternal dose of acyclovir 800 mg orally 5 times daily
other antibiotics and contrast agents were not statisti- for 7 days (Taddio 1994).
cally significant. Monitor renal function during therapy, Acyclovir is considered compatible with breastfeeding
particularly for high doses and in older pediatric patients (WHO 2002). Acyclovir may be used for the treatment
(>8 years). Outside of the neonatal period, reduced of genital herpes in breastfeeding women (ACOG
dosing or use of mg/m2 dosing in larger children may 2007; CDC [Workowski 2015]). The manufacturer
need to be considered; further studies are necessary recommends that caution be exercised when admin-
(Rao 2015). istering acyclovir to breastfeeding women. Breastfeed-
Drug Interactions ing mothers with herpetic lesions near or on the breast
Metabolism/Transport Effects Inhibits CYP1A2 should avoid breastfeeding (Gartner 2005); precau-
(weak) tions should be taken to prevent infant contact with
Avoid Concomitant Use active lesions (ACOG 2007).
Avoid concomitant use of Acyclovir (Systemic) with Dosage Forms: US
any of the following: Foscarnet; Varicella Virus Vac- Capsule, Oral:
cine; Zoster Vaccine (Live/Attenuated) Zovirax: 200 mg
Increased Effect/Toxicity Generic: 200 mg
Acyclovir (Systemic) may increase the levels/effects Solution, Intravenous:
of: CloZAPine; Mycophenolate; Tenofovir Products; Generic: 50 mg/mL (20 mL)
TiZANidine; Zidovudine Solution, Intravenous [preservative free]:
Generic: 50 mg/mL (10 mL, 20 mL)
The levels/effects of Acyclovir (Systemic) may be
Suspension, Oral:
increased by: Foscarnet; Mycophenolate; Tenofovir
Zovirax: 200 mg/5 mL (473 mL)
Products
Generic: 200 mg/5 mL (473 mL)
Decreased Effect
Tablet, Oral:
Acyclovir (Systemic) may decrease the levels/effects
Zovirax: 400 mg, 800 mg
of: Talimogene Laherparepvec; Varicella Virus Vac-
Generic: 400 mg, 800 mg
cine; Zoster Vaccine (Live/Attenuated)
Dietary Considerations Some products may contain Although some conflicting data, dental treatment may
sodium.
be a risk factor for asymptomatic viral shedding of
herpes simplex virus type-1 (HSV-1) into human saliva
Half-life Elimination Half-life elimination: Terminal: in patients with previous exposure to the virus (Hyland
Neonates and Infants ≤3 months: 3.8 ± 1.19 hours;
2007).
Infants >3 months to Children ≤12 years: 2.36 ± 0.97
hours; Adults: ~2.5 hours (with normal renal function); It is recommended to reappoint the patient if an active
20 hours (ESRD) (Gorlitsky 2017); Hemodialysis: ~5 lesion is present. If the lesion is already "crusted" over,
hours treatment will not induce spread of the virus but
80
ACYCLOVIR (TOPICAL)
treatment is aimed at patient comfort during the proce- Renal Impairment: Adult There are no dosage
dure relating to the wound healing on their lip. adjustments provided in the manufacturer’s labeling.
However, dosage adjustment is unlikely due to low
Acyclovir (Topical) (ay SYE kloe veer) systemic absorption.
Hepatic Impairment: Adult There are no dosage
Related Information adjustments provided in the manufacturer’s labeling.
Systemic Viral Diseases on page 1496 However, dosage adjustment is unlikely due to low
Viral Infections on page 1540 systemic absorption.
Related Sample Prescriptions Pediatric Herpes labialis (cold sores): Topical
Viral Infections - Sample Prescriptions on page 44 cream: Children ≥12 years and Adolescents: Apply 5
Brand Names: US Sitavig; Zovirax times/day for 4 days
Brand Names: Canada Zovirax Renal Impairment: Pediatric There are no dosage
Generic Availability (US) May be product dependent adjustments provided in the manufacturer’s labeling;
Pharmacologic Category Antiviral Agent, Topical however, dosage adjustment is unlikely due to low
Dental Use Treatment of initial and prophylaxis of systemic absorption.
recurrent mucosal and cutaneous herpes simplex Hepatic Impairment: Pediatric There are no dos-
(HSV-1 and HSV-2) infections in immunocompromised age adjustments provided in the manufacturer’s label-
patients ing; however, dosage adjustment is unlikely due to low
Use Herpes virus: systemic absorption.
Buccal tablet: Treatment of recurrent herpes labialis Mechanism of Action Acyclovir is converted to acy-
(cold sores) in immunocompetent adults clovir monophosphate by virus-specific thymidine kin-
Cream: Treatment of recurrent herpes labialis (cold ase then further converted to acyclovir triphosphate by
sores) in immunocompetent children ≥12 years of other cellular enzymes. Acyclovir triphosphate inhibits
age, adolescents, and adults DNA synthesis and viral replication by competing with
Ointment: Management of limited non-life-threatening deoxyguanosine triphosphate for viral DNA polymerase
mucocutaneous herpes simplex virus infections in and being incorporated into viral DNA.
immunocompromised patients Contraindications
Local Anesthetic/Vasoconstrictor Precautions Hypersensitivity to acyclovir, valacyclovir, or any com-
No information available to require special precautions ponent of the formulation
Effects on Dental Treatment Key adverse event(s) Buccal tablet: Additional contraindications: Hypersensi-
related to dental treatment: Topical (Zovirax cream): tivity to milk protein concentrate
Dry/cracked lips and dry/flaky skin were reported in Warnings/Precautions Genital herpes: Physical con-
fewer than 1 in 100 patients in clinical studies. tact should be avoided when lesions are present; trans-
Effects on Bleeding No information available to mission may also occur in the absence of symptoms.
require special precautions Treatment should begin with the first signs or symp-
Adverse Reactions toms. There are no data to support the use of acyclovir
>10%: Dermatologic: Local pain (ointment 30%; mild; ointment to prevent transmission of infection to other
includes transient burning and stinging) persons or prevent recurrent infections if no signs or
1% to 10%: symptoms are present.
Central nervous system: Lethargy (buccal tablet 1%)
Herpes labialis: Treatment should begin with the first
Dermatologic: Erythema (buccal tablet 1%), skin rash
signs or symptoms. Cream is for external use only to
(buccal tablet 1%)
the lips and face; do not apply to eye or inside the
Gastrointestinal: Aphthous stomatitis (buccal tablet
mouth or nose, or any mucous membranes. Ointment
1%), gingival pain (buccal tablet 1%)
should also not be used in the eye and be used with
Local: Application site reaction (cream 5%; including
caution in immunocompromised patients. Cream may
dry lips, desquamation, dryness of skin, cracked lips,
be irritating and cause contact sensitization. Buccal
burning skin, pruritus, flakiness of skin, and stinging
on skin); application site irritation (buccal tablet 1%) tablets are applied to the area of the upper gum above
<1%, postmarketing, and/or case reports: Anaphylaxis, the incisor tooth on the same side as the symptoms; do
angioedema, contact dermatitis, eczema, localized not apply to the inside of the lip or cheek. Some
edema, local pruritus, pruritus products may contain milk protein concentrate.
Dental Usual Dosage Warnings: Additional Pediatric Considerations
Herpes labialis (cold sores): Children ≥12 years and Some dosage forms may contain propylene glycol; in
Adults: Topical: Cream: Apply 5 times/day for 4 days neonates large amounts of propylene glycol delivered
Mucocutaneous HSV: Adults: Nonlife-threatening, orally, intravenously (eg, >3,000 mg/day), or topically
immunocompromised: Topical: Ointment: 1/2" ribbon have been associated with potentially fatal toxicities
of ointment for a 4" square surface area every 3 hours which can include metabolic acidosis, seizures, renal
(6 times/day) for 7 days failure, and CNS depression; toxicities have also been
Dosing reported in children and adults including hyperosmolal-
Adult & Geriatric ity, lactic acidosis, seizures, and respiratory depression;
Herpes labialis (cold sores), recurrent: use caution (AAP 1997; Shehab 2009).
Topical cream: Apply 5 times daily for 4 days Drug Interactions
Buccal tablet: Apply one 50 mg tablet as a single Metabolism/Transport Effects None known.
dose to the upper gum region (canine fossa) Avoid Concomitant Use There are no known inter-
HSV, mucocutaneous (non-life-threatening, immu- actions where it is recommended to avoid concomitant
nocompromised): Topical ointment: 1/2" ribbon of use.
ointment for a 4" square surface area every 3 hours Increased Effect/Toxicity There are no known sig-
(6 times daily) for 7 days nificant interactions involving an increase in effect.
81
ACYCLOVIR (TOPICAL)
Decreased Effect patients ≥2 years of age (Humira) or ≥4 years of age

Acyclovir (Topical) may decrease the levels/effects of: (Amjevita; Cyltezo); may be used alone or in combi-
Talimogene Laherparepvec nation with methotrexate
Pregnancy Risk Factor B Plaque psoriasis: Treatment of chronic plaque psor-
Pregnancy Considerations Adverse events were not iasis (moderate to severe) in adults who are candi-
observed in animal reproduction studies. When admin- dates for systemic therapy or phototherapy, and when
istered orally, acyclovir crosses the placenta. Refer to other systemic therapies are less appropriate (with
the Acyclovir (Systemic) monograph for details. The close monitoring and regular follow-up)
amount of acyclovir available systemically following Psoriatic arthritis: Treatment (to reduce signs/symp-
topical application of the cream or ointment is signifi- toms, inhibit progression of structural damage, and
cantly less in comparison to oral doses. improve physical function) of active psoriatic arthritis
Breastfeeding Considerations When administered in adults; may be used alone or in combination with
orally, acyclovir is present in breast milk. Refer to the nonbiologic disease-modifying antirheumatic drugs
Acyclovir (Systemic) monograph for details. The (DMARDs)
amount of acyclovir available systemically following Rheumatoid arthritis: Treatment (to reduce signs/
topical application of the cream, buccal tablet, or oint- symptoms, induce major clinical response, inhibit pro-
ment is significantly less in comparison to oral doses. gression of structural damage, and improve physical
Women with herpetic lesions near or on the breast function) of active rheumatoid arthritis (moderate to
should avoid breastfeeding. severe) in adults; may be used alone or in combination
Dosage Forms: US with methotrexate or other nonbiologic DMARDs
Cream, External: Ulcerative colitis: Treatment (to induce and sustain
Zovirax: 5% (5 g) clinical remission) of active ulcerative colitis (moderate
Generic: 5% (5 g) to severe) in adults who have had an inadequate
Ointment, External: response to immunosuppressants such as corticoste-
Zovirax: 5% (30 g) roids, azathioprine, or 6-mercaptopurine. (Note: Effi-
Generic: 5% (5 g, 15 g, 30 g) cacy in patients that are intolerant to or no longer
Tablet, Buccal: responsive to other TNF blockers has not been estab-
Sitavig: 50 mg lished.)
Dental Health Professional Considerations Uveitis (Humira only): Treatment of non-infectious
Although some conflicting data, dental treatment may intermediate, posterior, and panuveitis in adults and
be a risk factor for asymptomatic viral shedding of children ≥2 years of age
herpes simplex virus type-1 (HSV-1) into human saliva Local Anesthetic/Vasoconstrictor Precautions
in patients with previous exposure to the virus (Hyland No information available to require special precautions
2007). Effects on Dental Treatment No significant effects or
It is recommended to reappoint the patient if an active Effects on Bleeding Rare reports of pancytopenia
lesion is present. If the lesion is already "crusted" over, (including aplastic anemia), as well as medically signifi-
treatment will not induce spread of the virus but treat- cant thrombocytopenia, have been reported with tumor
ment is aimed at patient comfort during the procedure necrosis factor-alpha therapy; in patients undergoing
relating to the wound healing on their lip. active treatment, a medical consult is recommended
Adverse Reactions
Adalimumab (a da LIM yoo mab) >10%:
Central nervous system: Headache (12%)
Related Information Dermatologic: Skin rash (6% to 12%)
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis Hematologic & oncologic: Positive ANA titer (12%)
on page 1484 Immunologic: Antibody development (3% to 26%)
Brand Names: US Humira; Humira Pediatric Crohns Infection: Infection (children and adolescents: 45%)
Start; Humira Pen; Humira Pen-CD/UC/HS Starter; Local: Injection site reaction (5% to 20%)
Humira Pen-Ps/UV/Adol HS Start Neuromuscular & skeletal: Increased creatine phos-
Brand Names: Canada Humira phokinase (15%)
Pharmacologic Category Antirheumatic, Disease Respiratory: Upper respiratory tract infection (17%),
Modifying; Gastrointestinal Agent, Miscellaneous; sinusitis (11%)
Monoclonal Antibody; Tumor Necrosis Factor (TNF) 1% to 10%:
Blocking Agent Cardiovascular: Hypertension (5%), atrial fibrillation
Use (<5%), cardiac arrhythmia (<5%), chest pain (<5%),
Ankylosing spondylitis: Treatment (to reduce signs/ coronary artery disease (<5%), deep vein thrombosis
symptoms) of active ankylosing spondylitis in adults (<5%), hypertensive encephalopathy (<5%), myocar-
Crohn disease: Treatment (to reduce signs/symptoms dial infarction (<5%), palpitations (<5%), pericardial
and to induce and maintain clinical remission) of active effusion (<5%), pericarditis (<5%), peripheral edema
Crohn disease (moderate to severe) in adults and (<5%), subdural hematoma (<5%), syncope (<5%),
pediatric patients ≥6 years of age (Humira only) with tachycardia (<5%)
an inadequate response to conventional therapy or Central nervous system: Confusion (<5%), myasthe-
who have lost response to or are intolerant to nia (<5%), paresthesia (<5%), torso pain (<5%)
infliximab. Dermatologic: Cellulitis, erysipelas
Hidradenitis suppurativa (Humira only): Treatment Endocrine & metabolic: Hyperlipidemia (7%), hyper-
of moderate to severe hidradenitis suppurativa in cholesterolemia (6%), dehydration (<5%), ketosis
adults and children ≥12 years of age (<5%), menstrual disease (<5%), parathyroid dis-
Juvenile idiopathic arthritis: Treatment (to reduce ease (<5%)
signs/symptoms) of active polyarticular juvenile idio- Gastrointestinal: Nausea (9%), abdominal pain (7%),
pathic arthritis (moderate to severe) in pediatric cholecystitis (<5%), cholelithiasis (<5%), esophagitis
82
ADALIMUMAB
(<5%), gastrointestinal hemorrhage (<5%), vomiting with binding to TNFα receptor sites and subsequent
(<5%), diverticulitis of the gastrointestinal tract cytokine-driven inflammatory processes. Elevated TNF
Genitourinary: Urinary tract infection (≤8%), hematuria levels in the synovial fluid are involved in the pathologic
(5%), cystitis (<5%), pelvic pain (<5%) pain and joint destruction in immune-mediated arthritis.
Hematologic & oncologic: Adenoma (<5%), agranulo- Adalimumab decreases signs and symptoms of psori-
cytosis (<5%), paraproteinemia (<5%), polycythemia atic arthritis, rheumatoid arthritis, and ankylosing spon-
(<5%), carcinoma (including breast, gastrointestinal, dylitis. It inhibits progression of structural damage of
skin, urogenital), malignant lymphoma, malignant rheumatoid and psoriatic arthritis. Reduces signs and
melanoma symptoms and maintains clinical remission in Crohn
Hepatic: Increased serum alkaline phosphatase (5%), disease and ulcerative colitis; reduces epidermal thick-
hepatic necrosis (<5%) ness and inflammatory cell infiltration in plaque psor-
Hypersensitivity: Hypersensitivity reaction (children iasis.
5% to 6%; adults 1%) Pharmacodynamics/Kinetics
Infection: Serious infection (4%), herpes simplex infec- Half-life Elimination Terminal: ~2 weeks (range: 10
tion (≤4%), herpes zoster infection (≤4%), sepsis to 20 days)
Neuromuscular & skeletal: Back pain (6%), arthritis Time to Peak Serum: SubQ: 131 ± 56 hours
(<5%), arthropathy (<5%), bone disease (<5%), Pregnancy Considerations Adalimumab crosses the
bone fracture (<5%), limb pain (<5%), muscle placenta and can be detected in cord blood. Placental
cramps (<5%), myasthenia (<5%), osteonecrosis transfer significantly begins in the second trimester and
(<5%), septic arthritis (<5%), synovitis (<5%), tendon increases as pregnancy progresses (Julsgaard 2016;
disease (<5%), tremor (<5%), arthralgia (3%; plaque Nguyen 2016).
psoriasis)
Ophthalmic: Cataract (<5%) Following administration to pregnant patients with
Renal: Nephrolithiasis (<5%), pyelonephritis inflammatory bowel disease, cord blood and newborn
Respiratory: Flu-like symptoms (7%), asthma (<5%), concentrations of adalimumab are greater than mater-
bronchospasm (<5%), dyspnea (<5%), pleural effu- nal serum at delivery (Julsgaard 2016; Mahadevan
sion (<5%), respiratory depression (<5%), pharyng- 2013). The mean time to adalimumab clearance was
itis (juvenile idiopathic arthritis: ≤4%), pneumonia 4 months (range: 2.9 to 5 months) in a study in 36
(≤4%), tuberculosis (including reactivation of latent infants exposed in utero (Julsgaard 2016).
infection; disseminated, miliary, lymphatic, perito- Outcome data from a pregnancy registry are available.
neal, and pulmonary) Included were women with rheumatoid arthritis treated
Miscellaneous: Accidental injury (10%), abnormal with adalimumab at least during the first trimester
healing (<5%), postoperative complication (infection) (n=74), women with RA not treated with adalimumab
<1%, postmarketing, and/or case reports: Abscess (n=80), and healthy pregnant women without RA
(limb, perianal), alopecia, anal fissure, anaphylactoid (n=219). The incidence of major birth defects was not
shock, anaphylaxis, anemia, angioedema, aplastic significantly different between the treatment groups. No
anemia, appendicitis, asthenia, bacterial infection, pattern of specific defects was noted. There were no
basal cell carcinoma, blepharitis, bronchitis, cardiac adverse pregnancy outcomes associated with therapy
failure, cerebrovascular accident, cervical dysplasia, (Burmester 2017).
circulatory shock, clonus, cytopenia, dermal ulcer,
diarrhea, diplopia, endometrial hyperplasia, eosino- Administration of live vaccines should be postponed
philia, erythema multiforme, fever, fixed drug eruption, until after 6 months of age to an infant exposed to
fulminant necrotizing fasciitis, fungal infection, Guil- antitumor necrosis factor therapy in utero (Nguyen
lain-Barré syndrome, hepatic failure, hepatitis B (reac- 2016; van der Woude 2015).
tivation), hepatosplenic T-cell lymphomas (children, Inflammatory bowel disease is associated with adverse
adolescents, and young adults), hepatotoxicity (idio- pregnancy outcomes; management of maternal disease
syncratic) (Chalasani 2014), histoplasmosis, hyperre- should be optimized prior to pregnancy (Nguyen 2016;
flexia, hypersensitivity angiitis, increased serum van der Woude 2015). Maternal adalimumab serum
transaminases, interstitial pulmonary disease (includ- concentrations were found to remain stable during
ing pulmonary fibrosis), intestinal obstruction, intesti- pregnancy in a study of 9 women with Crohn disease
nal perforation, leukemia, leukopenia, lichenoid (Seow 2017). Recommendations for use of antitumor
eruption, liver metastases, lupus-like syndrome, lym- necrosis factor agents in pregnant women vary by
phadenopathy, lymphocytosis, malignant neoplasm of guideline. Some guidelines recommend avoiding use
ovary, meningitis (viral), Merkel cell carcinoma, multi- of adalimumab in the third trimester (Flint 2016). Other
ple sclerosis, musculoskeletal chest pain, mycobacte- guidelines recommend discontinuing as early as 20
rium avium complex, myositis (children and weeks' gestation (Götestam Skorpen 2016). However,
adolescents), neutropenia, nocturia, optic neuritis, women on antitumor necrosis factor maintenance may
pancreatitis, pancytopenia, protozoal infection, psor- continue treatment during pregnancy when needed and
iasis (including new onset, palmoplantar, pustular, or treatment may be initiated during pregnancy in some
exacerbation), pulmonary embolism, respiratory fail- cases (Nguyen 2016; van der Woude 2015).
ure, sarcoidosis, septic shock, skin granuloma (annu-
lare; children and adolescents), Stevens-Johnson Women exposed to adalimumab during pregnancy for
syndrome, streptococcal pharyngitis (children and the treatment of an autoimmune disease (eg, inflamma-
adolescents), supraventricular cardiac arrhythmia, tory bowel disease) may contact the OTIS Autoimmune
swelling of eye, systemic lupus erythematosus, testic- Diseases Study at 877-311-8972.
ular neoplasm, thrombocytopenia, urticaria, vascular Product Availability
disease, vasculitis (systemic), viral infection Amjevita (adalimumab-atto): FDA approved September
Mechanism of Action Adalimumab is a recombinant 2016; anticipated availability is currently unknown.
monoclonal antibody that binds to human tumor Amjevita is approved as biosimilar to Humira. Consult
necrosis factor alpha (TNF-alpha), thereby interfering the prescribing information for additional information.
83
ADALIMUMAB
Cyltezo (adalimumab-adbm): FDA approved August Effects on Bleeding No information available to

2017; anticipated availability is currently unknown. require special precautions
Cyltezo is approved as biosimilar to Humira. Informa- Adverse Reactions In liver transplant patients with
tion pertaining to this product within the monograph is baseline renal dysfunction, frequency of increased
pending revision. Consult the prescribing information serum creatinine has been observed to be as high as
for additional information. 32% to 51% at 48 and 96 weeks post-transplantation,
respectively; considering the concomitant use of other
Adapalene (a DAP a leen)
potentially nephrotoxic medications, baseline renal
insufficiency, and predisposing comorbidities, the role
Brand Names: US Differin; Differin [OTC]; Plixda of adefovir in these changes could not be established.
Brand Names: Canada Differin; Differin XP >10%:
Pharmacologic Category Acne Products; Retinoic Central nervous system: Headache (24% to 25%)
Acid Derivative; Topical Skin Product, Acne Gastrointestinal: Abdominal pain (15%), diar-
Use Acne vulgaris: Treatment of acne vulgaris. rhea (≤13%)
Local Anesthetic/Vasoconstrictor Precautions Genitourinary: Hematuria (grade ≥3: 11%)
No information available to require special precautions Hepatic: Hepatitis (exacerbation; ≤25% within 12
Effects on Dental Treatment No significant effects or weeks of adefovir discontinuation)
complications reported Neuromuscular & skeletal: Weakness (≤25%)
Effects on Bleeding No information available to 1% to 10%:
require special precautions Dermatologic: Pruritus, skin rash
Adverse Reactions Endocrine & metabolic: Hypophosphatemia
>10%: Dermatologic: Xeroderma (≤45%), exfoliation of (<2 mg/dL: 1% and 3% in pre-/post-liver transplant
skin (≤44%), erythema (≤38%), burning sensation of patients, respectively)
skin (≤29%), stinging of the skin (≤29%) Gastrointestinal: Flatulence (≤8%), dyspepsia (5% to
1% to 10%: Dermatologic: Skin abnormalities (1% to 9%), nausea, vomiting
6%; discomfort), desquamation (2%), pruritus (≤2%), Neuromuscular & skeletal: Back pain (≤10%)
skin irritation (1% to 2%), sunburn (1% to 2%) Renal: Increased serum creatinine (≥0.5 mg/dL: 2% to
≤1%, postmarketing, and/or case reports: Acne flare, 3% in compensated liver disease; incidence may be
angioedema (gel), application site pain (gel), conjunc- higher in patients with decompensated cirrhosis or in
tivitis, contact dermatitis, dermatitis, eczema, eyelid liver transplant recipients), renal failure
edema, facial edema (gel), skin discoloration, skin Respiratory: Cough (6% to 8%), rhinitis (≤5%)
<1%, postmarketing, and/or case reports: Fanconi's
rash (cream/gel), swelling of lips (gel)
syndrome, hepatitis, myopathy, nephrotoxicity, osteo-
Mechanism of Action Retinoid-like compound which
malacia, pancreatitis, proximal tubular nephropathy
is a modulator of cellular differentiation, keratinization,
Mechanism of Action Acyclic nucleotide reverse tran-
and inflammatory processes, all of which represent
scriptase inhibitor (adenosine analog) which interferes
important features in the pathology of acne vulgaris
with HBV viral RNA-dependent DNA polymerase result-
ing in inhibition of viral replication.
Onset of Action 8 to 12 weeks Pharmacodynamics/Kinetics
Half-life Elimination Terminal: 7 to 51 hours (gel) Half-life Elimination 7.5 hours; prolonged in renal
Pregnancy Risk Factor C impairment
Pregnancy Considerations Adverse effects were Time to Peak Median: 1.75 hours (range: 0.58 to 4
observed in animal reproduction studies. Retinoids hours)
may cause harm when administered during pregnancy. Pregnancy Considerations Information related to the
A case report described maternal use of adapalene 1 use of adefovir in pregnancy is limited (Yi 2012); use of
month prior to pregnancy and through 13 weeks' ges- other agents is recommended (AASLD [Terrault 2016]).
tation; cerebral and ocular malformations were reported
in the exposed fetus which resulted in termination of Health care providers are encouraged to enroll women
pregnancy (Autret 1997). In clinical trials, women of exposed to adefovir during pregnancy in the Hepsera
childbearing potential were required to have a negative pregnancy registry (800-258-4263).
pregnancy test prior to therapy.
Ado-Trastuzumab Emtansine
(a do tras TU zoo mab em TAN seen)
Adefovir (a DEF o veer)
Brand Names: US Kadcyla
Related Information
Brand Names: Canada Kadcyla
HIV Infection and AIDS on page 1477
Pharmacologic Category Antineoplastic Agent, Anti-
HER2; Antineoplastic Agent, Antibody Drug Conjugate;
Brand Names: US Hepsera Antineoplastic Agent, Antimicrotubular; Antineoplastic
Brand Names: Canada Hepsera Agent, Monoclonal Antibody
Pharmacologic Category Antihepadnaviral, Reverse Use Breast cancer, metastatic: Treatment (single-
Transcriptase Inhibitor, Nucleotide (Anti-HBV) agent) of HER2-positive, metastatic breast cancer in
Use Treatment of chronic hepatitis B with evidence of patients who previously received trastuzumab and a
active viral replication (based on persistent elevation of taxane, separately or in combination, and have either
ALT/AST or histologic evidence) received prior therapy for metastatic disease or devel-
Local Anesthetic/Vasoconstrictor Precautions oped disease recurrence during or within 6 months of
No information available to require special precautions completing adjuvant therapy.
Effects on Dental Treatment No significant effects or Local Anesthetic/Vasoconstrictor Precautions
complications reported No information available to require special precautions
84
ALBIGLUTIDE
Effects on Dental Treatment Key adverse event(s) emtansine during pregnancy can result in embryo-
related to dental treatment: Abnormal taste, oral dis- fetal harm. Advise patients of these risks and the
comfort, xerostomia and changes in salivation (normal need for effective contraception.
salivary flow resumes upon discontinuation)
Oligohydramnios and oligohydramnios sequence (man-
Effects on Bleeding Chemotherapy may result in ifested as pulmonary hypoplasia, skeletal malforma-
significant myelosuppression, thrombocytopenia (31%;
tions and neonatal death) were observed following
grades 3/4: 15%; Asians grades 3/4: 45%), anemia
trastuzumab exposure during pregnancy (trastuzumab
(14%; grades 3/4: 4%), neutropenia (7%; grades 3/4:
is the antibody component of ado-trastuzumab emtan-
2%). In patients who are under active treatment with
sine). Monitor for oligohydramnios if trastuzumab expo-
these agents, medical consult is suggested.
sure occurs during pregnancy or within 7 months prior
Adverse Reactions to conception; conduct appropriate fetal testing if oligo-
>10%: hydramnios occurs. Based on the mechanism of action,
Central nervous system: Fatigue (36%), headache the DM1 component of the ado-trastuzumab emtansine
(28%), peripheral neuropathy (21%; grades 3/4: formulation may also cause fetal harm if administered
2%), insomnia (12%) during pregnancy.
Dermatologic: Skin rash (12%)
Endocrine & metabolic: Decreased serum potas- European Society for Medical Oncology (ESMO) guide-
sium (33%) lines for cancer during pregnancy recommend delaying
Gastrointestinal: Nausea (40%), constipation (27%), treatment with HER-2 targeted agents until after deliv-
diarrhea (24%), abdominal pain (19%), vomiting ery in pregnant patients with HER-2 positive disease
(19%), xerostomia (17%), stomatitis (14%) (Peccatori 2013).
Hematologic & oncologic: Hemorrhage (32%; grades Evaluate pregnancy status prior to treatment in females
3/4: 2%), thrombocytopenia (31%; grades 3/4: 15%; of reproductive potential; effective contraception should
Asians grades 3/4: 45%), anemia (14%; grades
be used during therapy and for 7 months after the last
3/4: 4%)
dose of ado-trastuzumab emtansine. Males with female
Hepatic: Increased serum aspartate aminotransferase
partners of reproductive potential should use effective
(98%), increased serum alanine aminotransferase
contraception during therapy and for 4 months after the
(82%), increased serum transaminases (29%),
last dose. Ado-trastuzumab emtansine may impair fer-
increased serum bilirubin (17%)
tility in females and males.
Neuromuscular & skeletal: Musculoskeletal pain
(36%), arthralgia (19%), asthenia (18%), myal- If ado-trastuzumab emtansine exposure occurs during
gia (14%) pregnancy or within 7 months prior to conception,
Respiratory: Epistaxis (23%), cough (18%), dysp- healthcare providers should report the exposure to the
nea (12%) Genentech (888-835-2555).
Miscellaneous: Fever (19%)
1% to 10%:
Cardiovascular: Peripheral edema (7%), hypertension Albiglutide (al bi GLOO tide)
(5%), left ventricular dysfunction (2%) Brand Names: US Tanzeum [DSC]
Central nervous system: Dizziness (10%), chills (8%)
Pharmacologic Category Antidiabetic Agent, Gluca-
Dermatologic: Pruritus (6%)
gon-Like Peptide-1 (GLP-1) Receptor Agonist
Endocrine & metabolic: Hypokalemia (10%)
Use Diabetes mellitus, type 2: Adjunct to diet and
Gastrointestinal: Dyspepsia (9%), dysgeusia (8%)
exercise to improve glycemic control in the treatment
Genitourinary: Urinary tract infection (9%)
of type 2 diabetes mellitus
Hematologic & oncologic: Neutropenia (7%; grades
3/4: 2%) Local Anesthetic/Vasoconstrictor Precautions
Hepatic: Increased serum alkaline phosphatase (5%) No information available to require special precautions
Hypersensitivity: Hypersensitivity reaction (2%) Effects on Dental Treatment Key adverse event(s)
Immunologic: Antibody development (5%) related to dental treatment: Schedule type 1 and type 2
Ophthalmic: Blurred vision (5%), conjunctivitis (4%), diabetic patients for dental treatment in the morning in
dry eye syndrome (4%), increased lacrimation (3%) order to minimize chance of stress-induced hypoglyce-
Respiratory: Pneumonitis (≤1%) mia.
Miscellaneous: Infusion related reaction (1%) Effects on Bleeding No information available to
<1%: Anaphylactoid shock, hepatic encephalopathy, require special precautions
hepatotoxicity, idiopathic noncirrhotic portal hyperten- Adverse Reactions Reactions reported from mono-
sion (including nodular regenerative hyperplasia), por- therapy and combination therapy.
tal hypertension, tumor lysis syndrome >10%:
Mechanism of Action Ado-trastuzumab emtansine is Endocrine & metabolic: Hypoglycemia (combination
a HER2-antibody drug conjugate which incorporates therapy; 3% to 17%)
the HER2 targeted actions of trastuzumab with the Gastrointestinal: Diarrhea (13%), nausea (11%)
microtubule inhibitor DM1 (a maytansine derivative). Local: Injection site reaction (11% to 18%, including
The conjugate, which is linked via a stable thioether erythema at injection site [2%], hypersensitivity reac-
linker, allows for selective delivery into HER2 over- tion at injection site [1%], rash at injection site [1%],
expressing cells, resulting in cell cycle arrest and itching at injection site)
apoptosis. Respiratory: Upper respiratory tract infection (14%)
1% to 10%:
Cardiovascular: Atrial fibrillation (1%)
Half-life Elimination ~4 days Endocrine & metabolic: Increased gamma-glutamyl
Time to Peak Near the end of the infusion transferase (2%)
Pregnancy Considerations Gastrointestinal: Gastroesophageal reflux disease
[US Boxed Warning]: Exposure to ado-trastuzumab (4%), vomiting (4%)
85
ALBIGLUTIDE
Immunologic: Antibody development (non-neutraliz- Respiratory: Upper respiratory tract infection (≥5% to
ing; 6%) 21%), rhinitis (5% to 16%), bronchospasm (8% to
Infection: Influenza (5%) 15%; exacerbation of underlying pulmonary dis-
Neuromuscular & skeletal: Arthralgia (7%), back ease), pharyngitis (14%), exacerbation of asthma
pain (7%) (11% to 13%)
Respiratory: Cough (7%), pneumonia (2%) 1% to 10%:
<1%: Angioedema, appendicitis, atrial flutter, constipa- Cardiovascular: Tachycardia (≤7%), hypertension (1%
tion, hypersensitivity reaction, increased heart rate to 3%), chest pain (<3%), edema (<3%), extrasys-
(1-2 bpm), increased serum ALT, increased serum toles (<3%), chest discomfort, flushing, palpitations
bilirubin, pancreatitis Central nervous system: Shakiness (children and
Mechanism of Action Albiglutide is an agonist of adolescents 6 to 14 years: 9%), headache (3% to
human glucagon-like peptide-1 (GLP-1) receptor and 7%), dizziness (<7%), insomnia (1% to 3%), anxiety
augments glucose-dependent insulin secretion and (<3%), ataxia (<3%), depression (<3%), drowsiness
slows gastric emptying. (<3%), rigors (<3%), voice disorder (<3%), hyper-
Pharmacodynamics/Kinetics active behavior (children and adolescents 6 to 14
Half-life Elimination ~5 days years: 2%), malaise (2%), pain (2%), migraine
Time to Peak 3 to 5 days (≤2%), emotional lability (1%), fatigue (1%), rest-
Pregnancy Risk Factor C lessness, vertigo
Pregnancy Considerations Dermatologic: Diaphoresis (<3%), skin rash (<3%),
Adverse events have been observed in some animal urticaria (≤2%), pallor (children 2 to 6 years: 1%)
reproduction studies. Endocrine & metabolic: Increased serum glucose
(10%), diabetes mellitus (<3%)
In women with diabetes, maternal hyperglycemia can Gastrointestinal: Nausea (2% to 10%), vomiting (3%
be associated with congenital malformations as well as to 7%), unpleasant taste (inhalation site, 4%), gastro-
adverse effects in the fetus, neonate, and the mother enteritis (3%), increased appetite (children and ado-
(ACOG 2005; ADA 2018c; Metzger 2007). To prevent lescents 6 to 14 years: 3%), viral gastroenteritis (1%
adverse outcomes, prior to conception and throughout to 3%), diarrhea (<3%), eructation (<3%), flatulence
pregnancy maternal blood glucose and Hb1c should be (<3%), glossitis (<3%), xerostomia (<3%), gastro-
kept as close to target goals as possible but without intestinal signs and symptoms (children 2 to 6 years:
causing significant hypoglycemia (ADA 2018c; Blumer 2%), dyspepsia (1% to 2%), anorexia (children 2 to 6
2013). Agents other than albiglutide are currently rec- years: 1%)
ommended to treat diabetes in pregnant women (ADA Genitourinary: Urinary tract infection (≤3%), difficulty
2018c). in micturition
Because of the long washout period, consider stopping Hematologic & oncologic: Decreased hematocrit (7%),
albiglutide at least 1 month before a planned preg- decreased hemoglobin (7%), decreased white blood
nancy. cell count (4%), lymphadenopathy (3%)
Hepatic: Increased serum ALT (5%), increased serum
AST (4%)
Albuterol (al BYOO ter ole) Hypersensitivity: Hypersensitivity reaction (3% to 6%)
Infection: Cold symptoms (3%), infection (<3%; skin/
Related Information
appendage: ≤2%)
Respiratory Diseases on page 1467 Local: Application site reaction (HFA inhaler: 6%)
Brand Names: US ProAir HFA; ProAir RespiClick; Neuromuscular & skeletal: Muscle cramps (1% to 7%;
Proventil HFA; Ventolin HFA; VoSpire ER [DSC] frequency increases with age), musculoskeletal pain
Brand Names: Canada Airomir; Ventolin Diskus; Ven- (3% to 5%), back pain (2% to 4%), hyperkinesia
tolin HFA; Ventolin I.V. Infusion; Ventolin Nebules P.F.; (≤4%), leg cramps (<3%)
Ventolin Respirator Ophthalmic: Conjunctivitis (children 2 to 6 years: 1%)
Pharmacologic Category Beta2 Agonist Otic: Otitis media (≤4%), ear disease (<3%), otalgia
Use (<3%), tinnitus (<3%)
Bronchospasm: Treatment or prevention of broncho- Respiratory: Throat irritation (10%), viral upper respi-
spasm in patients with reversible obstructive airway ratory tract infection (7%), respiratory tract disease
disease (6%), nasopharyngitis (≥5%; children: 2%), orophar-
Exercise-induced bronchospasm: Prevention of yngeal pain (≥5%; children: 2%), sinusitis (≥5%),
exercise-induced bronchospasm upper respiratory tract inflammation (5%), cough
Local Anesthetic/Vasoconstrictor Precautions (≥3%), flu-like symptoms (3%), dyspnea (<3%), lar-
No information available to require special precautions yngitis (<3%), oropharyngeal edema (<3%), pulmo-
Effects on Dental Treatment Key adverse event(s) nary disease (<3%), bronchitis (≥2%), increased
related to dental treatment: Xerostomia (normal salivary bronchial secretions (2%), wheezing (1% to 2%),
flow resumes upon discontinuation) epistaxis (children and adolescents 6 to 14 years:
Effects on Bleeding No information available to 1%), nasal congestion (1%), sinus headache (1%)
require special precautions Miscellaneous: Fever (≥5% to 6%), accidental
Adverse Reactions Incidence of adverse effects is injury (<3%)
dependent upon age of patient, dose, and route of <1%, postmarketing, and/or case reports: Anaphylaxis,
administration. Frequency not always defined. angina pectoris, angioedema, atrial fibrillation, dys-
>10%: geusia, exacerbation of diabetes mellitus, gag reflex,
Central nervous system: Excitement (children and hoarseness, hyperglycemia, hypokalemia, hypoten-
adolescents 2 to 14 years: 20%), nervousness (4% sion, irritability, ketoacidosis, lactic acidosis, metabolic
to 15%) acidosis, muscle spasm (children and adolescents 6
Neuromuscular & skeletal: Tremor (≥5% to 38%; fre- to 14 years), mydriasis (children and adolescents 6 to
quency increases with age) 14 years), oropharyngeal irritation, paradoxical
86
ALDESLEUKIN
bronchospasm, peripheral vasodilation, stomach pain health care systems and in limited geographies, in order
(children and adolescents 6 to 14 years), supraven- to gather real-world experience. A national launch is
tricular tachycardia, tongue ulcer, weakness planned for 2020.
Mechanism of Action Relaxes bronchial smooth
muscle by action on beta2-receptors with little effect
on heart rate
Alclometasone (al kloe MET a sone)
Pharmacodynamics/Kinetics Brand Names: US Aclovate [DSC]
Onset of Action Nebulization solution: ≤5 minutes; Pharmacologic Category Corticosteroid, Topical
Oral inhalation: DPI: 5.7 minutes (median), MDI: 5.4 to Use Steroid-responsive dermatosis: Treatment of
8.2 minutes (median); Oral: Immediate release: ≤30
inflammation and pruritic manifestations of corticoste-
minutes
roid-responsive dermatosis in adults and pediatric
Duration of Action Nebulization solution: 3 to 6 patients ≥1 year.
hours; Oral inhalation: DPI: ~2 hours (median), MDI:
~4 to 6 hours; Oral: Immediate release: 6 to 8 hours,
Extended release: Up to 12 hours
Half-life Elimination Oral inhalation: 3.8 to ~5 hours;
Oral: Immediate release: 5 to 6 hours, Extended
release: 9.3 hours Effects on Bleeding No information available to
Time to Peak
Time to peak, serum: Adverse Reactions Frequency not always defined.
Nebulization solution: 30 minutes; Oral inhalation: Central nervous system: Localized burning (1% to 2%)
DPI: 30 minutes, MDI: 25 minutes (mean); Oral: Dermatologic: Local dryness (2%), papular rash (2%),
Immediate release: ≤2 hours, Extended release: 6 erythema (1% to 2%), pruritus (1% to 2%), acne
hours vulgaris, allergic dermatitis, atrophic striae, folliculitis,
Time to peak, FEV1: hypopigmentation, miliaria, perioral dermatitis, skin
Nebulization solution: ~1 to 2 hours; Oral inhalation: atrophy
DPI: Within 30 minutes, MDI: 47 minutes; Oral: Endocrine & metabolic: Cushing's syndrome, growth
Immediate release: 2 to 3 hours suppression, HPA-axis suppression
Pregnancy Considerations Infection: Secondary infection
Albuterol crosses the placenta (Boulton 1997). Local: Local irritation (2%)
Mechanism of Action Topical corticosteroids have
Congenital anomalies (cleft palate, limb defects) have anti-inflammatory, antipruritic, and vasoconstrictive
rarely been reported following maternal use during properties. May depress the formation, release, and
pregnancy. Multiple medications were used in most activity of endogenous chemical mediators of inflam-
cases, no specific pattern of defects has been reported, mation (kinins, histamine, liposomal enzymes, prosta-
and no relationship to albuterol has been established. glandins) through the induction of phospholipase A2
The amount of albuterol available systemically following inhibitory proteins (lipocortins) and sequential inhibition
inhalation is significantly less in comparison to oral of the release of arachidonic acid. Alclometasone has
doses. low range potency.
Uncontrolled asthma is associated with adverse events Pharmacodynamics/Kinetics
on pregnancy (increased risk of perinatal mortality, Onset of Action Initial response (Ruthven 1988):
preeclampsia, preterm birth, low birth weight infants). Eczema: 5.3 days; Psoriasis: 6.7 days
Poorly controlled asthma or asthma exacerbations may Time to Peak Peak response (Ruthven 1988):
have a greater fetal/maternal risk than what is associ- Eczema: 13.9 days; Psoriasis: 14.8 days
ated with appropriately used asthma medications. Albu- Pregnancy Risk Factor C
terol is the preferred short acting beta-agonist when Pregnancy Considerations
treatment for asthma is needed during pregnancy Adverse events have been observed with corticoste-
(ACOG 2008; GINA 2018; NAEPP 2007). If high doses roids following topical application in animal reproduction
are required during labor and delivery, monitoring of studies.
glucose concentrations in the newborn for 24 hours is
r e c o m m e n d e d , e s p e c i a l l y i n p r e t e r m i n f a n ts Systemic bioavailability of topical corticosteroids is var-
(GINA 2018). iable (integrity of skin, use of occlusion, etc) and may be
further influenced by trimester of pregnancy (Chi 2017).
Albuterol may affect uterine contractility. Maternal pul- In general, the use of topical corticosteroids is not
monary edema and other adverse events have been associated with a significant risk of adverse pregnancy
reported when albuterol was used for tocolysis. Albu- outcomes. However, there may be an increased risk of
terol is not approved for use as a tocolytic; use caution low birth weight infants following maternal use of potent
when needed to treat bronchospasm in pregnant or very potent topical products, especially in high doses.
women. Use of mild to moderate potency topical corticosteroids
Data collection to monitor pregnancy and infant out- is preferred in pregnant women and the use of large
comes following exposure to asthma medications is amounts or use for prolonged periods of time should be
ongoing. For additional information contact the Mothers avoided (Chi 2016; Chi 2017; Murase 2014). Also avoid
To Baby Pregnancy Studies conducted by the Organ- areas of high percutaneous absorption (Chi 2017). The
ization of Teratology Information Specialists at risk of stretch marks may be increased with use of
1-877-311-8972 or visit http://mothertobaby.org/preg- topical corticosteroids (Murase 2014).
nancystudies/.
Product Availability ProAir Digihaler: FDA approved Aldesleukin (al des LOO kin)
December 2018. ProAir Digihaler will be available in
2019 through a small number of "Early Experience" Brand Names: US Proleukin
Programs, which will be conducted in partnership with Brand Names: Canada Proleukin
87
ALDESLEUKIN
Pharmacologic Category Antineoplastic Agent, Bio- Renal: Acute renal failure (grade 4: 1%)
logical Response Modulator; Antineoplastic Agent, Mis- Respiratory: Rhinitis (10%), apnea (grade 4: 1%)
cellaneous <1%, postmarketing, and/or case reports: Agitation,
Use allergic interstitial nephritis, anaphylaxis, angioedema,
Melanoma, metastatic: Treatment of metastatic mela- asthma, atrial arrhythmia, atrioventricular block, blind-
noma ness (transient or permanent), bowel infarction, bra-
Renal cell cancer, metastatic: Treatment of metastatic dycardia, brain disease, bullous pemphigoid, capillary
renal cell cancer leak syndrome, cardiomyopathy, cellulitis, cerebral
Limitations of use: Careful patient selection is neces- edema, cerebral lesion, cerebral vasculitis, cerebro-
sary. Assess performance status (PS); patients with a vascular accident, cholecystitis, colitis, delirium,
more favorable PS (Eastern Cooperative Oncology depression (severe; leading to suicide), diabetes mel-
Group [ECOG] PS 0) at treatment initiation respond litus, duodenal ulcer, endocarditis, eosinophilia, exac-
better to aldesleukin (higher response rate and lower erbation of Crohn's disease, extrapyramidal reaction,
toxicity). Experience in patients with ECOG PS >1 is gastritis, hematemesis, hemoptysis, hemorrhage
limited. (including cerebral, gastrointestinal, retroperitoneal,
Local Anesthetic/Vasoconstrictor Precautions subarachnoid, subdural), hepatic failure, hepatitis,
No information available to require special precautions hepatosplenomegaly, hypertension, hyperthyroidism,
Effects on Dental Treatment Key adverse event(s) hyperuricemia, hyperventilation, hypothermia, hypo-
related to dental treatment: Stomatitis ventilation, hypoxia, IgA glomerulonephritis (cres-
Effects on Bleeding Chemotherapy may result in centic), increased blood urea nitrogen, increased
significant myelosuppression, including thrombocytope- nonprotein nitrogen, inflammatory arthritis, insomnia,
nia. In patients who are under active treatment, a intestinal necrosis, intestinal obstruction, intestinal
medical consult is suggested. perforation, ischemic heart disease, leukocytosis, lym-
Adverse Reactions phocytopenia, malignant hyperthermia, meningitis,
>10%: myasthenia gravis (oculo-bulbar), mydriasis, myocar-
Cardiovascular: Hypotension (71%, grade 4: 3%), ditis, myopathy, myositis, neuralgia, neuritis, neuro-
peripheral edema (28%), tachycardia (23%), edema pathy, neutropenia, optic neuritis, pancreatitis,
(15%), vasodilatation (13%), supraventricular tachy- paranoia, pericardial effusion, pericarditis, peripheral
cardia (12%, grade 4: 1%), cardiac disease (11%; gangrene, phlebitis, pneumonia, pneumothorax, pul-
includes blood pressure changes, HF and ECG monary edema, pulmonary embolism, renal tubular
changes) necrosis, respiratory acidosis, respiratory arrest, res-
Central nervous system: Chills (52%), confusion piratory failure, restricted systemic blood flow, rhabdo-
(34%, grade 4: 1%), malaise (27%), drowsiness myolysis, scleroderma, seizure, shock, Stevens-
(22%), anxiety (12%), pain (12%), dizziness (11%) Johnson syndrome, syncope, thrombosis, thyroiditis,
Dermatologic: Skin rash (42%), pruritus (24%), exfo- tissue necrosis at injection site, tracheoesophageal
liative dermatitis (18%) fistula, transient ischemic attacks, urticaria, ventricular
Endocrine & metabolic: Weight gain (16%), acidosis premature contractions
(12%, grade 4: 1%), hypomagnesemia (12%), hypo- Mechanism of Action Aldesleukin is a human
calcemia (11%) recombinant interleukin-2 product which promotes pro-
Gastrointestinal: Diarrhea (67%, grade 4: 2%), vomit- liferation, differentiation, and recruitment of T and B
ing (19% to 50%, grade 4: 1%), nausea (19% to cells, natural killer (NK) cells, and thymocytes; causes
35%), stomatitis (22%), anorexia (20%), abdominal cytolytic activity in a subset of lymphocytes and sub-
pain (11%) sequent interactions between the immune system and
Genitourinary: Oliguria (63%, grade 4: 6%) malignant cells; can stimulate lymphokine-activated
Hematologic & oncologic: Thrombocytopenia (37%, killer (LAK) cells and tumor-infiltrating lymphocytes
grade 4: 1%), anemia (29%), leukopenia (16%) (TIL) cells.
Hepatic: Hyperbilirubinemia (40%, grade 4: 2%), Pharmacodynamics/Kinetics
increased serum AST (23%, grade 4: 1%) Half-life Elimination
Immunologic: Antibody development (66% to 74%) IV:
Infection: Infection (13%, grade 4: 1%) Children: Distribution: 14 ± 6 minutes; Elimination: 51
Neuromuscular & skeletal: Weakness (23%) ± 11 minutes
Renal: Increased serum creatinine (33%, grade 4: 1%) Adults: Distribution: 13 minutes; Terminal: 85 minutes
Respiratory: Dyspnea (43%, grade 4: 1%), pulmonary Pregnancy Risk Factor C
disease (24%; includes pulmonary congestion, rales, Pregnancy Considerations Adverse events were
rhonchi), cough (11%), respiratory tract disease observed in animal reproduction studies. Use during
(11%; includes acute respiratory distress syndrome, pregnancy only if benefits to the mother outweigh
pulmonary infiltrates, and pulmonary changes) potential risk to the fetus. Effective contraception is
Miscellaneous: Fever (29%, grade 4: 1%) recommended for fertile males and/or females using
1% to 10%:
this medication.
Cardiovascular: Cardiac arrhythmia (10%), cardiac
arrest (grade 4: 1%), myocardial infarction (grade
4: 1%), ventricular tachycardia (grade 4: 1%) Alectinib (al EK ti nib)
Central nervous system: Coma (grade 4: 2%), psy-
chosis (grade 4: 1%), stupor (grade 4: 1%) Brand Names: US Alecensa
Gastrointestinal: Enlargement of abdomen (10%) Brand Names: Canada Alecensaro
Genitourinary: Anuria (grade 4: 5%) Pharmacologic Category Antineoplastic Agent, Ana-
Hematologic & oncologic: Blood coagulation disorder plastic Lymphoma Kinase Inhibitor; Antineoplastic
(grade 4: 1%; includes intravascular coagulopathy) Agent, Tyrosine Kinase Inhibitor
Hepatic: Increased serum alkaline phosphatase (10%) Use Non-small cell lung cancer, metastatic: Treat-
Infection: Sepsis (grade 4: 1%) ment of anaplastic lymphoma kinase (ALK)-positive,
88
ALEMTUZUMAB
metastatic non-small cell lung cancer (NSCLC) as

detected by an approved test. Alemtuzumab (ay lem TU zoo mab)
No information available to require special precautions Brand Names: US Campath; Lemtrada
Effects on Dental Treatment No significant effects or Brand Names: Canada Lemtrada; MabCampath
complications reported Pharmacologic Category Antineoplastic Agent, Anti-
Effects on Bleeding No reports of bleeding or throm- CD52; Antineoplastic Agent, Monoclonal Antibody;
bocytopenia. Monoclonal Antibody
Adverse Reactions Use
>10%: B-cell chronic lymphocytic leukemia: Campath or
Cardiovascular: Edema (30%), bradycardia (8% MabCampath [Canadian product]: Treatment (as a
to 18%) single agent) of B-cell chronic lymphocytic leukemia
Central nervous system: Fatigue (≤41%), head- (B-CLL)
ache (17%) Multiple sclerosis, relapsing: Lemtrada: Treatment of
patients with relapsing forms of multiple sclerosis
(MS), generally reserved for patients who have had
Endocrine & metabolic: Hyperglycemia (36%), hypo-
an inadequate response to 2 or more medications
calcemia (32%), hypokalemia (29%), hypophospha-
indicated for the treatment of MS.
temia (21%), hyponatremia (20%), weight gain (11%)
Gastrointestinal: Constipation (34%), nausea (18%), Local Anesthetic/Vasoconstrictor Precautions
diarrhea (16%), vomiting (12%)
Hematologic & oncologic: Anemia (56%, grades 3/4: Effects on Dental Treatment Key adverse event(s)
2%), lymphocytopenia (22%, grades 3/4: 5%) related to dental treatment: Stomatitis and mucositis.
Hepatic: Increased serum AST (51%), increased Effects on Bleeding Chemotherapy may result in
serum alkaline phosphatase (47%), hyperbilirubine- significant myelosuppression, including thrombocytope-
mia (39%), increased serum ALT (34%) nia. In patients who are under active treatment, a
Neuromuscular & skeletal: Increased creatine phos- medical consult is suggested.
phokinase (43%), weakness (≤41%), musculoskele- Adverse Reactions
tal pain (≤29%), myalgia (≤29%), back pain (12%) Multiple sclerosis:
Renal: Increased serum creatinine (28%) >10%:
Respiratory: Cough (19%), dyspnea (16%) Central nervous system: Headache (52%), fatigue
1% to 10%: (18%), insomnia (16%), paresthesia (10%)
Cardiovascular: Pulmonary embolism (1%) Dermatologic: Skin rash (53%), urticaria (16%), pru-
Dermatologic: Skin photosensitivity (10%) ritus (14%)
Ophthalmic: Visual disturbances (10%) Endocrine & metabolic: Thyroid disease (13%
Renal: Renal insufficiency (8%) to 37%)
<1%, postmarketing, and/or case reports: Interstitial Gastrointestinal: Nausea (21%), diarrhea (12%)
pulmonary disease, pneumonitis Genitourinary: Urinary tract infection (19%)
Hematologic & oncologic: Lymphocytopenia (100%)
Mechanism of Action Alectinib is a tyrosine kinase
Immunologic: Antibody development (neutralizing:
receptor inhibitor which inhibits anaplastic lymphoma
5% to 94%; anti-alemtuzumab: 2% to 83%; no
kinase (ALK) and RET (with similar potency to ALK; Ou
effect on drug efficacy)
2016). ALK gene abnormalities due to mutations or
Infection: Infection (71%), herpes virus infection
translocations may result in expression of oncogenic
(16%), fungal infection (12% to 13%; including oral
fusion proteins (eg, ALK fusion protein) which alter
candidiasis, vulvovaginal candidiasis)
signaling and expression and result in increased cellu-
Local: Infusion-related reaction (92%)
lar proliferation and survival in tumors which express Neuromuscular & skeletal: Arthralgia (12%), back
these fusion proteins. Inhibition of ALK phosphorylation pain (12%), limb pain (12%)
and ALK-mediated activation of downstream signaling Respiratory: Nasopharyngitis (25%), upper respira-
results in decreased tumor cell viability. Alectinib is tory tract infection (16%), oropharyngeal pain
more potent than crizotinib against ALK, and can inhibit (11%), sinusitis (11%)
most of the clinically observed acquired ALK resistance Miscellaneous: Fever (29%)
mutations to crizotinib (Ou 2016). 1% to 10%:
Pharmacodynamics/Kinetics Cardiovascular: Flushing (10%), tachycardia (8%),
Half-life Elimination Parent drug: 33 hours; M4: 31 chest discomfort (7%), peripheral edema (5%),
hours atrial fibrillation (≤3%), bradycardia (≤3%), chest
Time to Peak 4 hours pain (≤3%), hypertension (≤3%), hypoten-
Pregnancy Considerations Based on data from ani- sion (≤3%)
mal reproduction studies and its mechanism of action, Central nervous system: Dizziness (10%), chills
alectinib may be expected to cause fetal harm if admin- (9%), anxiety (7%), neurological signs and symp-
istered during pregnancy. Females of reproductive toms (≤3%; transient)
potential should use effective contraception during ther- Dermatologic: Dermatitis (8%), erythema of
apy and for 1 week after the final dose. Males with skin (5%)
female partners of reproductive potential should use Gastrointestinal: Abdominal pain (10%), vomiting
effective contraception during therapy and for 3 months (10%), oral herpes simplex infection (9%), dysgeu-
after the last dose. sia (8%), dyspepsia (8%), appendicitis (≤3%), gas-
Prescribing and Access Restrictions Available troenteritis (≤3%), tooth infection (≤3%)
through specialty pharmacies and distributors. Further Genitourinary: Microscopic hematuria (8%), uterine
information may be obtained from the manufacturer, hemorrhage (5%), genital herpes simplex (1%)
Genentech, at 1-888-249-4918 or at https://www.- Hematologic & oncologic: Decreased CD-4 cell count
alecensa.com/. (6%), decreased CD-8 cell counts (6%), decreased
89
ALEMTUZUMAB
T cell lymphocytes (5%), immune thrombocytopenia monocytogenes, meningitis (herpes), neutropenia,

(2%), hematoma (1%), petechia (1%) opportunistic infection, optic neuropathy, pancytope-
Hypersensitivity: Angioedema (≤3%) nia, pneumonitis, progressive multifocal leukoence-
Infection: Influenza (8%), herpes zoster infection phalopathy, pulmonary alveolar hemorrhage, pure
(4%), herpes simplex infection (2%), human papil- red cell aplasia, reactivation of disease, reduced ejec-
loma virus infection (2%) tion fraction, retinal pigment changes (epitheliopathy),
Neuromuscular & skeletal: Myasthenia (7%), muscle rheumatoid arthritis, serum sickness, suicidal ideation,
spasm (6%), myalgia (6%), neck pain (5%), asthe- suicidal tendencies, syncope, thyroiditis, tuberculosis,
nia (5%) tumor lysis syndrome, type 1 diabetes mellitus, vascu-
Ophthalmic: Graves ophthalmopathy (1%) litis, vitiligo
Respiratory: Cough (9%), dyspnea (8%), bronchitis Mechanism of Action Alemtuzumab binds to CD52, a
(7%), epistaxis (5%), bronchospasm (≤3%), pneu- nonmodulating antigen present on the surface of B and
monia (≤3%) T lymphocytes, a majority of monocytes, macrophages,
Frequency not defined: NK cells, and a subpopulation of granulocytes. After
Central nervous system: Pain binding to CD52+ cells, an antibody-dependent lysis of
Respiratory: Hypersensitivity pneumonitis, pneumo- malignant cells occurs. In multiple sclerosis, alemtuzu-
nitis (with fibrosis), pulmonary infiltrates mab immunomodulatory effects may include alteration
B-cell chronic lymphocytic leukemia: in the number, proportions, and properties of some
>10%: lymphocyte subsets following treatment.
Cardiovascular: Hypotension (16%), cardiac arrhyth- Pharmacodynamics/Kinetics
mia (14%), hypertension (14%) Half-life Elimination IV: Campath: 11 hours (follow-
Central nervous system: Chills (53%), head- ing first 30 mg dose; range: 2 to 32 hours); 6 days
ache (14%) (following the last 30 mg dose; range: 1 to 14 days);
Dermatologic: Urticaria (16%), skin rash (13%) Lemtrada: ~2 weeks
Hematologic & oncologic: Lymphocytopenia (97%; Pregnancy Considerations
grades 3/4: 97%), neutropenia (77%; grades 3/4: Human IgG is known to cross the placental barrier;
42% to 64%), anemia (76%; grades 3/4: 12% to therefore, alemtuzumab may also cross the barrier
38%), thrombocytopenia (71%; grades 3/4: 13% and cause fetal B- and T-lymphocyte depletion.
to 52%)
Infection: Infection (50% to 74%), CMV viremia Information related to the use of alemtuzumab in preg-
(55%), cytomegalovirus disease (6% to 16%) nant females with multiple sclerosis is limited (Alrough-
Respiratory: Dyspnea (14%) ani 2016; Tuohy 2015). Alemtuzumab induces
Miscellaneous: Fever (69%) persistent thyroid disorders which may cause adverse
1% to 10%: maternal and fetal events. In a patient who developed
Cardiovascular: Tachycardia (10%) Graves disease during alemtuzumab therapy, neonatal
Central nervous system: Insomnia (10%), anxiety Graves disease with thyroid storm developed in her
(8%), dysesthesia (>5%), fatigue (>5%) infant exposed in utero 1 year following maternal
Dermatologic: Erythema of skin (4%) treatment.
Gastrointestinal: Diarrhea (10%), anorexia (>5%),
Effective contraception is recommended during and for
nausea (>5%), stomatitis (>5%), vomiting (>5%)
at least 6 months (Campath) after treatment for females
Hematologic & oncologic: Febrile neutropenia
and males of reproductive potential or 4 months (Lem-
≥ grade 3: 5% to 10%), autoimmune thrombocyto-
trada) after a treatment course for females of reproduc-
penia (2%)
tive potential.
Immunologic: Antibody development (2% to 8%;
neutralizing: 2%) Data collection to monitor pregnancy and infant out-
Infection: Sepsis (≥ grade 3: 3% to 10%) comes following exposure to alemtuzumab is ongoing.
Neuromuscular & skeletal: Musculoskeletal pain Health care providers are encouraged to enroll females
(>5%), tremor (3%) exposed to alemtuzumab during pregnancy in the preg-
Respiratory: Bronchospasm (>5%) nancy exposure registry (1-866-758-2990).
<1%, postmarketing, and/or case reports (any indica- Prescribing and Access Restrictions As of Sep-
tion): Anaphylactic shock, anaphylaxis, anemia, anti- tember 4, 2012, alemtuzumab (Campath) is no longer
GBM disease, aplastic anemia, autoimmune hemolytic commercially available in the United States (or Europe);
anemia, autoimmune hepatitis, bone marrow aplasia, a restricted distribution program will allow access (free
bone marrow depression, bone marrow hypoplasia, of charge) for appropriate patients. Information on
cardiac failure, cardiomyopathy, cerebrovascular acci- necessary documentation and requirements is available
dent, cholecystitis, chronic inflammatory demyelinat- at Campath Distribution Program (1-877-422-6728) or
ing polyradiculoneuropathy, connective tissue disease Genzyme Medical Information (1-800-745-4447, option
(undifferentiated), Epstein-Barr-associated lympho- 2).
proliferative disorder, Epstein-Barr infection, goiter,
Goodpasture syndrome, graft versus host disease
(transfusion associated), Graves disease, Guillain- Alendronate (a LEN droe nate)
Barre syndrome, hemolytic anemia, hemophilia A
Related Information
(acquired [anti-Factor VIII antibodies]), hemorrhagic
stroke, hyperthyroidism, hypothyroidism, immunolog- Osteonecrosis of the Jaw on page 1486
ical signs and symptoms (hemophagocytic lymphohis- Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
tiocytosis), ischemic stroke, listeriosis (including on page 1484
gastroenteritis, encephalitis, sepsis), lymphoprolifera- Brand Names: US Binosto; Fosamax
tive disorder, malignant lymphoma, malignant mela- Brand Names: Canada Fosamax
noma, malignant neoplasm of thyroid, membranous Generic Availability (US) May be product dependent
glomerulonephritis, meningitis due to listeria Pharmacologic Category Bisphosphonate Derivative
90
ALENDRONATE
Use Neuromuscular & skeletal: Musculoskeletal pain

Osteoporosis: (≤6%; includes bone pain, joint pain, and muscle
Binosto: Treatment of osteoporosis in postmeno- pain), muscle cramps (≤1%)
pausal females and to increase bone mass in males <1%, postmarketing, and/or case reports: Alopecia,
with osteoporosis conjunctivitis, dizziness, duodenal ulcer (may be
Fosamax: Treatment and prevention of osteoporosis severe with complications), dysgeusia, episcleritis,
in postmenopausal females; treatment to increase erythema, erosive esophagitis, esophageal perfora-
bone mass in males with osteoporosis; treatment of tion, esophageal stenosis, esophageal ulcer, esoph-
glucocorticoid-induced osteoporosis in males and agitis, exacerbation of asthma, femur fracture (low-
females with low bone mineral density who are energy fractures, including subtrochanteric and dia-
receiving a daily dosage ≥7.5 mg of prednisone (or physeal), fever, hypersensitivity reaction (includes
equivalent) angioedema and urticaria), hypocalcemia (sympto-
Paget disease: Fosamax: Treatment of Paget disease matic), joint swelling, malaise, oropharyngeal ulcer;
of the bone in patients (males and females) who are osteonecrosis of the jaw, peripheral edema, pruritus,
symptomatic, at risk for future complications, or with scleritis, skin rash (occasionally with photosensitivity),
alkaline phosphatase ≥2 times the upper limit of Stevens-Johnson syndrome, toxic epidermal necroly-
normal sis, uveitis, vertigo, weakness
Local Anesthetic/Vasoconstrictor Precautions Dosing
No information available to require special precautions Adult & Geriatric Note: The optimal duration of
Effects on Dental Treatment Osteonecrosis of the osteoporosis treatment has not been determined. In
jaw (ONJ), generally associated with local infection and/ postmenopausal women with low fracture risk, con-
or tooth extraction and often with delayed healing, has sider a drug holiday after 5 years of oral bisphospho-
been reported in patients taking bisphosphonates. nate therapy. In postmenopausal women who remain
Symptoms included nonhealing extraction socket or at high fracture risk, consider extending treatment for
an exposed jawbone. Most reported cases of up to 10 years (AACE/ACE [Camacho 2016]; Adler
bisphosphonate-associated osteonecrosis have been 2016). Although evidence is limited, applying these
in cancer patients treated with intravenous bisphosph- recommendations to treatment duration in older men
onates. However, some have occurred in patients with may be considered (Adler 2016). Patients should
postmenopausal osteoporosis taking oral bisphospho- receive supplemental calcium and vitamin D if dietary
nates. The risk of developing ONJ in patients taking oral intake is inadequate.
bisphosphonates remains low with an estimated prev- Osteoporosis in postmenopausal females: Oral:
alence of 0.1% (one out of every 1000 cases of patients Prophylaxis: 5 mg once daily or 35 mg once weekly
exposed to oral bisphosphonates). The benefits of Treatment: 10 mg once daily or 70 mg once weekly
using the oral bisphosphonates to prevent osteoporosis Osteoporosis in males (to increase bone mass):
significantly outweighs the small risk of developing Oral: Treatment: 10 mg once daily or 70 mg once
bisphosphonate-associated ONJ. Also, at the present weekly
time, there are no validated diagnostic techniques to Osteoporosis secondary to glucocorticoids in
determine which patients are at increased risk of devel- males and females: Oral:
oping ONJ. ONJ in patients taking these drugs can Treatment: 5 mg once daily; a dose of 10 mg once
occur spontaneously. In addition, the risk of ONJ daily should be used in postmenopausal females
increases with specific procedures that increase bone who are not receiving estrogen.
trauma, particularly tooth extractions. Other factors that Prevention (off-label use): 5 mg once daily; a dose of
increase risk of ONJ in patients taking these drugs are 10 mg once daily should be used in postmeno-
age (>65 years of age), periodontitis, use of bisphosph- pausal females who are not receiving estrogen
onates for >2 years, smoking, wearing dentures, and (Saag 1998). Note: Use is not recommended in
diabetes. Patients who develop ONJ while on women who are pregnant or who plan on becoming
bisphosphonate therapy should receive care by an oral pregnant (ACR [Buckley 2017]).
surgeon. See Dental Health Professional Considera- Paget disease of bone in males and females: Oral:
tions. 40 mg once daily for 6 months
Effects on Bleeding No information available to Re-treatment: Following a 6-month post-treatment
require special precautions evaluation period, treatment with alendronate may
Adverse Reactions Note: Incidence of adverse be considered in patients who have relapsed based
effects (mostly GI) increases significantly in patients on increases in serum alkaline phosphatase, which
treated for Paget disease at 40 mg/day. should be measured periodically. Re-treatment may
>10%: Endocrine & metabolic: Decreased serum cal- also be considered in those who failed to normalize
cium (18%; transient, mild) their serum alkaline phosphatase. The Endocrine
1% to 10%: Society guidelines suggest re-treatment may be
Central nervous system: Headache (3%) required between 2 and 6 years (Singer 2014).
Endocrine & metabolic: Decreased serum phosphate Missed doses (once weekly): If a once-weekly dose is
(10%; transient, mild) missed, it should be given the next morning after
Gastrointestinal: Abdominal pain (2% to 7%), acid remembered; may then return to the original once-
regurgitation (1% to 5%), flatulence (≤4%), gastro- weekly schedule (original scheduled day of the
esophageal reflux disease (3%), constipation (≤3%), week), however, do not give 2 doses on the
diarrhea (≤3%), dyspepsia (1% to 3%), nausea (1% same day.
to 3%), esophageal ulcer (2%), dysphagia (1%), Bone loss associated with androgen deprivation
melena (1%), abdominal distension (≤1%), gastric therapy in prostate cancer, prevention (off-label
ulcer (≤1%; may be severe with complications), use): Oral: 70 mg once weekly (Greenspan 2007;
gastritis (≤1%) Greenspan 2008; Klotz 2013)
91
ALENDRONATE
Osteogenesis imperfecta (off-label use): Oral: Weight-directed dosing: Children ≥3 years and
10 mg once daily (Chevrel 2006) or 70 mg once Adolescents: Oral: 1 mg/kg/dose once weekly
weekly (Shapiro 2010; Xu 2016). (Paksu 2012); if using a solid dosage form, con-
Renal Impairment: Adult sider dose rounding to the nearest 10 mg (up or
CrCl ≥35 mL/minute: No dosage adjustment neces- down as appropriate) (Lethaby 2007). Dosing
sary. based on a prospective trial of 26 patients (age
CrCl <35 mL/minute: Use not recommended. range: 3 to 17 years); results showed after one
Hepatic Impairment: Adult No dosage adjustment year of treatment, increased BMD and decreased
necessary. alkaline phosphatase.
Pediatric O s t e o pe n i a / O s t e op o ro s i s , rh e u m a t ol o g y
Note: Patients should receive supplemental calcium patients (eg, JIA, SLE, dermatomyositis): Lim-
and vitamin D if dietary intake is inadequate. ited data available: Children ≥4 years and Adoles-
Osteogenesis imperfecta: Limited data available, cents:
dosing regimens and efficacy results variable ≤20 kg: Oral: 5 mg once daily
(Akcay 2008; Pizones 2005; Seikaly 2005; Ward >20 kg to 30 kg: Oral: 5 or 10 mg once daily
2011): Children ≥2 years and Adolescents: >30 kg: Oral: 10 mg once daily
≤30 kg: Oral: 5 mg once daily Dosing based on a prospective trial (multicenter
30 to <40 kg: 5 or 10 mg once daily and single center) (Bianchi 2000; Cimaz 2002;
≥40 kg: Oral: 10 mg once daily Unal 2006); results from trials showed bone min-
Dosing based on several prospective and retro- eral density (BMD) was significantly increased (to
spective trials; most smaller studies reported normal values in some patients) after alendronate
increased bone mineral density (BMD), decreased therapy; in some cases, bone turnover markers
frequency of fractures, alleviation of chronic pain, were reduced without a reduction of inflammatory
and in some patients increased mobility (Akcay activity (underlying rheumatologic disease
2008; Pizones 2005; Seikaly2005; Unal 2005; process)
Vyskocil 2005). The largest trial, a multicenter, Mechanism of Action A bisphosphonate which inhib-
randomized, placebo-controlled trial (n=109 in its bone resorption via actions on osteoclasts or on
treatment group, n=83 completed 2-year follow- osteoclast precursors; decreases the rate of bone
up) reported significant increases in lumbar spine resorption, leading to an indirect increase in bone
BMD; however, other efficacy markers including mineral density. In Paget disease, characterized by
long-bone fracture rate and pediatric disability disordered resorption and formation of bone, inhibition
score were no different than placebo (Ward 2011). of resorption leads to an indirect decrease in bone
Osteopenia associated with cystic fibrosis (CF): formation; but the newly-formed bone has a more
Limited data available: Children ≥5 years and Ado- normal architecture.
lescents: Oral: Contraindications
≤25 kg: 5 mg once daily Hypersensitivity to alendronate or any component of the
>25 kg: 10 mg once daily formulation; hypocalcemia; abnormalities of the
Dosing based on a randomized, placebo-controlled esophagus (eg, stricture, achalasia) which delay
trial of CF patients (n=128, treatment group: n=65) esophageal emptying; inability to stand or sit upright
with low apparent BMD age and inadequate for at least 30 minutes; increased risk of aspiration
response to calcium and calcifediol treatment; (effervescent tablets; oral solution)
results showed a significant increase in BMD Canadian labeling: Additional contraindications (not in
(16.3% vs 3.1% from baseline); evaluation of the US labeling): Renal insufficiency with creatinine
effect on fracture rate not possible due to sample clearance <35 mL/minute
size and duration (trial duration: 2 years); alendr- Documentation of allergenic cross-reactivity for
onate appeared to be well-tolerated with no nota- bisphosphonates is limited. However, because of sim-
ble difference in adverse effects reported ilarities in chemical structure and/or pharmacologic
(Bianchi 2013) actions, the possibility of cross-sensitivity cannot be
Osteopenia, nonambulatory patients (eg, cere- ruled out with certainty.
bral palsy, muscular dystrophy): Limited data Warnings/Precautions Use caution in patients with
available, efficacy results variable: Note: Due to renal impairment (not recommended for use in patients
added complexity of administration requirements with CrCl <35 mL/minute); hypocalcemia must be cor-
(eg, remaining in an upright position for an rected before therapy initiation; ensure adequate cal-
extended time) weekly dosing is preferred in these cium and vitamin D intake. May cause irritation to upper
patients. gastrointestinal mucosa. Esophagitis, dysphagia,
Fixed dosing (Apkon 2008; Houston 2014; Sholas esophageal ulcers, esophageal erosions, and esopha-
2005): Children ≥6 years and Adolescents: Oral: geal stricture (rare) have been reported; risk increases
in patients unable to comply with dosing instructions.
Usual reported dose: 35 mg once weekly. Dosing
Use with caution in patients with dysphagia, esopha-
based on experience in 42 patients (age range: 6
geal disease, gastritis, duodenitis, or ulcers (may wor-
to 16 years) from two case series and a retro-
sen underlying condition). Discontinue use if new or
spective trial. In the retrospective cohort study
worsening symptoms develop.
(n=29 mean age: 12 years), treatment showed a
non-statistically significant trend in Z-score stabi- Osteonecrosis of the jaw (ONJ), also referred to as
lization (Houston 2014). A case series of 10 medication-related osteonecrosis of the jaw (MRONJ),
patients (age range: 6 to 16 years) reported fewer has been reported in patients receiving bisphospho-
fractures after treatment started compared to the nates. Known risk factors for MRONJ include invasive
prior year; alendronate was reported as being well dental procedures (eg, tooth extraction, dental implants,
tolerated; one patient discontinued therapy for boney surgery), cancer diagnosis, concomitant therapy
hematemesis (also receiving high-dose ibuprofen (eg, chemotherapy, corticosteroids, angiogenesis inhib-
therapy) (Sholas 2005). itors), poor oral hygiene, ill-fitting dentures, and
92
ALENDRONATE
comorbid disorders (anemia, coagulopathy, infection, with same drug or another bisphosphonate; avoid use
preexisting dental or periodontal disease). Risk may in patients with a history of these symptoms in associ-
increase with increased duration of bisphosphonate ation with bisphosphonate therapy.
use. According to a position paper by the American
Association of Maxillofacial Surgeons (AAOMS), Conjunctivitis, uveitis, episcleritis, and scleritis have
MRONJ has been associated with bisphosphonate been reported with alendronate; patients presenting
and other antiresorptive agents (denosumab), and anti- with signs of ocular inflammation may require further
angiogenic agents (eg, bevacizumab, sunitinib) used for ophthalmologic evaluation. Potentially significant drug-
the treatment of osteoporosis or malignancy; risk of drug interactions may exist, requiring dose or frequency
MRONJ is significantly higher in cancer patients receiv- adjustment, additional monitoring, and/or selection of
ing antiresorptive therapy compared to patients receiv- alternative therapy. Consult drug interactions database
ing osteoporosis treatment (regardless of medication for more detailed information. Each effervescent tablet
used or dosing schedule). MRONJ risk is also
contains 650 mg of sodium (NaCl 1650 mg); use with
increased with intravenous antiresorptive use com-
caution in patients following a sodium-restricted diet.
pared to the minimal risk associated with oral
bisphosphonate use, although risk appears to increase Warnings: Additional Pediatric Considerations
with oral bisphosphonates when duration of therapy The potential adverse effects of bisphosphonate ther-
exceeds 4 years (AAOMS [Ruggiero 2014]). The man- apy on the immature bones of growing children are
ufacturer's labeling states that in patients requiring concerning and data to fully describe are insufficient.
invasive dental procedures, discontinuing bisphospho- Animal data has shown alendronate (high-dose) inhibits
nates may reduce the risk of ONJ and clinical judgment longitudinal bone growth (Rauch 2004); pediatric
should guide the decision. However, the AAOMS sug- patients with osteogenesis imperfecta (OI) treated with
gests there is currently no evidence that interrupting pamidronate for 4 years showed increased height z
oral bisphosphonate therapy alters the risk of ONJ scores (Zeitlin 2003); pediatric growth effects with other
following tooth extraction, and that in patients receiving bisphosphonates is lacking. Possible decreased bone
oral bisphosphonates for <4 years who have no clinical
remodeling affecting growth or fracture healing may
risk factors, no alternations or delay in any procedure
common to oral/maxillofacial surgeons, periodontists, occur with bisphosphonate therapy; a case-report in
and other dental providers is necessary (special con- an adolescent treated with high-dose pamidronate
siderations apply to patients receiving dental implants). described abnormal long-bone modeling (Rauch
Conversely, in patients receiving oral bisphosphonates 2004); a large, placebo-controlled OI trial (n=109, age
for >4 years or in patients receiving oral bisphospho- range: 4 to 19 years) reported that alendronate did not
nates for <4 years who have also taken corticosteroids interfere with fracture healing (Ward 2011). Rapid and in
or antiangiogenic medications concomitantly, the some cases significant weight gain has been reported
AAOMS recommends considering a 2-month, drug-free with pamidronate therapy in pediatric patients which
period prior to invasive dental procedures (recommen- may negatively affect rehabilitation in patients with OI
dation based on a theoretical benefit). Patients devel- (Zeitlin 2003). Monitor patients closely.
oping ONJ during therapy should receive care by an Drug Interactions
oral surgeon (AAOMS [Ruggiero 2014]). According to Metabolism/Transport Effects None known.
the manufacturer, discontinuation of the bisphospho-
nate therapy should be considered (based on risk/
benefit evaluation) in patients who develop ONJ. Avoid concomitant use of Alendronate with any of the
following: Parathyroid Hormone
Atypical femur fractures (AFF) have been reported in Increased Effect/Toxicity
patients receiving bisphosphonates. The fractures
Alendronate may increase the levels/effects of: Defer-
include subtrochanteric femur (bone just below the hip
asirox
joint) and diaphyseal femur (long segment of the thigh
bone). Some patients experience prodromal pain weeks The levels/effects of Alendronate may be increased
or months before the fracture occurs. It is unclear if by: Aminoglycosides; Angiogenesis Inhibitors (Sys-
bisphosphonate therapy is the cause for these frac- temic); Aspirin; Nonsteroidal Anti-Inflammatory Agents
tures; atypical femur fractures have also been reported
Decreased Effect
in patients not taking bisphosphonates, and in patients
Alendronate may decrease the levels/effects of: Para-
receiving glucocorticoids. Patients receiving long-term
(>3 to 5 years) bisphosphonate therapy may be at an thyroid Hormone
increased risk (Adler 2016; NOF [Cosman 2014]); how- The levels/effects of Alendronate may be decreased
ever, benefits of therapy (when used for osteoporosis) by: Antacids; Calcium Salts; Iron Salts; Magnesium
generally outweigh absolute risk of AFF within the first 5 Salts; Multivitamins/Minerals (with ADEK, Folate,
years of treatment (Adler 2016). Patients presenting
Iron); Multivitamins/Minerals (with AE, No Iron); Proton
with thigh or groin pain with a history of receiving
bisphosphonates should be evaluated for femur frac- Pump Inhibitors
ture. Consider interrupting bisphosphonate therapy in Food Interactions All food and beverages interfere
patients who develop a femoral shaft fracture; assess with absorption. Coadministration with dairy products
for fracture in the contralateral limb. may decrease alendronate absorption. Beverages
(especially orange juice, coffee, and mineral water)
Severe (and occasionally debilitating) bone, joint, and/
and food may reduce the absorption of alendronate as
or muscle pain have been reported during bisphospho-
nate treatment. The onset of pain ranged from a single much as 60%. Management: Alendronate must be
day to several months. Consider discontinuing therapy taken first thing in the morning and ≥30 minutes before
in patients who experience severe symptoms; symp- the first food, beverage (except plain water), or other
toms usually resolve upon discontinuation. Some medication of the day.
patients experienced recurrence when rechallenged Dietary Considerations Ensure adequate calcium
93
ALENDRONATE
and vitamin D intake; if dietary intake is inadequate, extrapolated to patient-years of bisphosphonate expo-
dietary supplementation is recommended. Women and sure, this prevalence rate of 0.1% equates to a fre-
men should consume: quency of 28 cases per 100,000 person-years of oral
Calcium: 1,000 mg/day (men: 50 to 70 years) or bisphosphonate treatment. An Australian group (Mav-
1,200 mg/day (women ≥51 years and men ≥71 years) rokokki 2007), identified the frequency of BP-associated
(IOM 2011; NOF [Cosman 2014]) ONJ in osteoporotic patients, mainly taking weekly oral
Vitamin D: 800 to 1,000 int. units/day (men and women alendronate, was 1 in 8,470 to 1 in 2,260 (0.01% to
≥50 years) (NOF [Cosman 2014]). Recommended 0.04%) patients. If extractions were carried out, the
Dietary Allowance (RDA): 600 int. units daily (men calculated frequency was 1 in 1,130 to 1 in 296
and women ≤70 years) or 800 int. units/day (men (0.09% to 0.34%) patients. The median time to onset
and women ≥71 years) (IOM 2011). of ONJ in alendronate patients was 24 months.
According to the 2011 report by the American Dental
Half-life Elimination Exceeds 10 years
Association (ADA), the incidence of BP-associated ONJ
Pregnancy Risk Factor C remains low and the benefits of using oral bisphosph-
Pregnancy Considerations Adverse events were onates significantly outweighs the risk of developing
observed in animal reproduction studies. It is not known BP-associated ONJ for treatment and prevention of
if bisphosphonates cross the placenta, but fetal expo- osteoporosis and cancer treatment (Hellstein 2011).
sure is expected (Djokanovic 2008; Stathopoulos 2011). The full 47-page report can be accessed at http://www.-
Bisphosphonates are incorporated into the bone matrix ada.org/~/media/ADA/Member%20Center/FIles/
and gradually released over time. The amount available topics_ARONJ_report.ashx.
in the systemic circulation varies by dose and duration
of therapy. Theoretically, there may be a risk of fetal The ADA review of 2011 stated the incidence of oral
harm when pregnancy follows the completion of ther- BP-associated ONJ was one case for every 1,000
apy; however, available data have not shown that individuals exposed to oral bisphosphonates (0.1%)
exposure to bisphosphonates during pregnancy signifi- (Hellstein 2011).
cantly increases the risk of adverse fetal events (Djo- The most comprehensive review to date on osteonec-
kanovic 2008; Levy 2009; Stathopoulos 2011). Until rosis of the jaw bone (ONJ) has been published in the
additional data is available, most sources recommend Journal of Bone and Mineral Research (Khan 2015),
discontinuing bisphosphonate therapy in women of and written by an International Task Force of authors,
reproductive potential as early as possible prior to a totaling 34, from academe; industry; clinical medical
planned pregnancy; use in premenopausal women and dental practice; oral and maxillofacial surgery; bone
should be reserved for special circumstances when and mineral research; epidemiology; medical and den-
rapid bone loss is occurring (Bhalla 2010; Pereira tal oncology; orthopedic surgery; osteoporosis
2012; Stathopoulos 2011). Because hypocalcemia has research; muscle and bone research; endocrinology
been described following in utero bisphosphonate and diagnostic sciences. The work provides a system-
exposure, exposed infants should be monitored for atic review of the literature and international consensus
hypocalcemia after birth (Djokanovic 2008; Stathopou- on the classification, incidence, pathophysiology, diag-
los 2011). nosis, and management of ONJ in both oncology and
Breastfeeding Considerations It is not known if osteoporosis patient populations. This review of the
alendronate is excreted into breast milk. The manufac- literature from January 2003 to April 2014, with 299
turer recommends that caution be exercised when references, offers recommendations for management of
administering alendronate to nursing women. ONJ based on multidisciplinary international con-
Dosage Forms: US sensus.
Solution, Oral:
Generic: 70 mg/75 mL (75 mL) Prevalence and incidence of ONJ in osteoporosis
Tablet, Oral: patients from the Task Force report:
Fosamax: 70 mg Prevalence – the percent of osteoporotic population
Generic: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg affected with ONJ
Tablet Effervescent, Oral:
Binosto: 70 mg After reviewing all literature reports on this subject, the
Dental Health Professional Considerations A Task Force concluded that the prevalence of ONJ in
patients prescribed oral BPs for the treatment of osteo-
review of 2,408 published cases of bisphosphonate-
porosis ranges from 0% to 0.04% with the majority
associated osteonecrosis of the jaw bone (BP-associ-
being below 0.001%. However, the Task Force does
ated ONJ) was done by Filleul 2010. BP therapy was
cite the study of (Lo et al) that evaluated the Kaiser
associated with 89% of the cases to treat malignancies
Permanente database and found the prevalence of
and 11% of the cases to treat nonmalignant conditions.
ONJ in those receiving BPs for more than 2 years to
Information on the specific bisphosphonate used was
range from 0.05% to 0.21% and appeared to be related
available for 1,694 of the patients. Intravenous therapy
to duration of exposure. As mentioned above, the
(primarily zoledronic acid) was received by 88% of the
American Dental Association has previously reported
patients and 12% received oral treatment (primarily
that the prevalence of ONJ in osteoporosis patients
alendronate). Of all the cases of BP-associated ONJ,
using oral BPs to be 1 out of 1,000 or 0.1% (Hell-
67% were preceded by tooth extraction and for 26% of
stein 2011).
patients, there was no predisposing factor identified.
Incidence - the rate at which ONJ occurs or the number
A 2010 retrospective case review reported the preva-
of times it happens
lence of BP-associated ONJ in patients using alendro-
nate-type drugs was one out of 952 patients or ~0.1% From currently available data, the incidence of ONJ in
(Lo 2010). Of the 8,572 respondents, nine cases of ONJ the osteoporosis patient population appears to be low
were identified; five had developed ONJ spontaneously ranging from 0.15% to less than 0.001% person-years
and four developed ONJ after tooth extraction. When drug exposure. In terms of the osteoporosis patient
94
ALFENTANIL
population taking oral BPs, the incidence ranges from Use

1.04 to 69 per 100,000 patient years of drug exposure. Analgesia: Analgesic adjunct for the maintenance of
anesthesia with barbiturate/nitrous oxide/oxygen;
analgesic with nitrous oxide/oxygen in the mainte-
Alendronate and Cholecalciferol nance of general anesthesia; analgesic component
(a LEN droe nate & kole e kal SI fer ole)
for monitored anesthesia care.
Related Information Anesthetic: Primary anesthetic for induction of anes-
Alendronate on page 90 thesia in general surgery when endotracheal intuba-
Cholecalciferol on page 305 tion and mechanical ventilation are required.
Brand Names: US Fosamax Plus D Local Anesthetic/Vasoconstrictor Precautions
Brand Names: Canada Fosavance
Pharmacologic Category Bisphosphonate Deriva-
related to dental treatment: Patients may experience
tive; Vitamin D Analog
orthostatic hypotension as they stand up after treat-
Use ment; especially if lying in dental chair for extended
Osteoporosis: Treatment of osteoporosis in postme- periods of time. Use caution with sudden changes in
nopausal females; increase bone mass in males with position during and after dental treatment.
osteoporosis Erythromycin inhibits the liver metabolism of alfentanil
Limitations of use: Not for use in the treatment of resulting in increased sedation and prolonged respi-
vitamin D deficiency. ratory depression. Clarithromycin may act similarly.
Local Anesthetic/Vasoconstrictor Precautions Effects on Bleeding No information available to
No information available to require special precautions require special precautions
Effects on Dental Treatment Osteonecrosis of the Adverse Reactions
jaw (ONJ), generally associated with local infection and/ >10%:
or tooth extraction and often with delayed healing, has Cardiovascular: Hypertension (18%), chest wall
been reported in patients taking bisphosphonates. rigidity (17%), bradycardia (14%), tachycardia (12%)
Symptoms included nonhealing extraction socket or Gastrointestinal: Nausea (28%), vomiting (18%)
an exposed jawbone. Most reported cases of 1% to 10%:
bisphosphonate-associated osteonecrosis have been Cardiovascular: Hypotension (10%), cardiac arrhyth-
in cancer patients treated with intravenous bisphosph- mia (1% to 3%)
onates. However, some have occurred in patients with Central nervous system: Dizziness (3% to 9%), drows-
postmenopausal osteoporosis taking oral bisphospho- iness (≤3%), sedation (≤3%; postoperative)
nates. The risk of developing ONJ in patients taking oral Neuromuscular & skeletal: Muscle movements (3% to
bisphosphonates remains low with an estimated prev- 9%; skeletal)
Ophthalmic: Blurred vision (1% to 3%)
alence of 0.1% (one out of every 1000 cases of patients
Respiratory: Apnea (3% to 9%), respiratory depres-
exposed to oral bisphosphonates). The benefits of
sion (1% to 3%; postoperative)
using the oral bisphosphonates to prevent osteoporosis
significantly outweighs the small risk of developing Cardiovascular: Peripheral vasodilation
bisphosphonate-associated ONJ. Also, at the present Gastrointestinal: Constipation
time, there are no validated diagnostic techniques to Ophthalmic: Miosis
determine which patients are at increased risk of devel- <1%, postmarketing, and/or case reports: Anaphylaxis,
oping ONJ. ONJ in patients taking these drugs can bronchospasm, confusion (postoperative), drug
occur spontaneously. In addition, the risk of ONJ dependence, euphoria (postoperative), headache,
increases with specific procedures that increase bone hypercapnia, laryngospasm, muscle rigidity (neck
trauma, particularly tooth extractions. Other factors that and extremities), myoclonus, pruritus, shivering, urti-
increase risk of ONJ in patients taking these drugs are caria
age (>65 years of age), periodontitis, use of bisphosph- Mechanism of Action Binds with stereospecific recep-
onates for >2 years, smoking, wearing dentures, and tors at many sites within the CNS, increases pain
diabetes. Patients who develop ONJ while on threshold, alters pain perception, inhibits ascending
bisphosphonate therapy should receive care by an oral pain pathways; is an ultra short-acting opioid
surgeon. See Dental Health Professional Considera- Pharmacodynamics/Kinetics
tions. Onset of Action Rapid, within 5 minutes
Effects on Bleeding No information available to Duration of Action Dose dependent: 30 to 60
require special precautions minutes
Adverse Reactions See individual agents. Half-life Elimination
Mechanism of Action See individual agents. Newborns (premature): 5.33 to 9 hours (Davis 1988;
Pregnancy Considerations Animal reproduction Marlow 1990)
studies have not been conducted with this combination. Children: 40 to 63 minutes (Davis 1988; Meistelman
1987; Roure 1987)
See individual agents.
Adults: 90 to 111 minutes
Dental Health Professional Considerations See
Pregnancy Considerations Adverse events have
Alendronate monograph.
been observed in some animal reproduction studies.
Alfentanil is known to cross the placenta, which may
Alfentanil (al FEN ta nil) result in severe respiratory depression in the newborn
(Mattingly 2003). When used for pain relief during labor,
Brand Names: Canada Alfenta; Alfentanil Injection, opioids may temporarily affect the heart rate of the fetus
USP (ACOG 2002). Use during labor and immediately prior
Pharmacologic Category Analgesic, Opioid; Anilido- to labor is not recommended by the manufacturer.
piperidine Opioid Controlled Substance C-II
95
ALFUZOSIN
Alfuzosin (al FYOO zoe sin) Alirocumab (al i ROK ue mab)
Related Information Brand Names: US Praluent

Clinical Risk Related to Drugs Prolonging QT Interval Brand Names: Canada Praluent
on page 1462 Pharmacologic Category Antilipemic Agent, PCSK9
Brand Names: US Uroxatral Inhibitor; Monoclonal Antibody
Brand Names: Canada Apo-Alfuzosin®; Sandoz-Alfu- Use
zosin; Teva-Alfuzosin PR; Xatral Hyperlipidemia, primary: Adjunct to diet and maxi-
Pharmacologic Category Alpha1 Blocker mally tolerated statin therapy for the treatment of
Use Benign prostatic hyperplasia: Treatment of signs adults with heterozygous familial hypercholesterole-
and symptoms of benign prostatic hyperplasia (BPH) mia (HeFH) or clinical atherosclerotic cardiovascular
Local Anesthetic/Vasoconstrictor Precautions disease, who require additional lowering of LDL-C.
Alfuzosin is one of the drugs confirmed to prolong the Local Anesthetic/Vasoconstrictor Precautions
QT interval and is accepted as having a risk of causing No information available to require special precautions
torsade de pointes. The risk of drug-induced torsade de Effects on Dental Treatment No significant effects or
pointes is extremely low when a single QT interval complications reported
prolonging drug is prescribed. In terms of epinephrine, Effects on Bleeding No information available to
it is not known what effect vasoconstrictors in the local require special precautions
anesthetic regimen will have in patients with a known Adverse Reactions
history of congenital prolonged QT interval or in patients >10%: Local: Injection site reaction (7% to 17%)
taking any medication that prolongs the QT interval. 1% to 10%:
Until more information is obtained, it is suggested that Gastrointestinal: Diarrhea (5%)
the clinician consult with the physician prior to the use of Hematologic & oncologic: Bruise (2%)
a vasoconstrictor in suspected patients, and that the Hepatic: Liver enzyme disorder (3%), increased serum
vasoconstrictor (epinephrine, mepivacaine and levonor- transaminases (>3 x ULN: 2%)
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used Hypersensitivity: Hypersensitivity reaction (9%; includ-
with caution. ing hypersensitivity angiitis, pruritus, severe hyper-
Effects on Dental Treatment No significant effects or sensitivity, skin rash, urticaria)
complications reported Immunologic: Antibody development (2% to 5%; neu-
Effects on Bleeding No information available to tralizing: 1% [loss of efficacy: <1%])
require special precautions Infection: Influenza (6%)
Neuromuscular & skeletal: Myalgia (4%), muscle
Adverse Reactions
spasm (3%)
1% to 10%:
Respiratory: Cough (3%)
Central nervous system: Dizziness (6%), fatigue (3%),
Frequency not defined: Endocrine & metabolic:
headache (3%), pain (1% to 2%)
Decreased LDL cholesterol (<25 mg/dL)
Gastrointestinal: Abdominal pain (1% to 2%), consti-
<1%, postmarketing, and/or case reports: Flu-like
pation (1% to 2%), dyspepsia (1% to 2%), nausea
symptoms
(1% to 2%)
Mechanism of Action Alirocumab is a human mono-
Genitourinary: Impotence (1% to 2%)
clonal antibody (IgG1isotype) that binds to proprotein
Respiratory: Upper respiratory tract infection (3%),
convertase subtilisin kexin type 9 (PCSK9). PCSK9
bronchitis (1% to 2%), pharyngitis (1% to 2%), sinus-
binds to the low-density lipoprotein receptors (LDLR)
itis (1% to 2%)
on hepatocyte surfaces to promote LDLR degradation
<1%, postmarketing, and/or case reports: Angina pec-
within the liver. LDLR is the primary receptor that clears
toris (preexisting CAD), angioedema, atrial fibrillation, circulating LDL; therefore, the decrease in LDLR levels
chest pain, diarrhea, edema, flushing, hepatic injury by PCSK9 results in higher blood levels of LDL-C. By
(including cholestatic), hypotension, intraoperative inhibiting the binding of PCSK9 to LDLR, alirocumab
floppy iris syndrome (with cataract surgery), jaundice, increases the number of LDLRs available to clear LDL,
orthostatic hypotension, priapism, pruritus, rhinitis, thereby lowering LDL-C levels.
skin rash, syncope, systolic hypotension, tachycardia, Pharmacodynamics/Kinetics
thrombocytopenia, toxic epidermal necrolysis, urtica- Onset of Action Peak effect: Proprotein convertase
ria, vomiting subtilisin kexin type 9 (PCSK9) suppression: 4 to 8
Mechanism of Action An antagonist of alpha1-adre- hours
noreceptors in the lower urinary tract. Smooth muscle Half-life Elimination SubQ: Steady-state: 17 to 20
tone is mediated by the sympathetic nervous stimula- days; reduced to 12 days when administered with a
tion of alpha1-adrenoreceptors, which are abundant in statin
the prostate, prostatic capsule, prostatic urethra, and Time to Peak SubQ: 3 to 7 days
bladder neck. Blockade of these adrenoreceptors can Pregnancy Considerations Adverse events were not
cause smooth muscles in the bladder neck and prostate observed in animal reproduction studies. Information
to relax, resulting in an improvement in urine flow rate specific to alirocumab in pregnancy is not available.
and a reduction in BPH symptoms. However, IgG molecules are known to cross the pla-
Pharmacodynamics/Kinetics centa, with increasing amounts during the second and
Half-life Elimination 10 hours third trimesters of pregnancy. Health care providers are
Time to Peak Plasma: 8 hours following a meal encouraged to enroll women exposed to alirocumab
Pregnancy Risk Factor B during pregnancy in the MotherToBaby Pregnancy
Pregnancy Considerations Adverse events have not Studies by contacting the Organization of Teratology
been observed in animal reproduction studies. Information Specialists (OTIS) (877-311-8972) or
Dental Health Professional Considerations See https://mothertobaby.org/ongoing-study/praluent/aliro-
Local Anesthetic/Vasoconstrictor Precautions cumab/.
96
ALLOPURINOL
Prescribing and Access Restrictions Only avail- Pharmacologic Category Antineoplastic Agent, Ret-
able via specialty pharmacies. Call 844-772-5836 or inoic Acid Derivative
visit https://www.praluenthcp.com/support for additional Use
information. Kaposi sarcoma: Topical treatment of cutaneous
lesions in AIDS-related Kaposi sarcoma.
Aliskiren (a lis KYE ren)
Limitations of use: Alitretinoin is not indicated when
systemic therapy is necessary (eg, >10 new Kaposi
Related Information sarcoma lesions in previous month, symptomatic vis-
Cardiovascular Diseases on page 1442 ceral involvement, symptomatic pulmonary Kaposi
Brand Names: US Tekturna sarcoma, symptomatic lymphedema). There is no
Brand Names: Canada Rasilez experience in using alitretinoin (topical) in combination
Pharmacologic Category Renin Inhibitor with systemic treatment for Kaposi sarcoma.
Hypertension: Management of hypertension in adults
and pediatric patients ≥6 years of age Effects on Dental Treatment No significant effects or
Note: Not recommended for the initial treatment of complications reported
hypertension (ACC/AHA [Whelton 2017]). Effects on Bleeding No information available to
Local Anesthetic/Vasoconstrictor Precautions require special precautions
No information available to require special precautions Adverse Reactions
Effects on Dental Treatment No significant effects or >10%:
complications required Central nervous system: Pain (≤34%), paresthesia
Effects on Bleeding No information available to (3% to 22%)
require special precautions Dermatologic: Skin rash (25% to 77%), pruritus (8%
Adverse Reactions to 11%)
1% to 10%:
1% to 10%:
Dermatologic: Skin rash (1%) Cardiovascular: Edema (3% to 8%)
Gastrointestinal: Diarrhea (2%) Dermatologic: Exfoliative dermatitis (3% to 9%), der-
Neuromuscular & skeletal: Increased creatine phos- matological disease (≤8%)
phokinase (>300% increase: 1%) Mechanism of Action Alitretinoin is a naturally occur-
Renal: Increased blood urea nitrogen (≤7%), ring endogenous retinoid that binds to and activates
increased serum creatinine (≤7%) intracellular retinoid receptors (RAR and RXR sub-
Respiratory: Cough (1%) types); this results in altered expression of the genes
<1%, postmarketing, and/or case reports: Abdominal controlling cellular differentiation and proliferation in
pain, anaphylaxis, anemia, angioedema, decreased normal and neoplastic cells, inhibiting the growth of
hematocrit, decreased hemoglobin, dyspepsia, eryth- Kaposi sarcoma
ema, gastroesophageal reflux disease, gout, hepatic Pregnancy Risk Factor D
insufficiency, hyperkalemia, hyponatremia, increased Pregnancy Considerations Adverse events were
liver enzymes, increased uric acid, myositis, nausea, observed in animal reproduction studies using an oral
nephrolithiasis, periorbital edema, peripheral edema, preparation; studies have not been conducted using the
pruritus, rhabdomyolysis, seizure, severe hypoten- topical product. Alitretinoin may cause fetal harm if
sion, Stevens-Johnson syndrome, tonic-clonic seiz- significant absorption occurs in a female who is preg-
ures, toxic epidermal necrolysis, urticaria, vomiting nant. Females of reproductive potential should avoid
Mechanism of Action Decreases plasma renin activity becoming pregnant.
and inhibits conversion of angiotensinogen to angioten-
sin I. Allopurinol (al oh PURE i nole)
Onset of Action Maximum antihypertensive effect: Brand Names: US Aloprim; Zyloprim
Within 2 weeks Brand Names: Canada Alloprin; Zyloprim
Half-life Elimination ~24 hours (range: 16 to 32 Pharmacologic Category Antigout Agent; Xanthine
hours) Oxidase Inhibitor
Time to Peak 1 to 3 hours Use
Pregnancy Considerations [US Boxed Warning]: Oral:
Drugs that act on the renin-angiotensin system Gout, treatment: Management of primary or secon-
can cause injury and death to the developing fetus. dary gout (acute attack, tophi, joint destruction, uric
Discontinue as soon as possible once pregnancy is acid lithiasis, and/or nephropathy)
detected. The use of drugs which act on the renin- Guideline recommendations: EULAR guidelines:
angiotensin system are associated with oligohydram- Urate-lowering therapy (ULT) (eg, allopurinol) is
nios. Oligohydramnios, due to decreased fetal renal indicated in all patients with recurrent flares, tophi,
function, may lead to fetal lung hypoplasia and skeletal urate arthropathy, and/or renal stones. ULT initia-
malformations. Use is also associated with anuria, tion is recommended close in time to first diagnosis
hypotension, renal failure, skull hypoplasia, and death in patients presenting at a young age (<40 years of
in the fetus/neonate. The exposed fetus should be age) or with very high serum uric acid levels
monitored for fetal growth, amniotic fluid volume, and (>8 mg/dL) and/or comorbidities (eg, renal impair-
organ formation. Infants exposed in utero should be ment, hypertension, ischemic heart disease, heart
monitored for hyperkalemia, hypotension, and oliguria. failure) (EULAR [Richette 2017]).
Nephrolithiasis, prevention of recurrent calcium
Alitretinoin (Topical) (a li TRET i noyn) stones: Management in patients with hyperuricosu-
ria (uric acid excretion >800 mg/day in men and
Brand Names: US Panretin >750 mg/day in women)
97
ALLOPURINOL
Tumor lysis syndrome, prevention: Management of neutropenia, oliguria, onycholysis, optic neuritis, pain,
hyperuricemia associated with cancer treatment for pancytopenia, paralysis, paresthesia, pericarditis,
leukemia, lymphoma, and other malignancies peripheral neuropathy, peripheral vascular disease,
Limitations of use: Allopurinol is not recommended for pharyngitis, proctitis, pruritus, pulmonary embolism,
the treatment of asymptomatic hyperuricemia. Allo- purpuric rash, respiratory failure, respiratory insuffi-
purinol reduces serum and urinary uric acid concen- ciency, reticulocytosis, rhinitis, seizure, sepsis, septic
trations; its use should be individualized for each shock, skin edema, splenomegaly, status epilepticus,
patient and requires an understanding of its mode Stevens-Johnson syndrome, stomatitis, tachypnea,
of action and pharmacokinetics. thrombocytopenia, thrombophlebitis, tinnitus, tongue
IV: edema, toxic epidermal necrolysis, tremor, tumor lysis
Tumor lysis syndrome, prevention : Management of syndrome, twitching, uremia, urinary tract infection,
hyperuricemia associated with cancer treatment for urticaria, vasculitis, vasodilation, ventricular fibrillation,
leukemia, lymphoma, or solid tumor malignancies in vertigo, vesicobullous dermatitis, water intoxication
patients who cannot tolerate oral therapy. Mechanism of Action Allopurinol inhibits xanthine
Local Anesthetic/Vasoconstrictor Precautions oxidase, the enzyme responsible for the conversion of
No information available to require special precautions hypoxanthine to xanthine to uric acid. Allopurinol is
Effects on Dental Treatment No significant effects or metabolized to oxypurinol which is also an inhibitor of
complications reported xanthine oxidase; allopurinol acts on purine catabolism,
Effects on Bleeding No information available to reducing the production of uric acid without disrupting
require special precautions the biosynthesis of vital purines.
Adverse Reactions Pharmacodynamics/Kinetics
1% to 10%: Onset of Action
Dermatologic: Maculopapular rash (≤3%; pruritic), skin Gout: Decrease in serum and urine uric acid: 2 to 3
rash (≤2%) days; peak effect: 1 week or longer; normal serum
Endocrine & metabolic: Gout (≤6%; acute) urate levels achieved typically within 1 to 3 weeks
Gastrointestinal: Nausea (1%), vomiting (≤1%) Cancer therapy-induced hyperuricemia: Median time
Renal: Renal failure syndrome (≤1%), renal insuffi- to plasma uric acid control: 27 hours (Cortes 2010)
ciency (≤1%) Half-life Elimination Parent drug: ~1 to 2 hours;
Frequency not defined: Oxypurinol: ~15 hours
Gastrointestinal: Diarrhea Time to Peak Plasma: Oral: Allopurinol: 1.5 hours;
Hepatic: Increased serum alanine aminotransferase, Oxypurinol: 4.5 hours
increased serum alkaline phosphatase, increased Pregnancy Considerations Adverse events were
serum aspartate aminotransferase observed in some animal reproduction studies. Allopur-
<1%, postmarketing, and/or case reports: Abdominal inol crosses the placenta (Torrance 2009). An increased
pain, acute respiratory distress syndrome, ageusia, risk of adverse fetal events has not been observed
agitation, agranulocytosis, albuminuria, alopecia, (limited data) (Hoeltzenbein 2013).
amblyopia, amnesia, anemia, anorexia, aplastic ane-
mia, apnea, arthralgia, asthenia, asthma, bone mar-
row aplasia, bone marrow suppression, bradycardia, Almotriptan (al moh TRIP tan)
bronchospasm, cardiac disorder, cardiac failure, cata- Related Information
ract, cellulitis, cerebral infarction, cerebrovascular
Temporomandibular Dysfunction (TMD), Chronic Pain,
accident, chills, cholestatic jaundice, chronic myelo-
and Fibromyalgia on page 1559
cytic leukemia (blast crisis), coma, confusion, conjunc-
Brand Names: US Axert [DSC]
tivitis, constipation, decreased libido, depression,
diaphoresis, disseminated intravascular coagulation, Brand Names: Canada Axert; Mylan-Almotriptan;
dizziness, drowsiness, dysgeusia, dyspepsia, dysto- Sandoz-Almotriptan
nia, ecchymoses, ECG abnormality, eczema, edema, Pharmacologic Category Antimigraine Agent; Sero-
electrolyte disorder, enlargement of abdomen, tonin 5-HT1B, 1D Receptor Agonist
enlargement of salivary glands, eosinophilia, eosino- Use Acute treatment of migraine with or without aura in
philic fibrohistiocytic bone marrow lesion, epistaxis, adults (with a history of migraine) and adolescents (with
exfoliative dermatitis, facial edema, fever, flatulence, a history of migraine lasting ≥4 hours when left
flushing, foot-drop, furunculosis, gastritis, gastrointes- untreated)
tinal hemorrhage, glycosuria, granulomatous hepatitis, Local Anesthetic/Vasoconstrictor Precautions
gynecomastia, headache, hematuria, hemolytic ane- No information available to require special precautions
mia, hemorrhage, hemorrhagic pancreatitis, hepatic Effects on Dental Treatment Key adverse effect(s)
failure, hepatic necrosis, hepatomegaly, hepatotoxic- related to dental treatment: Xerostomia (normal salivary
ity, hyperbilirubinemia, hypercalcemia, hyperglycemia, flow resumes upon discontinuation)
hyperkalemia, hyperlipidemia, hypernatremia, hyper- Effects on Bleeding No information available to
phosphatemia, hypersensitivity angiitis, hypersensitiv- require special precautions
ity reaction, hypertension, hyperuricemia, Adverse Reactions
hypervolemia, hypocalcemia, hypokalemia, hypomag- 1% to 10%:
nesemia, hyponatremia, hypoprothrombinemia, hypo- Central nervous system: Drowsiness (≤5%), dizziness
tension, hypotonia, impotence, increased serum (≤4%), headache (≤2%)
creatinine, infection, injection site reaction, insomnia, Gastrointestinal: Nausea (1% to 3%), vomiting (≤2%),
intestinal obstruction, iritis, jaundice, lactic acidosis, xerostomia (1%)
leukocytosis, leukopenia, lichen planus, low cardiac Neuromuscular & skeletal: Paresthesia (≤1%)
output, lymphadenopathy, lymphocytosis, macular ret- <1%, postmarketing, and/or case reports: Abdominal
initis, malaise, male infertility, mental status changes, cramps, abdominal discomfort, abdominal pain,
metabolic acidosis, mucositis, myalgia, myoclonus, abnormal dreams, altered sense of smell, anaphylac-
myopathy, necrotizing angiitis, nephritis, neuritis, tic shock, anaphylaxis, angina pectoris, angioedema,
98
ALOSETRON
anxiety, arthralgia, arthritis, ataxia, back pain, blephar- Renal: Renal function abnormality (3%; patients with
ospasm, blurred vision, bronchitis, central nervous high cardiovascular risk: 23%), renal disease
system stimulation, chest pain, chills, cold extremities, (patients with high cardiovascular risk: 17%), renal
colitis, confusion, conjunctivitis, coronary artery vaso- insufficiency (patients with high cardiovascular
spasm, decreased visual acuity, depression, dermati- risk: 8%)
tis, diaphoresis, diarrhea, diplopia, dry eye syndrome, Respiratory: Nasopharyngitis (5%), upper respiratory
dysgeusia, dysmenorrhea, dyspepsia, dyspnea, epis- tract infection (5%)
taxis, erythema, euphoria, eye irritation, eye pain, <1%, postmarketing, and/or case reports: Anaphylaxis,
fatigue, fever, gastritis, gastroenteritis, gastroesopha- angioedema, constipation, decreased creatinine clear-
geal reflux disease, hemiplegia, hyperacusis, hyper- ance, diarrhea, hepatic failure, hypersensitivity reac-
cholesterolemia, hyperglycemia, hyperhidrosis, tion, increased liver enzymes, intestinal obstruction,
hyperreflexia, hypersensitivity reaction, hypertension, nausea, pancreatitis, serum sickness, severe arthral-
hypertonia, hyperventilation, hypoesthesia, increased gia (FDA Safety Alert, Aug 28, 2015), skin rash,
creatine phosphokinase, increased gamma-glutamyl Stevens-Johnson syndrome, urticaria
transferase, increased thirst, insomnia, ischemic heart Mechanism of Action Alogliptin inhibits dipeptidyl
disease, lack of concentration, laryngismus, laryngitis, peptidase 4 (DPP-4) enzyme resulting in prolonged
limb pain, malaise, mastalgia, myalgia, myasthenia, active incretin levels. Incretin hormones (eg, gluca-
myocardial infarction, myopathy, neck pain, neck stiff- gon-like peptide-1 [GLP-1] and glucose-dependent
ness, nervousness, neuropathy, nightmares, nystag- insulinotropic polypeptide [GIP]) regulate glucose
mus, otalgia, otitis media, palpitations, pharyngitis, homeostasis by increasing insulin synthesis and
pruritus, restlessness, rhinitis, scotoma, seizure, shak- release from pancreatic beta cells and decreasing
iness, sialorrhea, sinusitis, skin photosensitivity, skin glucagon secretion from pancreatic alpha cells.
rash, sneezing, syncope, tachycardia, tinnitus, tremor, Decreased glucagon secretion results in decreased
hepatic glucose production. Under normal physiologic
vasodilation, ventricular fibrillation, ventricular tachy-
circumstances, incretin hormones are released by the
cardia, vertigo, weakness
intestine throughout the day and levels are increased in
Mechanism of Action Selective agonist for serotonin response to a meal; incretin hormones are rapidly
(5-HT1B and 5-HT1D receptors) in cranial arteries; inactivated by the DPP-4 enzyme.
causes vasoconstriction and reduces sterile inflamma- Pharmacodynamics/Kinetics
tion associated with antidromic neuronal transmission Half-life Elimination ~21 hours
correlating with relief of migraine Time to Peak ~1 to 2 hours
Pregnancy Considerations Adverse events were not
Half-life Elimination Mean: 3 to 5 hours (Baldwin
observed in animal reproduction studies.
2004; McEnroe 2005)
Time to Peak Plasma: 1 to 3 hours In women with diabetes, maternal hyperglycemia can
Pregnancy Risk Factor C be associated with congenital malformations as well as
Pregnancy Considerations Adverse events were adverse effects in the fetus, neonate, and the mother
observed in animal reproduction studies. Information (ACOG 2018; ADA 2019; Metzger 2007). To prevent
related to almotriptan use in pregnancy is limited adverse outcomes prior to conception and throughout
(Källén, 2011; Nezvalová-Henriksen, 2010; Nezvalová- pregnancy, maternal blood glucose and HbA1c should
Henriksen, 2012). Until additional information is avail- be kept as close to target goals as possible but without
able, other agents are preferred for the initial treatment causing significant hypoglycemia (ADA 2019; Blumer
of migraine in pregnancy (Da Silva, 2012; MacGregor, 2013). Agents other than alogliptin are currently recom-
mended to treat diabetes in pregnant women
2012; Williams, 2012).
(ADA 2019).
Alogliptin (al oh GLIP tin)

Alosetron (a LOE se tron)
Brand Names: US Nesina
Brand Names: US Lotronex
Brand Names: Canada Nesina
Pharmacologic Category Selective 5-HT3 Receptor
Pharmacologic Category Antidiabetic Agent, Dipep- Antagonist
tidyl Peptidase 4 (DPP-4) Inhibitor
Use Irritable bowel syndrome: Treatment of women
Use Diabetes mellitus, type 2: Management of adults with severe diarrhea-predominant irritable bowel syn-
with type 2 diabetes mellitus as an adjunct to diet and drome (IBS) who have chronic IBS symptoms (gener-
exercise as monotherapy or in combination therapy ally lasting 6 months or longer), have had anatomic or
Local Anesthetic/Vasoconstrictor Precautions biochemical abnormalities of the GI tract excluded, and
No information available to require special precautions who have not responded adequately to conventional
Effects on Dental Treatment Alogliptin-dependent therapy.
patients with diabetes (noninsulin dependent, type 2) Local Anesthetic/Vasoconstrictor Precautions
should be appointed for dental treatment in morning in No information available to require special precautions
order to minimize chance of stress-induced hypoglyce- Effects on Dental Treatment No significant effects or
mia. complications reported
Effects on Bleeding No information available to Effects on Bleeding No information available to
require special precautions require special precautions
Adverse Reactions Adverse Reactions
1% to 10%: >10%: Gastrointestinal: Constipation (9% to 29%; dose
Cardiovascular: Cardiac failure (4%) related)
Central nervous system: Headache (4%) 1% to 10%:
Genitourinary: Decreased estimated GFR (5%) Central nervous system: Fatigue (≥3%), head-
Hepatic: Increased serum ALT (>3 times ULN: 1%) ache (≥3%)
99
ALOSETRON
Gastrointestinal: Abdominal distress (≤1% to 7%), Use

abdominal pain (≤1% to 7%), nausea (6%), gastro- Anxiety disorders (immediate release tablet, oral con-
intestinal distress (≤5%), gastrointestinal pain (≤5%), centrate, orally-disintegrating tablets): Treatment of
gastroenteritis (≥3%), vomiting (≥3%), diarrhea (2% generalized anxiety disorder (GAD), short-term anxi-
to 3%), flatulence (1% to 3%), hemorrhoids (1% to ety and anxiety association with depression
3%), abdominal distention (2%), acid regurgitation Panic disorder (extended-release tablets, oral solu-
(≤2%), gastroesophageal reflux disease (≤2%) tion, orally-disintegrating tablets, immediate-release
Genitourinary: Urinary tract infection (≥3%) tablets): Treatment of panic disorder, with or without
Neuromuscular & skeletal: Muscle spasm (≥3%) agoraphobia
Respiratory: Cough (≥3%), nasopharyngitis (≥3%), Local Anesthetic/Vasoconstrictor Precautions
upper respiratory tract infection (≥3%) No information available to require special precautions
<1%, postmarketing, and/or case reports: Abnormal Effects on Dental Treatment Key adverse event(s)
bilirubin levels, abnormal erythrocytes, active gastro- related to dental treatment: Significant xerostomia and
intestinal lesion, allergic skin reaction, alopecia, anxi- changes in salivation (normal salivary flow resumes
ety, cardiac arrhythmia, cholecystitis, cognitive upon discontinuation)
dysfunction, colitis, confusion, cystitis, decreased gas- Effects on Bleeding No information available to
trointestinal motility, depression, dermatitis, diaphore-
sis, disruption of body temperature regulation,
Adverse Reactions
disturbance in fluid balance, diverticulitis, drowsiness,
>10%:
dyspepsia, extrasystoles, fecal impaction, gastrointes-
Central nervous system: Drowsiness (immediate-
tinal obstruction, gastrointestinal perforation, gastro-
release: 41% to 77%; extended-release: 23%),
intestinal spasm, gastrointestinal ulcer, hematoma,
fatigue (immediate-release: 49%; extended-release:
hemoglobinopathy, hemorrhage, hepatitis, hyperacid-
14%), sedation (extended-release: 45%), ataxia
ity, hyperglycemia, hypertension, hypoesthesia, hypo-
glycemia, hypothalamic disease, intestinal (immediate-release: 40%; extended-release: 7% to
obstruction, intussusception, ischemic colitis, memory 9%), memory impairment (immediate-release: 33%;
impairment, mesenteric ischemia (small bowel), extended-release: 15%), irritability (immediate-
muscle cramps, muscle rigidity, myalgia, occult blood release: 33%; extended-release: ≥1%), cognitive
in stools, ostealgia, pain, pituitary insufficiency, procti- dysfunction (immediate-release: 29%), dysarthria
tis, respiratory tract disease, sedation, sexual disorder, (immediate-release: 23%; extended-release: 11%),
skeletal pain, skin rash, tachyarrhythmia, tremor, diz ziness (imm ediate-releas e: 2 % to 21 %;
ulcerative colitis, urinary frequency, urticaria extended-release: ≥1%), depression (extended-
Mechanism of Action Alosetron is a potent and release: 1% to 12%)
selective antagonist of a subtype of the serotonin Dermatologic: Skin rash (immediate-release: 11%;
5-HT3 receptor. 5-HT3 receptors are ligand-gated ion extended-release: <1%)
channels extensively distributed on enteric neurons in Endocrine & metabolic: Weight gain (immediate-
the human gastrointestinal tract, as well as other release: 27%; extended-release: 5%), weight loss
peripheral and central locations. Activation of these (immediate-release: 23%), decreased libido (6%
channels affect the regulation of visceral pain, colonic to 14%)
transit, and gastrointestinal secretions. In patients with Gastrointestinal: Increased appetite (immediate-
irritable bowel syndrome, blockade of these channels release: 33%; extended-release: 7%), decreased
may reduce pain, abdominal discomfort, urgency, and appetite (immediate-release: 28%), constipation
diarrhea. (immediate-release: 26%; extended-release: 8%),
Pharmacodynamics/Kinetics xerostomia (immediate-release: 15%)
Half-life Elimination 1.5 hours Genitourinary: Difficulty in micturition (immediate-
Time to Peak 1 hour release: 12%; extended-release: ≥1%)
Pregnancy Considerations Adverse events have not 1% to 10%:
been observed in animal reproduction studies. Cardiovascular: Hypotension (immediate-release: 5%;
extended-release: <1%), chest pain (extended-
release: ≥1%), palpitations (extended-release: ≥1%)
ALPRAZolam (al PRAY zoe lam) Central nervous system: Confusion (immediate-
release: 10%; extended-release: 2%), altered mental
Related Information
status (extended-release: 7%), disinhibition (immedi-
Dentin Hypersensitivity, Acid Erosion, High Caries
ate-release: 3%), disturbance in attention (extended-
Index, Management of Alveolar Osteitis, and Xerosto-
release: 3%), equilibrium disturbance (extended-
mia on page 1548
release: 3%), akathisia (immediate-release: 2%),
Management of the Patient With Anxiety or Depression disorientation (extended-release: 2%), lethargy
on page 1564 (extended-release: 2%), talkativeness (immediate-
Temporomandibular Dysfunction (TMD), Chronic Pain, release: 2%), derealization (≥1% to 2%), agitation
and Fibromyalgia on page 1559 (extended-release: ≥1%), depersonalization
Related Sample Prescriptions (extended-release: ≥1%), headache (extended-
Sedation (Prior to Dental Treatment) - Sample Prescrip- release: ≥1%), insomnia (extended-release: ≥1%),
tions on page 46 malaise (extended-release: ≥1%), nervousness
Brand Names: US ALPRAZolam Intensol; ALPRAZo- (extended-release: ≥1%), nightmares (extended-
lam XR; Xanax; Xanax XR release: ≥1%), restlessness (≥1%), vertigo
Brand Names: Canada Xanax; Xanax TS (extended-release: ≥1%), anxiety (extended-release:
Generic Availability (US) May be product dependent 1%), feeling hot (immediate-release: 1%; extended-
Pharmacologic Category Benzodiazepine release: <1%), hypersomnia (extended-release: 1%),
Dental Use Preoperative anxiety hypoesthesia (extended-release: 1%), dystonia
100
ALPRAZOLAM
Dermatologic: Allergic skin reaction (≤4%), dermatitis in 3 or 4 divided doses; some patients may require
(immediate-release: ≤4%), diaphoresis (extended- as much as 10 mg/day.
release: ≥1%), pruritus (extended-release: 1%) Extended release: 0.5 to 1 mg once daily; titrate
Endocrine & metabolic: Menstrual disease (immedi- dose every 3 to 4 days in increments ≤1 mg/day
ate-release: 10%; extended-release: 2%), increased (range: 3 to 6 mg/day).
libido (immediate-release: 8%; extended-release: Switching from immediate release to extended
≥1%), change in libido (immediate-release: 7%), release: Patients may be switched to extended
hot flash (extended-release: 2%) release tablets by taking the total daily dose of
Gastrointestinal: Nausea (extended-release: 6%), sia- the immediate release tablets and giving it once
lorrhea (immediate-release: 4% to 6%; extended- daily using the extended release preparation.
release: ≥1%), anorexia (extended-release: 2%), Preoperative anxiety (off-label use): Oral: 0.5 mg
abdominal pain (extended-release: ≥1%), diarrhea 60-90 minutes before procedure (De Witte 2002)
(extended-release: ≥1%), dyspepsia (extended- Dose reduction: Abrupt discontinuation should be
release: ≥1%), vomiting (extended-release: ≥1%) avoided. Daily dose may be decreased by 0.5 mg
Genitourinary: Sexual disorder (immediate-release: every 3 days; however, some patients may require a
7%; extended-release: 2%), dysmenorrhea slower reduction. If withdrawal symptoms occur,
(extended-release: 4%), urinary incontinence (imme- resume previous dose and discontinue on a less
diate-release: 2%; extended-release: <1%) rapid schedule.
Neuromuscular & skeletal: Arthralgia (extended- Geriatric Note: Titrate gradually, if needed and toler-
release: 2%), dyskinesia (extended-release: 2%), ated. Periodic reassessment and consideration of
myalgia (extended-release: 2%), back pain dosage reduction is recommended.
(extended-release: ≥1%), muscle cramps Immediate release: Initial 0.25 mg 2 to 3 times/day
(extended-release: ≥1%), muscle twitching Extended release: Initial: 0.5 mg once daily
(extended-release: ≥1%), tremor (extended-release: Dose reduction: Refer to adult dosing.
≥1%), weakness (extended-release: ≥1%), limb pain Renal Impairment: Adult There are no dosage
(extended-release: 1%) adjustments provided in the manufacturer's labeling;
Ophthalmic: Blurred vision (extended-release: ≥1%) use caution.
Respiratory: Dyspnea (extended-release: 2%), hyper- Hepatic Impairment: Adult
ventilation (extended-release: ≥1%), nasal conges- Advanced liver disease:
tion (extended-release: ≥1%), allergic rhinitis Immediate release tablet, oral concentrate, orally-
(extended-release: 1%) disintegrating tablet: 0.25 mg 2 to 3 times daily.
Frequency not defined: Extended release: 0.5 mg once daily
Central nervous system: Drug dependence, drug with- Pediatric Note: Titrate dose to effect; use lowest
drawal effective dose. The usefulness of this medication
<1%, postmarketing, and/or case reports: Abnormal should be periodically reassessed.
dreams, aggressive behavior, amnesia, angioedema, Anxiety:
apathy, chest tightness, choking sensation, clumsi- Children ≥7 years and Adolescents <18 years:
ness, cold and clammy skin, diplopia, dysgeusia, Limited data available: Oral: Immediate release:
dysphagia, edema, emotional lability, epistaxis, Initial: 0.005 to 0.02 mg/kg/dose 3 times daily
euphoria, falling, fever, galactorrhea, gastrointestinal (Kliegman 2007); dosing based on a trial in
disease, gynecomastia, hallucination, hangover effect, patients 7 to 16 years of age (n=13), initial doses
hepatic failure, hepatitis, homicidal ideation, hyper- of 0.005 mg/kg or 0.125 mg/dose were given 3
prolactinemia, hypomania, hypotonia, impaired con- times/day for situational anxiety and increments of
sciousness, impulse control disorder, increased 0.125 to 0.25 mg/dose were used to increase
energy, increased liver enzymes, increased serum doses to maximum of 0.02 mg/kg/dose or
bilirubin, increased thirst, intoxicated feeling, jaundice, 0.06 mg/kg/day; a range of 0.375 to 3 mg/day
jitteriness, mania, mydriasis, otalgia, outbursts of was needed (Pfefferbaum 1987). Another study
anger, paraplegia, peripheral edema, photophobia, in 17 children (8 to 17 years of age) with over-
psychomotor retardation, relaxation, rhinorrhea, rig- anxious disorder or avoidant disorders used initial
ors, seizure, sensation of cold, sinus tachycardia, skin daily doses of 0.25 mg for children <40 kg and
photosensitivity, sleep apnea, sleep talking, Stevens- 0.5 mg for those >40 kg. The dose was titrated at
Johnson syndrome, stupor, suicidal ideation, syncope, 2-day intervals to a maximum of 0.04 mg/kg/day.
tinnitus, urinary frequency, urticaria, voice disorder Required doses ranged from 0.5 to 3.5 mg/day
Dental Usual Dosage Preoperative anxiety (off-label with a mean of 1.6 mg/day. Based on clinical
use): Adults: Oral: 0.5 mg 60-90 minutes before proce- global ratings, alprazolam appeared to be better
dure (De Witte, 2002) than placebo; however, this difference was not
Dosing statistically significant (Simeon 1992).
Adult Note: Titrate dose gradually as needed and Adolescents ≥18 years: Oral: Immediate release:
tolerated. Periodic reassessment and consideration Initial: 0.25 to 0.5 mg 3 times daily; titrate dose
of dosage reduction is recommended. upward as needed every 3 to 4 days; usual
Anxiety disorders: Oral: Immediate release tablet, maximum daily dose: 4 mg/day. Patients requiring
oral concentrate, orally-disintegrating tablet: Initial: doses >4 mg/day should be increased cautiously.
0.25 to 0.5 mg 3 times daily; titrate dose every 3 to Periodic reassessment and consideration of dos-
4 days; usual maximum: 4 mg/day. Patients requiring age reduction is recommended.
doses >4 mg/day should be increased cautiously. Panic disorder: Adolescents ≥18 years: Oral:
Panic disorder: Oral: Immediate release: Initial: 0.5 mg 3 times daily;
Immediate release tablet, oral concentrate, orally- titrate dose upward as needed every 3 to 4 days
disintegrating tablet: Initial: 0.5 mg 3 times daily; in increments ≤1 mg/day; mean dose used in
titrate dose every 3 to 4 days in increments controlled trials: 5 to 6 mg/day; maximum daily
≤1 mg/day. Mean effective dosage: 5 to 6 mg/day, dose: 10 mg/day (rarely required)
101
ALPRAZOLAM
Extended release: Initial: 0.5 to 1 mg once daily; concentrations up to 50%. Elderly patients may be at
titrate dose upward as needed every 3 to 4 days in an increased risk of death with use; risk has been found
increments ≤1 mg/day; usual dose: 3 to 6 mg/ highest within the first 4 months of use in elderly
day; maximum daily dose: 10 mg/day (rarely dementia patients (Jennum 2015; Saarelainen 2018).
required)
Causes CNS depression (dose related) which may
Switching from immediate release to extended
release: Administer the same total daily dose, impair physical and mental capabilities. Patients must
but give once daily; if effect is not adequate, titrate be cautioned about performing tasks that require men-
dose as above. tal alertness (eg, operating machinery or driving).
Premenstrual dysphoric disorder: Limited data Effects with other sedative drugs or ethanol may be
available: Adolescents: Oral: Initial dose: 0.25 mg potentiated. Benzodiazepines have been associated
3 times daily; titrate as needed. Usual daily dose: with falls and traumatic injury and should be used with
1.25 to 2.25 mg/day (Kliegman 2011) extreme caution in patients who are at risk of these
Discontinuation of therapy: Abrupt discontinuation events (Nelson 1999). Hazardous sleep-related activ-
should be avoided. Daily dose must be gradually ities such as sleep-driving, cooking and eating food,
decreased no more frequently than every 3 days; and making phone calls while asleep have been noted
however, some patients may require a slower with benzodiazepines (Dolder 2008).
reduction. If withdrawal symptoms occur, resume Use caution in patients with depression, particularly if
previous dose and discontinue on a less rapid suicidal risk may be present. Episodes of mania or
schedule. hypomania have occurred in depressed patients treated
Renal Impairment: Pediatric There are no dosage with alprazolam. May cause physical or psychological
adjustments provided in the manufacturer's labeling. dependence. Acute withdrawal may be precipitated in
Mechanism of Action Binds to stereospecific benzo- patients after administration of flumazenil. Tolerance
diazepine receptors on the postsynaptic GABA neuron does not develop to the anxiolytic effects (Vinkers
at several sites within the central nervous system, 2012). Chronic use of this agent may increase the
including the limbic system, reticular formation. perioperative benzodiazepine dose needed to achieve
Enhancement of the inhibitory effect of GABA on neuro- desired effect.
nal excitability results by increased neuronal membrane
permeability to chloride ions. This shift in chloride ions Benzodiazepines have been associated with anterog-
results in hyperpolarization (a less excitable state) and rade amnesia (Nelson 1999). Paradoxical reactions,
stabilization. Benzodiazepine receptors and effects including hyperactive or aggressive behavior, have
appear to be linked to the GABA-A receptors. Benzo- been reported with benzodiazepines; risk may be
diazepines do not bind to GABA-B receptors. increased in adolescent/pediatric patients, geriatric
Contraindications Hypersensitivity to alprazolam or patients, or patients with a history of alcohol use dis-
any component of the formulation (cross-sensitivity with order or psychiatric/personality disorders (Mancuso
other benzodiazepines may exist); acute narrow-angle 2004). Does not have analgesic, antidepressant, or
glaucoma; concurrent use with ketoconazole, itracona- antipsychotic properties.
zole, or other potent CYP3A4 inhibitors. Drug Interactions
Canadian labeling: Additional contraindications (not in Metabolism/Transport Effects Substrate of
US labeling): Myasthenia gravis; severe hepatic insuf- CYP3A4 (major); Note: Assignment of Major/Minor
ficiency; severe respiratory insufficiency; sleep apnea. substrate status based on clinically relevant drug
Warnings/Precautions [US Boxed warning]: Con- interaction potential; Inhibits CYP3A4 (weak)
comitant use of benzodiazepines and opioids may Avoid Concomitant Use
result in profound sedation, respiratory depression, Avoid concomitant use of ALPRAZolam with any of
coma, and death. Reserve concomitant prescribing the following: Azelastine (Nasal); Bromperidol; Con-
of these drugs for use in patients for whom alter- ivaptan; Fusidic Acid (Systemic); Idelalisib; Indinavir;
native treatment options are inadequate. Limit dos- Itraconazole; Ketoconazole (Systemic); OLANZapine;
ages and durations to the minimum required. Orphenadrine; Oxomemazine; Paraldehyde; Pimo-
Follow patients for signs and symptoms of respira- zide; Sodium Oxybate; Thalidomide
tory depression and sedation. Increased Effect/Toxicity
ALPRAZolam may increase the levels/effects of: Alco-
Rebound or withdrawal symptoms, including seizures, hol (Ethyl); ARIPiprazole; Azelastine (Nasal); Blonan-
may occur following abrupt discontinuation or large serin; Brexanolone; Buprenorphine; CloZAPine; CNS
decreases in dose (more common in adult patients Depressants; Dofetilide; Flibanserin; Flunitrazepam;
receiving >4 mg/day or prolonged treatment); the risk HYDROcodone; Lomitapide; Methadone; Methotrime-
of seizures appears to be greatest 24 to 72 hours prazine; MetyroSINE; Mirtazapine; NiMODipine;
following discontinuation of therapy. Breakthrough anxi- Opioid Agonists; Orphenadrine; OxyCODONE; Paral-
ety may occur at the end of dosing interval. Potentially dehyde; Pimozide; Piribedil; Pramipexole; ROPINIR-
significant interactions may exist, requiring dose or ole; Rotigotine; Selective Serotonin Reuptake
frequency adjustment, additional monitoring, and/or Inhibitors; Sodium Oxybate; Suvorexant; Thalidomide;
selection of alternative therapy. Use with caution in Zolpidem
patients receiving concurrent CYP3A4 inhibitors, mod-
erate or strong CYP3A4 inducers, and major CYP3A4 The levels/effects of ALPRAZolam may be increased
substrates; consider alternative agents that avoid or by: Alizapride; Aprepitant; Brimonidine (Topical); Bro-
lessen the potential for CYP-mediated interactions. mopride; Bromperidol; Cannabidiol; Cannabis; Chlor-
Use with caution in renal impairment or predisposition methiazole; Chlorphenesin Carbamate; Clofazimine;
to urate nephropathy; has weak uricosuric properties. Conivaptan; CYP3A4 Inhibitors (Moderate); CYP3A4
Use with caution in or debilitated patients (use lower Inhibitors (Strong); Dimethindene (Topical); Doxyl-
starting dose), patients with hepatic disease (including amine; Dronabinol; Droperidol; Duvelisib; Erythromy-
alcoholics) or respiratory disease, or obese patients. cin (Systemic); Esketamine; FluvoxaMINE;
Cigarette sm oking may decrease alprazolam Fosaprepitant; Fosnetupitant; Fusidic Acid (Systemic);
102
ALPROSTADIL
HydrOXYzine; Idelalisib; Indinavir; Itraconazole; Kava The relative infant dose (RID) of alprazolam is 7.9%
Kava; Ketoconazole (Systemic); Larotrectinib; Lofex- when calculated using a mean breast milk concentra-
idine; Magnesium Sulfate; Melatonin; Methotrimepra- tion and compared to a weight-adjusted maternal dose
zine; MiFEPRIStone; Minocycline; Nabilone; of 0.5 mg.
Netupitant; OLANZapine; Ombitasvir, Paritaprevir,
and Ritonavir; Ombitasvir, Paritaprevir, Ritonavir, and In general, breastfeeding is considered acceptable
Dasabuvir; Oxomemazine; Palbociclib; Perampanel; when an RID of a medication is <10% (Anderson
Rufinamide; Simeprevir; Stiripentol; Tapentadol; Tedu- 2016; Ito 2000). However, some sources note breast-
glutide; Tetrahydrocannabinol; Tetrahydrocannabinol feeding should only be considered if the RID is <5% for
and Cannabidiol; Trimeprazine psychotropic agents (Larsen 2015).
Decreased Effect The RID of alprazolam was calculated using a mean
The levels/effects of ALPRAZolam may be decreased maximum milk concentration of 3.7 ng/mL, providing an
by: Bosentan; CYP3A4 Inducers (Moderate); CYP3A4 estimated daily infant dose via breast milk of 0.555 mcg/
Inducers (Strong); Dabrafenib; Deferasirox; Enzaluta- kg/day. This milk concentration was obtained following
mide; Ivosidenib; Lorlatinib; Mitotane; Pitolisant; Sar- administration of a single oral dose of alprazolam
ilumab; Siltuximab; St John's Wort; Theophylline 0.5 mg to eight postpartum females. Peak breast milk
Derivatives; Tocilizumab; Yohimbine concentrations of alprazolam occurred at ~1 hour and
Food Interactions The Cmax of the extended release the half-life was ~14 hours; metabolites were not
formulation is increased by 25% when a high-fat meal is detected (Oo 1995).
given 2 hours before dosing. Tmax is decreased 33%
when food is given immediately prior to dose and Case reports have noted drowsiness (Ito 1993) or CNS
increased by 33% when food is given ≥1 hour after depression (Kelly 2012) in infants exposed to alprazo-
dose. Management: Administer without regard to food. lam while breastfeeding. Symptoms of withdrawal were
Dietary Considerations Orally-disintegrating tablets described in an infant following alprazolam exposure in
may contain phenylalanine. utero and via breast milk (Anderson 1989).
Breastfeeding is not recommended by the manufac-
Half-life Elimination
turer. If a benzodiazepine is needed in breastfeeding
Adults: Mean: 11.2 hours (Immediate release range:
6.3 to 26.9 hours; Extended release range: 10.7 to females, use of shorter acting agents is preferred
15.8 hours); Orally-disintegrating tablet: Mean: 12.5 (Larsen 2015; WHO 2002).
hours (range: 7.9 to 19.2 hours) Controlled Substance C-IV
Alcoholic liver disease: 19.7 hours (range: 5.8 to 65.3 Dosage Forms: US
hours) Concentrate, Oral:
Obesity: 21.8 hours (range: 9.9 to 40.4 hours) ALPRAZolam Intensol: 1 mg/mL (30 mL)
Elderly: 16.3 hours (range: 9 to 26.9 hours) Tablet, Oral:
Time to Peak Xanax: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Immediate release: 1 to 2 hours Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Extended release: Adolescents and Adults: ~9 hours, Tablet Disintegrating, Oral:
relatively steady from 4 to 12 hours (Glue 2006); Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
decreased by 1 hour when administered at bedtime Tablet Extended Release 24 Hour, Oral:
(as compared to morning administration); decreased ALPRAZolam XR: 0.5 mg, 1 mg, 2 mg, 3 mg
by 33% when administered with a high-fat meal; Xanax XR: 0.5 mg, 1 mg, 2 mg, 3 mg
increased by 33% when administered ≥1 hour after Generic: 0.5 mg, 1 mg, 2 mg, 3 mg
a high-fat meal Dental Health Professional Considerations
Orally-disintegrating tablet: 1.5 to 2 hours; occurs ~15 Patient should not drive themselves to and from the
minutes earlier when administered with water; dental office. It is recommended an adult companion
increased to ~4 hours when administered with a accompany the patient to their appointment.
high-fat meal
Pregnancy Risk Factor D
Pregnancy Considerations Benzodiazepines have Alprostadil (al PROS ta dill)
the potential to cause harm to the fetus. Alprazolam Brand Names: US Caverject; Caverject Impulse;
and its metabolites cross the human placenta. Terato- Edex; Muse; Prostin VR
genic effects have been observed with some benzodia-
Brand Names: Canada Alprostadil Injection USP;
zepines; however, additional studies are needed. The
Caverject; Muse Pellet; Prostin VR
incidence of premature birth and low birth weights may
be increased following maternal use of benzodiaze- Pharmacologic Category Prostaglandin; Vasodilator
pines; hypoglycemia and respiratory problems in the Use
neonate may occur following exposure late in preg- Patent ductus arteriosus (Prostin VR Pediatric):
nancy. Neonatal withdrawal symptoms may occur within Temporary maintenance of patency of ductus arterio-
days to weeks after birth and "floppy infant syndrome" sus in neonates with ductal-dependent congenital
(which also includes withdrawal symptoms) has been heart disease until surgery can be performed. These
reported with some benzodiazepines (Bergman 1992; defects include cyanotic (eg, pulmonary atresia, pul-
Iqbal 2002; Wikner 2007). When treating pregnant monary stenosis, tricuspid atresia, Fallot's tetralogy,
females with panic disorder, psychosocial interventions transposition of the great vessels) and acyanotic (eg,
should be considered prior to pharmacotherapy (APA interruption of aortic arch, coarctation of aorta, hypo-
2009). If a benzodiazepine is needed in pregnancy, plastic left ventricle) heart disease.
agents other than alprazolam are preferred (Larsen Erectile dysfunction:
2015). Caverject, Edex, Caverject Impulse: Treatment of
Breastfeeding Considerations Alprazolam is erectile dysfunction due to vasculogenic, psycho-
present in breast milk. genic, neurogenic, or mixed etiology; Caverject
103
ALPROSTADIL
may be a useful adjunct to other diagnostic tests in Half-life Elimination 30 seconds to 10 minutes
the diagnosis of erectile dysfunction Time to Peak
Muse: Treatment of erectile dysfunction Acyanotic congenital heart disease: Usual: 1.5 to 3
Local Anesthetic/Vasoconstrictor Precautions hours; Range: 15 minutes to 11 hours
No information available to require special precautions Cyanotic congenital heart disease: Usual: ~30
Effects on Dental Treatment No significant effects or minutes
complications reported Erectile dysfunction: Intracavernosal: 30 to 60
Effects on Bleeding No information available to minutes; Transurethral: ~16 minutes
require special precautions Pregnancy Risk Factor C (Muse)
Adverse Reactions Pregnancy Considerations Adverse events have
Intraurethral: been observed in animal reproduction studies. Alpros-
>10%: Genitourinary: Penile pain, urethral burning tadil is not indicated for use in women. The manufac-
2% to 10%: turer of Muse recommends a condom barrier when
Central nervous system: Dizziness, headache, pain being used during sexual intercourse with a pregnant
Genitourinary: Testicular pain, urethral bleeding woman.
(minor), vulvovaginal pruritus (female partner)
<2%: Leg pain, perineal pain, tachycardia
Intracavernosal injection: Alteplase (AL te plase)
>10%: Genitourinary: Penile pain
1% to 10%: Related Information
Cardiovascular: Hypertension Cardiovascular Diseases on page 1442
Central nervous system: Dizziness, headache Brand Names: US Activase; Cathflo Activase
Genitourinary: Prolonged erection (>4 hours, 4%), Brand Names: Canada Activase rt-PA; Cathflo Acti-
penile disease, penile rash, penile swelling, Peyr- vase
onie's disease Pharmacologic Category Thrombolytic Agent
Local: Bruising at injection site, hematoma at injec- Use
tion site Activase:
<1%: Balanitis, injection site hemorrhage, priap- Acute ischemic stroke: Treatment of acute ischemic
ism (0.4%) stroke (AIS) as soon as possible but within 3 hours of
Intravenous: symptom onset.
>10%: Pulmonary embolism: Management of acute massive
Cardiovascular: Flushing pulmonary embolism (PE)
Respiratory: Apnea ST-elevation myocardial infarction: Management of
Miscellaneous: Fever ST-elevation myocardial infarction (STEMI) for the
1% to 10%: lysis of thrombi in coronary arteries.
Cardiovascular: Bradycardia, cardiac arrest, edema, Limitations of use: The risk of stroke may outweigh
hypertension, hypotension, tachycardia the benefit produced by thrombolytic therapy in
Central nervous system: Dizziness, headache,
patients whose acute myocardial infarction (MI)
seizure
puts them at low risk for death or heart failure.
Endocrine & metabolic: Hypokalemia
Recommended criteria for treatment:
Gastrointestinal: Diarrhea
STEMI (ACCF/AHA [O’Gara 2013]): Ischemic symp-
Hematologic & oncologic: Disseminated intravascu-
toms within 12 hours of treatment or evidence of
lar coagulation
ongoing ischemia 12 to 24 hours after symptom
Infection: Sepsis
Local: Local pain (in structures other than the injec- onset with a large area of myocardium at risk or
tion site) hemodynamic instability.
Neuromuscular & skeletal: Back pain STEMI ECG definition: New ST-segment elevation
Respiratory: Cough, flu-like symptoms, nasal con- at the J point in at least 2 contiguous leads of ≥2
gestion, sinusitis, upper respiratory tract infection mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in
<1%: Anemia, anuria, bradypnea, cardiac failure, cer- women in leads V2-V3 and/or of ≥1 mm (0.1 mV) in
ebral hemorrhage, gastroesophageal reflux disease, other contiguous precordial leads or limb leads.
hematuria, hemorrhage, hyperbilirubinemia, hyper- New or presumably new left bundle branch block
emia, hyperirritability, hyperkalemia, hypoglycemia, (LBBB) may interfere with ST-elevation analysis
hypothermia, jitteriness, lethargy, neck hyperexten- and should not be considered diagnostic in iso-
sion, peritonitis, second degree atrioventricular lation.
block, shock, stiffness, supraventricular tachycardia, At non-PCI-capable hospitals, the ACCF/AHA rec-
thrombocytopenia, ventricular fibrillation, wheezing ommends thrombolytic therapy administration
(bronchial) when the anticipated first medical contact
Mechanism of Action Causes vasodilation by means (FMC)-to-device time at a PCI-capable hospital
of direct effect on vascular and ductus arteriosus is >120 minutes due to unavoidable delays.
smooth muscle; relaxes trabecular smooth muscle by AIS: Onset of stroke symptoms within 3 hours of
dilation of cavernosal arteries when injected along the treatment
penile shaft, allowing blood flow to and entrapment in Pulmonary embolism (PE), acute (hemodynamically
the lacunar spaces of the penis (ie, corporeal veno- unstable/massive): Acute PE in patients with sus-
occlusive mechanism) tained hypotension (SBP <90 mm Hg for 15
Pharmacodynamics/Kinetics minutes) or with signs/symptoms of shock and
Onset of Action Erectile dysfunction: 5 to 20 minutes without a high bleeding risk (Kearon 2012;
Duration of Action Ductus arteriosus will begin to Kearon 2016).
close within 1 to 2 hours after drug is stopped; Erectile Cathflo Activase: Restoration of function to central
dysfunction: Intended duration <1 hour venous access device
104
AMANTADINE

No information available to require special precautions Alvimopan (al VI moe pan)
Brand Names: US Entereg
related to dental treatment: As with all drugs which may
Pharmacologic Category Gastrointestinal Agent,
affect hemostasis, bleeding is the major adverse effect
Miscellaneous; Opioid Antagonist, Peripherally-Acting
associated with alteplase. Hemorrhage may occur at
Use Postoperative ileus: To accelerate the time to
virtually any site; risk is dependent on multiple varia-
upper and lower GI recovery following surgeries includ-
bles, including the dosage administered, concurrent use
ing partial bowel resection with primary anastomosis
of multiple agents which alter hemostasis, and patient
predisposition. Rapid lysis of coronary artery thrombi by
thrombolytic agents may be associated with reperfu-
sion-related atrial and/or ventricular arrhythmias. See complications reported
Effects on Bleeding.
Effects on Bleeding Bleeding is the major adverse require special precautions
effect associated with thrombolytic agents, such as Adverse Reactions Note: Incidence reported limited
alteplase. It is unlikely that ambulatory patients present- to bowel resection patients only.
ing for dental treatment will be taking parenteral throm- 1% to 10%:
bolytic therapy. Endocrine & metabolic: Hypokalemia (10%)
Adverse Reactions Gastrointestinal: Dyspepsia (2% to 7%)
>10%: Cardiovascular: Intracranial hemorrhage (CVA: Genitourinary: Urinary retention (3%)
Within 90 days: 15%, within 36 hours: 6%; AMI: <1%) Hematologic and oncologic: Anemia (5%)
1% to 10%: Neuromuscular & skeletal: Back pain (3%)
Cerebrovascular accident (new ischemic stroke in Frequency not defined:
CVA: 6%) Cardiovascular: Myocardial infarction
Dermatologic: Ecchymosis (AMI: 1%) Mechanism of Action An opioid receptor antagonist
Gastrointestinal: Gastrointestinal hemorrhage which blocks opioid binding at the mu receptor; alvimo-
(AMI: 5%) pan has restricted ability to cross the blood-brain barrier
Genitourinary: Genitourinary tract hemorrhage at therapeutic doses. It selectively and competitively
(AMI: 4%) binds to the GI tract mu opioid receptors and antago-
Frequency not defined: nizes the peripheral effects of opioids on gastrointesti-
Hematologic & oncologic: Arterial embolism, major nal motility and secretion. Does not affect opioid
hemorrhage, pulmonary embolism analgesic effects or induce opioid withdrawal symp-
Infection: Sepsis toms.
1%, postmarketing, and/or case reports: Anaphylaxis, Pharmacodynamics/Kinetics
angioedema, atrioventricular block, atrioventricular Half-life Elimination 10 to 17 hours
dissociation, cardiac arrhythmia, cardiac failure, car- Time to Peak Plasma: Parent drug: ~2 hours; Metab-
diac tamponade, cardiogenic shock, cerebral edema, olite: 36 hours
cerebral herniation, deep vein thrombosis, embolism, Pregnancy Risk Factor B
epistaxis, fever, gingival hemorrhage, hypersensitivity Pregnancy Considerations Adverse events have not
reaction, hypotension, ischemia (recurrent), laryngeal been observed in animal reproduction studies.
edema, mitral valve insufficiency, myocardial reinfarc-
tion, myocardial rupture, nausea, pericardial effusion, Amantadine (a MAN ta deen)
pericarditis, pleural effusion, pulmonary edema, retro-
peritoneal hemorrhage, seizure, skin rash, throm- Related Information
boembolism, urticaria, vomiting Systemic Viral Diseases on page 1496
Mechanism of Action Initiates local fibrinolysis by Brand Names: US Gocovri; Osmolex ER
binding to fibrin in a thrombus (clot) and converts Pharmacologic Category Anti-Parkinson Agent, Dop-
entrapped plasminogen to plasmin amine Agonist; Antiviral Agent; Antiviral Agent, Ada-
Pharmacodynamics/Kinetics mantane
Duration of Action >50% present in plasma cleared Use
~5 minutes after infusion terminated, ~80% cleared Drug-induced extrapyramidal symptoms (immedi-
within 10 minutes; fibrinolytic activity persists for up to ate release and extended-release tablet only):
1 hour after infusion terminated (Semba 2000) Treatment of drug-induced extrapyramidal symptoms.
Influenza A prophylaxis (immediate release only):
Half-life Elimination Initial: 5 minutes
Chemoprophylaxis against signs and symptoms of
Pregnancy Considerations Adverse events have influenza A virus infection; also refer to current Advi-
been observed in animal reproduction studies. The risk sory Committee on Immunization Practices (ACIP)
of bleeding may be increased in pregnant women. guidelines for recommendations during current influ-
Outcome information is available following alteplase enza season.
use in pregnancy (Hirano 2013; Leonhardt 2006; Li Influenza A treatment (immediate release only):
2012; Özkan 2013). Currently, most guidelines consider Treatment of uncomplicated respiratory tract illness
pregnancy to be a relative contraindication for its use caused by influenza A virus strains; also refer to
(ACCF/AHA [O’Gara 2013]; AHA/ASA [Jauch 2013]; current ACIP guidelines for recommendations during
Kearon 2012; Kearon 2016; O'Connor 2010). Alteplase current influenza season.
should not be withheld from pregnant women in life- Parkinson disease:
threatening situations but should be avoided when safer Extended release:
alternatives are available (Bates 2012; Leonhardt 2006; Capsule: Treatment of dyskinesia in patients with
Li 2012). Parkinson disease receiving levodopa-based
105
AMANTADINE
therapy, with or without concomitant dopaminergic increased serum bilirubin, increased serum creatinine,
medications. keratitis, leukocytosis, leukopenia, mania, mydriasis,
Tablet: Treatment of Parkinson disease. neuroleptic malignant syndrome (associated with dos-
Immediate release: Treatment of idiopathic Parkinson age reduction or abrupt withdrawal of amantadine),
disease (paralysis agitans), postencephalitic parkin- neutropenia, oculogyric crisis, optic nerve palsy, par-
sonism, parkinsonism in association with cerebral esthesia, pathological gambling, pruritus, psychosis,
arteriosclerosis, and symptomatic parkinsonism, pulmonary edema, seizure, skin photosensitivity, skin
which may follow injury to the nervous system by rash, slurred speech, stupor, tachycardia, tachypnea,
carbon monoxide intoxication. tremor, urinary retention, visual disturbance (including
Local Anesthetic/Vasoconstrictor Precautions punctate subepithelial or other corneal opacity),
No information available to require special precautions weakness
Effects on Dental Treatment Key adverse event(s) Mechanism of Action
related to dental treatment: Xerostomia (prolonged use Antiviral:
may cause significant xerostomia; normal salivary flow The mechanism of amantadine’s antiviral activity has
resumes upon discontinuation); Patients may experi- not been fully elucidated. It appears to primarily
ence orthostatic hypotension as they stand up after prevent the release of infectious viral nucleic acid
treatment; especially if lying in dental chair for extended into the host cell by interfering with the transmem-
periods of time. Use caution with sudden changes in brane domain of the viral M2 protein. Amantadine is
position during and after dental treatment. also known to prevent viral assembly during replica-
Effects on Bleeding No information available to tion. Amantadine inhibits the replication of influenza
require special precautions A virus isolates from each of the subtypes (ie, H1N1,
Adverse Reactions H2N2 and H3N2), but has very little or no activity
>10%: against influenza B virus isolates.
Cardiovascular: Orthostatic hypotension (≤29%; may Parkinson disease:
be more common in men), presyncope (≤29%), The exact mechanism of amantadine in the treatment
syncope (≤29%), peripheral edema (1% to 16%) of Parkinson disease and drug-induced extrapyrami-
Central nervous system: Dizziness (≤29%), delusions dal symptoms is not known. Data from early animal
(≤25%), hallucination (≤25%), illusion (≤25%), para- studies suggest that amantadine may have direct
noia (≤25%), falling (13%) and indirect effects on dopamine neurons; however,
Gastrointestinal: Xerostomia (1% to 16%; may be recent studies have demonstrated that amantadine is
more common in women), constipation (1% to 13%) a weak, noncompetitive NMDA receptor antagonist.
1% to 10%: Although amantadine has not been shown to pos-
Cardiovascular: Livedo reticularis (1% to 6%; may be sess direct anticholinergic activity, clinically, it exhib-
more common in women) its anticholinergic-like side effects (dry mouth, urinary
Central nervous system: Insomnia (5% to 10%), anxi- retention, and constipation).
ety (1% to 7%), depression (1% to 6%), headache Pharmacodynamics/Kinetics
(1% to 6%), abnormal dreams (1% to 5%; may be Onset of Action Antidyskinetic: Within 48 hours
more common in women), agitation (1% to 5%), Half-life Elimination Normal renal function: 16 ± 6
ataxia (1% to 5%; may be more common in men hours (9 to 31 hours); Healthy, older (≥60 years)
and adults ≥65 years old), confusion (1% to 5%), males: 29 hours (range: 20 to 41 hours) (Aoki 1988);
drowsiness (1% to 5%), fatigue (1% to 5%), irritability End-stage renal disease: 8 days
(1% to 5%), nervousness (1% to 5%), dyschromia Time to Peak Plasma: Extended-release capsule: 12
(3%), dystonia (3%), apathy (2%), suicidal idea- hours (mean; range: 6 to 20 hours); extended-release
tion (≤2%) tablet: 7.5 hours (median; range: 5.5 to 12 hours);
Gastrointestinal: Nausea (5% to 10%; may be more immediate release: 2 to 4 hours
common in women), decreased appetite (6%), ano- Pregnancy Risk Factor C
rexia (1% to 5%), diarrhea (1% to 5%), vomiting (3%)
Genitourinary: Urinary tract infection (10%), benign
Adverse events have been observed in animal repro-
prostatic hypertrophy (6%)
duction studies and teratogenic events have been
Hematologic & oncologic: Bruise (6%)
observed in humans (case reports) (Seier 2017).
Neuromuscular & skeletal: Joint swelling (3%), muscle
spasm (3%) When treatment for Parkinson disease is needed,
Ophthalmic: Blurred vision (4%), cataract (3%; may be agents other than amantadine are recommended in
more common in women), xerophthalmia (3%) pregnant women (Seier 2017).
Respiratory: Dry nose (1% to 5%), cough (3%)
<1%, postmarketing, and/or case reports: Abnormal Untreated influenza infection is associated with an
gait, abnormality in thinking, acute respiratory tract increased risk of adverse events to the fetus and an
failure, aggressive behavior, agranulocytosis, amne- increased risk of complications or death to the mother.
sia, anaphylaxis, cardiac arrhythmia (including malig- Other agents are currently recommended for the treat-
nant arrhythmias), cardiac failure, coma, corneal ment or prophylaxis influenza in pregnant women and
edema, decreased libido, decreased visual acuity, women up to 2 weeks postpartum. Appropriate antiviral
delirium, diaphoresis, dysphagia, dyspnea, eczema, agents are currently recommended as an adjunct to
edema, EEG pattern changes, euphoria, fever, hyper- vaccination and should not be used as a substitute for
kinesia, hypersensitivity reaction, hypertension, hyper- v a c c i n a t i o n i n p r e g n a n t w o m e n ( C D C 2 0 11 ;
tonia, hypokinesia, hypotension, impulse control CDC 2014).
disorder, increased blood urea nitrogen, increased
creatine phosphokinase, increased gamma-glutamyl Ambrisentan (am bri SEN tan)
transferase, increased lactate dehydrogenase,
increased libido, increased serum alkaline phospha- Brand Names: US Letairis
tase, increased serum ALT, increased serum AST, Brand Names: Canada Volibris
106
AMIFAMPRIDINE
Pharmacologic Category Endothelin Receptor [US Boxed Warning]: Exclude pregnancy before the
Antagonist; Vasodilator initiation of treatment with ambrisentan. Females of
Use Pulmonary arterial hypertension: Treatment of reproductive potential must have a negative pregnancy
pulmonary artery hypertension (PAH) (World Health test prior to initiation of therapy. Females of reproduc-
Organization [WHO] Group I) to improve exercise tive potential must use acceptable methods of con-
ability and delay clinical worsening; in combination traception during treatment and for 1 month after
with tadalafil to reduce the risks of disease progres- treatment. Obtain monthly pregnancy tests during
sion and hospitalization for worsening PAH, and to treatment and 1 month after discontinuation of
improve exercise ability. Studies establishing effec- treatment. One highly effective form of contraception
tiveness included predominantly patients with WHO (intrauterine device, contraceptive implant, or tubal
Functional Class II to III symptoms and etiologies of sterilization) or a combination of contraceptive methods
idiopathic or heritable PAH (60%) or PAH associated (hormone contraceptive with a barrier method or 2
with connective tissue diseases (34%). barrier methods) may be used. If the partner has had
Note: According to treatment guidelines from the Fifth a vasectomy, a hormone or barrier method must also be
World Symposium on Pulmonary Hypertension used. A missed menses or suspected pregnancy
(WSPH), only a small number of PAH patients with should be reported to a health care provider and prompt
WHO-FC IV symptoms (ie, severely ill patients) were immediate pregnancy testing. Sperm counts may be
included in clinical trials, therefore, most experts con- reduced in men during treatment (as observed with
sider ambrisentan second-line therapy in these bosentan).
patients (WSPH [Gailè 2013]).
No information available to require special precautions Amifampridine (AM i fam pri deen)
related to dental treatment: Endothelin antagonists Brand Names: US Firdapse
have caused bleeding gums; there have been no Pharmacologic Category Cholinergic Agonist; Potas-
specific reports for ambrisentan sium Channel Blocker
Effects on Bleeding No information available to Use Lambert-Eaton myasthenic syndrome: Treat-
require special precautions ment of Lambert-Eaton myasthenic syndrome (LEMS)
Adverse Reactions Frequency not always defined. Local Anesthetic/Vasoconstrictor Precautions
Cardiovascular: Peripheral edema (14% to 38%), flush- Amifampridine causes increases in blood pressure.
ing (4%) Consider monitoring blood pressure prior to using local
Central nervous system: Headache (34%) anesthetic with a vasoconstrictor.
Gastrointestinal: Dyspepsia (3%) Effects on Dental Treatment No significant effects or
Genitourinary: Oligospermia complications reported
Hematologic & oncologic: Decreased hemoglobin (7% Effects on Bleeding No information available to
to 10%; dose-dependent), anemia (7%), decreased require special precautions
hematocrit Adverse Reactions
Respiratory: Nasal congestion (6% to 16%), cough >10%:
(13%), bronchitis (4%), sinusitis (3%) Cardiovascular: Hypertension (12%)
<1%, postmarketing, and/or case reports: Cardiac fail- Central nervous system: Paresthesia (62%), head-
ure, dizziness, fatigue, fluid retention, hypersensitivity, ache (14%), muscle spasm (12%)
hypotension, increased liver enzymes, nausea, vomit- Gastrointestinal: Abdominal pain (14%), diarrhea
ing, weakness (14%), nausea (14%)
Mechanism of Action Blocks endothelin receptor sub- Hepatic: Increased liver enzymes (14%)
types ETA and ET B on vascular endothelium and Neuromuscular & skeletal: Back pain (14%)
smooth muscle. Stimulation of ETA receptors, located
Respiratory: Upper respiratory tract infection (33%)
primarily in pulmonary vascular smooth muscle cells is
1% to 10%:
associated with vasoconstriction and cellular prolifera-
Cardiovascular: Peripheral edema (≥5%)
tion. Stimulation of ETB receptors, located in both
Central nervous system: Dizziness (10%), myasthenia
pulmonary vascular endothelial cells and smooth
muscle cells is associated with vasodilation, antiproli- (10%), falling (7%), depression (≥5%), insomnia
ferative effects, and endothelin clearance. Although (≥5%), seizure (2%)
ambrisentan blocks both ETA and ETB receptors, the Dermatologic: Erythema (≥5%)
affinity is greater for the ETA receptor (>4,000-fold Endocrine & metabolic: Hypercholesterolemia (≥5%)
higher affinity). Gastrointestinal: Constipation (7%), gastroesophageal
Pharmacodynamics/Kinetics reflux disease (≥5%)
Half-life Elimination ~9 hours Genitourinary: Urinary tract infection (≥5%)
Time to Peak ~2 hours Hematologic: Lymphadenopathy (7%)
Pregnancy Considerations Infection: Influenza (≥5%), viral infection (≥5%)
Ambrisentan is contraindicated in pregnancy. Neuromuscular & skeletal: Asthenia (10%), limb pain
(10%), increased creatine phosphokinase (≥5%)
[US Boxed Warning]: Do not administer ambrisen- Ophthalmic: Cataract (10%)
tan to a pregnant female because it may cause fetal Respiratory: Bronchitis (7%), dyspnea (≥5%)
harm. Ambrisentan is very likely to produce serious Miscellaneous: Fever (≥5%)
birth defects if used by pregnant females because Mechanism of Action Increases acetylcholine release
this effect has been seen consistently when it is in nerve terminals via potassium channel blockade
administered to animals. (Wirtz 2010).
Females with pulmonary arterial hypertension are Pharmacodynamics/Kinetics
encouraged to avoid pregnancy (McLaughlin 2009; Half-life Elimination 1.8 to 2.5 hours
Taichman 2014). Time to Peak 20 minutes to 1 hour
107
AMIFAMPRIDINE

observed in some animal reproduction studies. Infor- Amikacin (Oral Inhalation) (am i KAY sin)
mation related to the use of amifampridine in pregnancy
is limited (Pelufo-Pellicer 2006). Brand Names: US Arikayce
Pharmacologic Category Antibiotic, Aminoglycoside
Use
Amikacin (Systemic) (am i KAY sin) Mycobacterium avium complex: Treatment of Myco-
bacterium avium complex (MAC) lung disease in
Brand Names: Canada Amikacin Sulfate Injection,
adults who have limited or no alternative treatment
USP; Amikin
options, as part of a combination antibacterial drug
Pharmacologic Category Antibiotic, Aminoglycoside regimen in patients who do not achieve negative
Use Serious infections: Treatment of serious infections sputum cultures after a minimum of 6 consecutive
(eg, bone infections, respiratory tract infections, endo- months of a multidrug background regimen therapy.
carditis, septicemia) due to gram-negative organisms, Limitation of use: Amikacin oral inhalation has only
including Pseudomonas, Escherichia coli, Proteus, been studied in patients with refractory MAC lung
Providencia, Klebsiella, Enterobacter, Serratia, and Aci- disease defined as patients who did not achieve
netobacter negative sputum cultures after a minimum of 6 con-
Local Anesthetic/Vasoconstrictor Precautions secutive months of a multidrug background regimen
No information available to require special precautions therapy. The use of amikacin is not recommended for
Effects on Dental Treatment No significant effects or patients with non-refractory MAC lung disease.
complications reported Local Anesthetic/Vasoconstrictor Precautions
Effects on Bleeding No information available to No information available to require special precautions
require special precautions Effects on Dental Treatment Key adverse event(s)
Adverse Reactions related to dental treatment: Oral candidiasis has been
1% to 10%: reported
Central nervous system: Neurotoxicity Effects on Bleeding No information available to
Genitourinary: Nephrotoxicity require special precautions
Otic: Auditory ototoxicity, vestibular ototoxicity Adverse Reactions
<1%, postmarketing, and/or case reports: Arthralgia, >10%:
drowsiness, drug fever, dyspnea, eosinophilia, head- Central nervous system: Voice disorder (47%), fatigue
ache, hypersensitivity reaction, hypotension, nausea, (≤16%), headache (10%)
paresthesia, skin rash, tremor, vomiting, weakness Gastrointestinal: Diarrhea (13%), nausea (12%)
Mechanism of Action Inhibits protein synthesis in Neuromuscular & skeletal: Musculoskeletal pain
susceptible bacteria by binding to 30S ribosomal sub- (17%), asthenia (≤16%)
units Otic: Ototoxicity (17%)
Pharmacodynamics/Kinetics Respiratory: Cough (39%), bronchospasm (29%),
Half-life Elimination Renal function and age depend- hemoptysis (18%), upper airway symptoms (17%),
ent: exacerbation of pulmonary symptoms (15%), pneu-
Infants: Low birth weight (1 to 3 days): 7 to 9 hours; monia (10%)
Full-term >7 days: 4 to 5 hours (Howard 1975) 1% to 10%:
Children: 1.6 to 2.5 hours Cardiovascular: Chest discomfort (5%)
Adolescents: 1.5 ± 1 hour Central nervous system: Dizziness (6%), anxiety (5%),
Adults: Normal renal function: ~2 hours; Anuria/end- equilibrium disturbance (1%)
stage renal disease: 17 to 150 hours (Aronoff 2007) Dermatologic: Skin rash (6%)
Time to Peak Serum: IM: 60 minutes; IV: Within 30 Endocrine & metabolic: Weight loss (6%)
minutes following a 30-minute infusion Gastrointestinal: Vomiting (7%), oral candidiasis (4%),
Pregnancy Risk Factor D dysgeusia (3%), xerostomia (2%)
Pregnancy Considerations Neuromuscular & skeletal: Neuromuscular symp-
Amikacin crosses the placenta. toms (2%)
Otic: Tinnitus (8%)
Aminoglycosides may cause fetal harm if administered Respiratory: Change in bronchial secretions (5%),
to a pregnant woman. There are several reports of total bronchitis (4%), hypersensitivity pneumonitis (3% to
irreversible bilateral congenital deafness in children 4%), epistaxis (3%), respiratory failure (3%), pneu-
whose mothers received a different aminoglycoside mothorax (2%)
(streptomycin) during pregnancy. Although serious side Miscellaneous: Fever (7%), decreased exercise toler-
effects to the fetus/infant have not been reported follow- ance (1%)
ing maternal use of all aminoglycosides, a potential for Frequency not defined: Genitourinary: Nephrotoxicity
harm exists. Mechanism of Action Inhibits protein synthesis in
susceptible bacteria by binding to 30S ribosomal sub-
Due to pregnancy-induced physiologic changes, some
units
pharmacokinetic parameters of intravenous amikacin
may be altered (Bernard 1977).
Half-life Elimination ~5.9 to 19.5 hours
Amikacin may be one of the preferred antibiotics when Pregnancy Considerations
an aminoglycoside is needed for multidrug resistant TB Aminoglycosides may cause fetal harm if administered
in pregnancy (HHS [OI] 2018). Amikacin is recom- to a pregnant woman. Systemic absorption of amikacin
mended as part of a multiantibiotic treatment regimen following oral inhalation is expected to be low compared
of Mycobacterium avium complex (MAC) in patients to intravenous administration; however, systemic expo-
with cystic fibrosis in certain situations (Floto 2016); sure was associated with total irreversible bilateral
use of the IV route should be reserved for life-threat- congenital deafness in children whose mothers
ening infections in pregnant females (Panchaud 2016). received a different aminoglycoside during pregnancy.
108
AMINOLEVULINIC ACID (TOPICAL)
Refer to the Amikacin (Systemic) monograph for

details. Aminocaproic Acid (a mee noe ka PROE ik AS id)
Related Information
AMILoride (a MIL oh ride) Antiplatelet and Anticoagulation Considerations in Den-
tistry on page 1454
Related Information
Brand Names: US Amicar
Cardiovascular Diseases on page 1442
Pharmacologic Category Antifibrinolytic Agent; Anti-
Brand Names: Canada Midamor hemophilic Agent; Hemostatic Agent; Lysine Analog
Pharmacologic Category Antihypertensive; Diuretic, Use To enhance hemostasis when fibrinolysis contrib-
Potassium-Sparing utes to bleeding (causes may include cardiac surgery,
Use hematologic disorders, neoplastic disorders, abruptio
Heart failure or hypertension: Counteracts potassium placentae, hepatic cirrhosis, and urinary fibrinolysis)
loss induced by other diuretics in the treatment of Local Anesthetic/Vasoconstrictor Precautions
hypertension or heart failure; usually used in conjunc- No information available to require special precautions
tion with more potent diuretics such as thiazides or Effects on Dental Treatment No significant effects or
loop diuretics complications reported (see Effects on Bleeding)
Note: Potassium-sparing diuretics are not recom- Effects on Bleeding Used as an off-label indication to
mended for the initial treatment of hypertension prevent or treat dental bleeding in patients with Hemo-
(ACC/AHA [Whelton 2017]). philia A; may cause thrombocytopenia
Local Anesthetic/Vasoconstrictor Precautions Adverse Reactions Frequency not defined.
No information available to require special precautions Cardiovascular: Arrhythmia, bradycardia, edema, hypo-
tension, intracranial hypertension, peripheral ische-
mia, syncope, thrombosis
Central nervous system: Confusion, delirium, dizziness,
Effects on Bleeding No information available to fatigue, hallucinations, headache, malaise, seizure,
require special precautions stroke
Adverse Reactions Dermatologic: Rash, pruritus
1% to 10%: Gastrointestinal: Abdominal pain, anorexia, cramps,
Central nervous system: Dizziness, fatigue, headache diarrhea, GI irritation, nausea, vomiting
Endocrine & metabolic: Hyperkalemia (up to 10%; risk Genitourinary: Dry ejaculation
reduced in patients receiving kaliuretic diuretics), Hematologic: Agranulocytosis, bleeding time increased,
dehydration, gynecomastia, hyperchloremic meta- leukopenia, thrombocytopenia
bolic acidosis, hyponatremia Local: Injection site necrosis, injection site pain, injec-
Gastrointestinal: Abdominal pain, change in appetite, tion site reactions
constipation, diarrhea, gas pain, nausea, vomiting Neuromuscular & skeletal: CPK increased, myalgia,
Genitourinary: Impotence myositis, myopathy, rhabdomyolysis (rare), weakness
Ophthalmic: Vision decreased, watery eyes
Neuromuscular & skeletal: Muscle cramps, weakness
Otic: Tinnitus
Respiratory: Cough, dyspnea
Renal: BUN increased, intrarenal obstruction (glomer-
<1%, postmarketing, and/or case reports: Alopecia,
ular capillary thrombosis), myoglobinuria (rare), renal
bladder spasm, cardiac arrhythmia, chest pain, dysu- failure (rare)
ria, gastrointestinal hemorrhage, increased intraocular Respiratory: Dyspnea, nasal congestion, pulmonary
pressure, jaundice, orthostatic hypotension, palpita- embolism
tions, polyuria Miscellaneous: Allergic reaction, anaphylactoid reac-
Mechanism of Action Blocks epithelial sodium chan- tion, anaphylaxis
nels in the late distal convoluted tubule (DCT), and Postmarketing and/or case reports: Hepatic lesion,
collecting duct which inhibits sodium reabsorption from hyperkalemia, myocardial lesion
the lumen. This effectively reduces intracellular sodium, Mechanism of Action Binds competitively to plasmi-
decreasing the function of Na+/K+ATPase, leading to nogen; blocking the binding of plasminogen to fibrin and
potassium retention and decreased calcium, magne- the subsequent conversion to plasmin, resulting in
sium, and hydrogen excretion. As sodium uptake inhibition of fibrin degradation (fibrinolysis).
capacity in the DCT/collecting duct is limited, the natriu- Pharmacodynamics/Kinetics
retic, diuretic, and antihypertensive effects are generally Onset of Action ~1 to 72 hours
considered weak. Half-life Elimination 1 to 2 hours
Pharmacodynamics/Kinetics Time to Peak Oral: 1.2 ± 0.45 hours
Onset of Action Within 2 hours; Peak effect: 6 to 10 Pregnancy Risk Factor C
hours Pregnancy Considerations Animal reproduction
Duration of Action ~24 hours studies have not been conducted.
Half-life Elimination Normal renal function: 6 to 9
hours; renal impairment (CrCl <50 mL/minute): 21 to Aminolevulinic Acid (Topical)
144 hours (George 1980) (a MEE noh lev yoo lin ik AS id)
Time to Peak Serum:3 to 4 hours Brand Names: US Ameluz; Levulan Kerastick

Pregnancy Risk Factor B Brand Names: Canada Levulan Kerastick
Pregnancy Considerations Adverse events were not Pharmacologic Category Photosensitizing Agent,
observed in animal reproduction studies. Topical; Topical Skin Product
109
AMINOLEVULINIC ACID (TOPICAL)
Use Pharmacodynamics/Kinetics
Actinic keratoses: Onset of Action Peak fluorescence intensity of pro-
Gel (Ameluz): Lesion-directed and field-directed top- toporphyrin IX (PpIX): Actinic keratosis: Solution: 11
ical treatment of mild to moderate actinic keratosis of hours ± 1 hour; Perilesional skin: 12 hours ± 1 hour
the face and scalp; to be used in conjunction with Half-life Elimination Mean fluorescence clearance
photodynamic therapy with narrowband red light half-life of PpIX for lesions: Solution: 30 ± 10 hours
illumination (using BF-RhodoLED lamp). Time to Peak Gel: 3 hours
Solution (Levulan Kerastick): Topical treatment of Pregnancy Considerations Animal reproduction
minimally to moderately thick actinic keratoses of studies have not been conducted. Systemic absorption
the face, scalp, or upper extremities; to be used in following topical application is negligible.
conjunction with photodynamic therapy with blue
light illumination (using BLU-U blue light). Aminophylline (am in OFF i lin)
No information available to require special precautions Related Information
Effects on Dental Treatment Key adverse event(s) Respiratory Diseases on page 1467
related to dental treatment: Bleeding/hemorrhage (lim- Theophylline on page 1253
ited to application/treatment site). Brand Names: Canada Aminophylline Injection
Effects on Bleeding Bleeding/hemorrhage at applica- Pharmacologic Category Phosphodiesterase
tion or treatment site. Enzyme Inhibitor, Nonselective
Adverse Reactions Use
>10%: Reversible airflow obstruction: Treatment of acute
Central nervous system: Localized burning (≤92%; exacerbations of symptoms and reversible airflow
severe: ≤73%) obstruction due to asthma or other chronic lung dis-
Dermatologic: Stinging of the skin (severe: ≤73%), eases (eg, emphysema, chronic bronchitis) as an
crusted skin (≤71%; severe: ≤5%), desquamation adjunct to inhaled beta-2 selective agonists and sys-
(≤71%; severe: ≤22%), local dryness (≤65%; severe: temically administered corticosteroids.
≤22%), hyperpigmentation (≤64%), hypopigmenta- Guideline recommendations:
tion (≤36%), localized vesiculation (≤36%), exfolia- Asthma: The 2007 National Heart, Lung, and Blood
tion of skin (≤19%), skin erosion (≤14%; may be Institute Asthma Guidelines and the 2018 Global
severe), dermatological disease (5% to 12%) Initiative for Asthma Guidelines (GINA) recommend
Local: Application site reaction (100%), application against aminophylline for the treatment of asthma
site erythema (65% to 99%), local pain (≤92%; exacerbations because of poor efficacy and safety
severe: ≤30%), application site irritation (72%), local- concerns (GINA 2018; NAEPP 2007).
ized edema (1% to 51%; may be severe), application COPD: The 2018 Global Initiative for Chronic Obstruc-
site discharge (≤36%), application site pruritus (8% tive Lung Disease Guidelines recommends against
aminophylline for the treatment of COPD exacerba-
to 34%; severe: 1% to 7%), application site indu-
tions because of significant adverse effects
ration (12%)
(GOLD 2018).
1% to 10%:
Central nervous system: Paresthesia (9%), hyperal-
gesia (6%), local discomfort (3%), dysesthesia
(≤2%), pain (≤1%), chills, headache
Effects on Dental Treatment Prescribe erythromycin
products with caution to patients taking theophylline
Dermatologic: Urticaria (1% to 7%; may be severe),
products. Erythromycin will delay the normal metabolic
pustules (1% to 4%), dermal ulcer (≤4%), excoriation
inactivation of theophyllines leading to increased blood
(≤2%), pruritic rash (perilesional: <2%), skin blis-
levels; this has resulted in nausea, vomiting, and CNS
ter (<2%)
restlessness.
Hematologic & oncologic: Squamous cell carcinoma
(2% to <10%), squamous cell carcinoma of skin (2%
to <10%), hemorrhage (≤4%)
Adverse Reactions Frequency not defined. Adverse
Local: Localized tenderness (1% to 2%)
events observed at therapeutic serum levels:
Ophthalmic: Eyelid edema Central nervous system: Headache, insomnia, irritabil-
Respiratory: Sinusitis (2% to <10%) ity, restlessness, seizure
<1%, postmarketing, and/or case reports: Blurred Dermatologic: Allergic skin reaction, exfoliative derma-
vision, diplopia, eye irritation, fatigue, feeling hot, titis
fever, local inflammation, local swelling, nervousness, Gastrointestinal: Diarrhea, nausea, vomiting
ocular hyperemia, petechia, photophobia, pruritus, Genitourinary: Diuresis (transient)
pustular rash, skin discoloration, skin photosensitivity, Neuromuscular & skeletal: Tremor
temporary amnesia Mechanism of Action Theophylline has two distinct
Mechanism of Action Aminolevulinic acid is a meta- actions; smooth muscle relaxation (ie, bronchodilation)
bolic precursor of the photosensitizer protoporphyrin IX and suppression of the response of the airways to
(PpIX). Photosensitization following local/topical appli- stimuli (ie, non-bronchodilator prophylactic effects).
cation of aminolevulinic acid occurs through the meta- Bronchodilation is mediated by inhibition of two isoen-
bolic conversion to PpIX. When exposed to light of zymes, phosphodiesterase (PDE III and, to a lesser
appropriate wavelength and energy, accumulated PpIX extent, PDE IV) while non-bronchodilation effects are
produces a photodynamic reaction resulting in local mediated through other molecular mechanisms. Theo-
cytotoxicity. Precancerous and cancerous cells exhibit phylline increases the force of contraction of diaphrag-
a higher rate of porphyrin induction compared to normal matic muscles through enhancement of calcium uptake
cells. through adenosine-mediated channels.
110
AMIODARONE
Pharmacodynamics/Kinetics Pregnancy Risk Factor C

Half-life Elimination Theophylline: Highly variable Pregnancy Considerations Teratogenic effects have
and dependent upon age, hepatic function, cardiac been reported in animal reproduction studies. Salicy-
function, lung disease, and smoking history lates have been noted to cross the placenta and enter
Premature infants, postnatal age 3 to 15 days: 30 fetal circulation. Aminosalicylic acid has been used
hours (range: 17 to 43 hours) safely during pregnancy; however, it should only be
Premature infants, postnatal age 25 to 57 days: 20 used if there are no alternatives for the treatment of
hours (range: 9.4 to 30.6 hours) multidrug-resistant tuberculosis (MMWR, 2003).
Term infants, postnatal age 1 to 2 days: 25.7 hours
(range: 25 to 26.5 hours)
Term infants, postnatal age 3 to 30 weeks: 11 hours Amiodarone (a MEE oh da rone)
(range: 6 to 29 hours) Related Information
Children 1 to 4 years: 3.4 hours (range: 1.2 to 5.6
hours)
Clinical Risk Related to Drugs Prolonging QT Interval
Children and Adolescents 6 to 17 years: 3.7 hours
on page 1462
(range: 1.5 to 5.9 hours)
Adults ≥18 years to ≤60 years (asthma, nonsmoking, Brand Names: US Cordarone [DSC]; Nexterone; Pac-
otherwise healthy): 8.7 hours (range: 6.1 to 12.8 erone
hours) Brand Names: Canada Cordarone
Elderly >60 years (nonsmoking, healthy): 9.8 hours Pharmacologic Category Antiarrhythmic Agent,
(range: 1.6 to 18 hours) Class III
Time to Peak Serum: Theophylline: Within 30 minutes Use Ventricular arrhythmias: Management of life-
Pregnancy Considerations Adverse events were threatening recurrent ventricular fibrillation (VF) or
observed in some animal reproduction studies. Theo- recurrent hemodynamically unstable ventricular tachy-
phylline crosses the placenta. Refer to Theophylline cardia (VT) refractory to other antiarrhythmic agents or
monograph for additional information. in patients intolerant of other agents used for these
conditions
Aminosalicylic Acid (a mee noe sal i SIL ik AS id) Amiodarone is one of the drugs confirmed to prolong
the QT interval and is accepted as having a risk of
Brand Names: US Paser causing torsade de pointes. The risk of drug-induced
Pharmacologic Category Antitubercular Agent torsade de pointes is extremely low when a single QT
Use Adjunctive treatment of tuberculosis used in combi- interval prolonging drug is prescribed. In terms of epi-
nation with other antitubercular agents nephrine, it is not known what effect vasoconstrictors in
Local Anesthetic/Vasoconstrictor Precautions the local anesthetic regimen will have in patients with a
No information available to require special precautions known history of congenital prolonged QT interval or in
Effects on Dental Treatment NSAID formulations are patients taking any medication that prolongs the QT
known to reversibly decrease platelet aggregation via interval. Until more information is obtained, it is sug-
mechanisms different than observed with aspirin. The gested that the clinician consult with the physician prior
dentist should be aware of the potential of abnormal to the use of a vasoconstrictor in suspected patients,
coagulation. Caution should also be exercised in the and that the vasoconstrictor (epinephrine, mepivacaine
use of NSAIDs in patients already on anticoagulant and levonordefrin [Carbocaine® 2% with Neo-Cobe-
therapy with drugs such as warfarin (Coumadin®). frin®]) be used with caution.
Effects on Bleeding No information available to Effects on Dental Treatment Key adverse event(s)
require special precautions related to dental treatment: Distortion of the sense of
Adverse Reactions Frequency not defined. taste along with abnormal salivation; rare occurrence of
Cardiovascular: Pericarditis, vasculitis xerostomia (normal salivary flow resumes upon discon-
Central nervous system: Brain disease tinuation).
Dermatologic: Skin rash (including exfoliative derma- Effects on Bleeding No information available to
titis) require special precautions
Endocrine & metabolic: Goiter (with or without myxe- Adverse Reactions
dema), hypoglycemia, hypothyroidism >10%:
Gastrointestinal: Abdominal pain, diarrhea, nausea, Cardiovascular: Hypotension (intravenous: 20%; oral:
vomiting <1%; refractory in rare cases)
Hematologic & oncologic: Agranulocytosis, hemolytic Endocrine & metabolic: Phospholipidemia (pulmonary
anemia, leukopenia, thrombocytopenia phospholipidosis; oral: 50%; intravenous: <1%)
Hepatic: Hepatitis, jaundice Gastrointestinal: Nausea (oral: 10% to 33%; intra-
Miscellaneous: Fever venous: 4%), vomiting (10% to 33%; intrave-
Ophthalmic: Optic neuritis nous: <2%)
Respiratory: Eosinophilic pneumonitis Ophthalmic: Epithelial keratopathy (98% to 99%; vor-
Mechanism of Action Aminosalicylic acid (PAS) is a tex; Raizman 2016)
highly-specific bacteriostatic agent active against M. Respiratory: Pulmonary toxicity (oral: 2% to 17%;
tuberculosis. Structurally related to para-aminobenzoic intravenous: <1%)
acid (PABA) and its mechanism of action is thought to 1% to 10%:
be similar to the sulfonamides, a competitive antago- Cardiovascular: Bradycardia (2% to 6%), atrioventric-
nism with PABA; disrupts plate biosynthesis in sensitive ular block (≤5%), sinus bradycardia (≤5%), exacer-
organisms. bation of cardiac arrhythmia (oral: 2% to 5%), cardiac
Pharmacodynamics/Kinetics failure (2% to 3%), cardiac arrhythmia (1% to 3%),
Half-life Elimination Reduced with renal impairment edema (oral: 1% to 3%; intravenous: <1%), flushing
Time to Peak Serum: 6 hours (oral: 1% to 3% intravenous: <1%), sinus node
111
AMIODARONE
dysfunction (≤3%), ventricular tachycardia (2%), hypoesthesia, induration, inflammation, intravascular

atrial fibrillation (intravenous: <2%), cardiogenic amiodarone deposition/mass, pain, phlebitis, pigment
shock (intravenous: <2%), nodal arrhythmia (intra- changes, pruritus, skin sloughing, thrombophlebitis,
venous: <2%), prolonged Q-T interval on ECG (<2%; thrombosis, urticaria), interstitial pneumonitis, jaun-
associated with worsening arrhythmia), torsades de dice, lupus-like syndrome, malignant neoplasm of
pointes (<2%), ventricular fibrillation (<2%) skin, malignant neoplasm of thyroid, mass (pulmo-
Central nervous system: Abnormal gait (oral: ≤9%), nary), muscle spasm, myasthenia, myopathy, myxe-
ataxia (oral: ≤9%), fatigue (oral: ≤9%), involuntary dema (including myxedema coma), neutropenia,
body movements (oral: ≤9%), malaise (oral: ≤9%), nonimmune anaphylaxis, optic neuropathy, pancyto-
dizziness (oral: 4% to 9%; intravenous: <1%), par- penia, pleural effusion, pleurisy, pruritus, pulmonary
esthesia (oral: 4% to 9%), altered sense of smell alveolar hemorrhage, pulmonary infiltrates, respiratory
(oral: 1% to 3%), headache (oral: 1% to 3%), insom- failure, rhabdomyolysis, SIADH, sinoatrial arrest, skin
nia (oral: 1% to 3%), sleep disorder (oral: 1% to 3%) carcinoma, skin granuloma, skin rash, spontaneous
Dermatologic: Skin photosensitivity (10%), solar der- ecchymoses, thyroid nodule, thyrotoxicosis, toxic epi-
ma titis (oral: ≤9 %), Stev ens -J ohn son sy n- dermal necrolysis, urticaria, vasculitis, ventricular pre-
drome (<2%) mature contractions, visual field defect, wheezing,
Endocrine & metabolic: Hypothyroidism (1% to 10%), xerostomia
decreased libido (oral: 1% to 3%), hyperthyroid-
Mechanism of Action Class III antiarrhythmic agent
ism (2%)
which inhibits adrenergic stimulation (alpha- and beta-
Gastrointestinal: Anorexia (oral: 4% to 9%), constipa-
blocking properties), affects sodium, potassium, and
tion (oral: 4% to 9%), altered salivation (oral: 1% to
calcium channels, prolongs the action potential and
3%), dysgeusia (oral: 1% to 3%), abdominal pain
(oral: 1% to 3%), diarrhea (intravenous: <2%) refractory period in myocardial tissue; decreases AV
Hematologic & oncologic: Disorder of hemostatic com- conduction and sinus node function
ponents of blood (oral: 1% to 3%), thrombocytope-
nia (<2%) Onset of Action Oral: 2 days to 3 weeks; IV: (electro-
Hepatic: Abnormal hepatic function tests (4%), hepatic physiologic effects) within hours; antiarrhythmic
disease (oral: 1% to 3%), increased serum alanine effects: 2 to 3 days to 1 to 3 weeks; mean onset of
aminotransferase (<2%), increased serum aspartate effect may be shorter in children vs adults and in
aminotransferase (<2%) patients receiving IV loading doses; Peak effect: 1
Neuromuscular & skeletal: Tremor (oral: ≤9%) week to 5 months
Ophthalmic: Blurred vision (oral: ≤10%; intravenous: Duration of Action
<1%), visual halos around lights (oral: ≤10%), visual After discontinuing therapy: Variable, 2 weeks to
disturbance (oral: 4% to 9%), optic neuritis (1%) months: Children: Less than a few weeks; Adults:
Renal: Renal insufficiency (<2%) Several months
Respiratory: Pneumonitis (oral: ≤9%), pulmonary fib- Note: Duration after discontinuation may be shorter in
rosis (oral: ≤9%; intravenous: <1%), acute respira- children than adults
tory distress syndrome (≤2%), pulmonary edema Half-life Elimination Note: Half-life is shortened in
(intravenous: <2%) children vs adults
Miscellaneous: Fever (intravenous: 3%; oral: <1%) Amiodarone:
Frequency not defined: Single dose: 58 days (range: 15 to 142 days)
Cardiovascular: Asystole Oral chronic therapy: Mean range: 40 to 55 days
Central nervous system: Peripheral neuropathy (range: 26 to 107 days)
Ophthalmic: Dry eye syndrome, photophobia IV single dose: Mean range: 9 to 36 days
Respiratory: Hypersensitivity pneumonitis, pneumoni- N-desethylamiodarone (active metabolite): Prolonged
tis (alveolar) in severe left ventricular dysfunction
<1%, postmarketing, and/or case reports: Acute pan- Single dose: 36 days (range: 14 to 75 days)
creatitis, acute renal failure, agranulocytosis, alopecia, Oral chronic therapy: 61 days
anaphylactic shock, anaphylaxis, angioedema, aplas- IV single dose: Mean range: 9 to 30 days
tic anemia, back pain, blue-gray skin pigmentation, Time to Peak Oral: Serum: 3 to 7 hours
bronchiolitis obliterans organizing pneumonia, bron-
chospasm, bullous dermatitis, cardiac conduction dis-
turbance (including bundle branch block, infra-HIS
Amiodarone crosses the placenta (~10% to 50%) and
block, and antegrade conduction via an accessory
pathway), cholestasis, cholestatic hepatitis, confusion, may cause fetal harm when administered to a pregnant
cough, delirium, demyelinating disease (polyneurop- woman. Reported risks include neonatal bradycardia,
athy), disorientation, drug-induced Parkinson's dis- QT prolongation, and periodic ventricular extrasystoles;
ease, drug reaction with eosinophilia and systemic neonatal hypothyroidism (with or without goiter); neo-
symptoms, dyspnea, eczema, eosinophilic pneumo- natal hyperthyroxinemia; neurodevelopmental abnor-
nitis, epididymitis, erythema multiforme, exfoliative malities independent of thyroid function; jerk
dermatitis, granulocytosis, hallucination, hemolytic nystagmus with synchronous head titubation; fetal
anemia, hemoptysis, hepatic cirrhosis, hepatic failure, growth retardation; and/or premature birth. Oral or IV
hepatitis, hepatotoxicity (idiosyncratic) (Chalasani amiodarone should be used in pregnant women only to
2014), hypoesthesia, hypoxia, idiopathic intracranial treat arrhythmias refractory to other treatments or when
hypertension, impotence, increased intracranial pres- other treatments are contraindicated (Page [ACC/AHA/
sure, increased lactate dehydrogenase, increased HRS 2015]; ESG/AEPC/DGesGM/ESC 2011).
serum alkaline phosphatase, increased serum crea- Dental Health Professional Considerations Amio-
tinine, infusion site reaction (including cellulitis, darone is one of the drugs confirmed to prolong the QT
edema, erythema, extravasation possibly leading to interval. See Local Anesthetic/Vasoconstrictor Precau-
venous/infusion site necrosis, granuloma, tions
112
AMITRIPTYLINE
involuntary movements and tardive dyskinesia),

Amitriptyline (a mee TRIP ti leen) fatigue, hallucination, headache, hyperpyrexia, insom-
nia, lack of concentration, nightmares, numbness,
Related Information paresthesia, peripheral neuropathy, restlessness,
Dentin Hypersensitivity, Acid Erosion, High Caries sedation, seizure, tingling of extremities
Index, Management of Alveolar Osteitis, and Xerosto- Dermatologic: Allergic skin rash, alopecia, diaphoresis,
mia on page 1548 skin photosensitivity, urticaria
Temporomandibular Dysfunction (TMD), Chronic Pain, Endocrine & metabolic: Altered serum glucose,
and Fibromyalgia on page 1559 decreased libido, galactorrhea, gynecomastia,
Vasoconstrictor Interactions With Antidepressants on increased libido, SIADH, weight gain, weight loss
page 1606 Gastrointestinal: Ageusia, anorexia, constipation, diar-
Brand Names: US Elavil [DSC] rhea, melanoglossia, nausea, paralytic ileus, parotid
Brand Names: Canada Elavil; Levate gland enlargement, stomatitis, unpleasant taste, vom-
Pharmacologic Category Antidepressant, Tricyclic iting, xerostomia
(Tertiary Amine) Genitourinary: Breast hypertrophy, impotence, testicu-
Use Major depressive disorder (unipolar): Treatment lar swelling, urinary frequency, urinary retention, uri-
of unipolar major depressive disorder nary tract dilation
Local Anesthetic/Vasoconstrictor Precautions Hematologic & oncologic: Bone marrow depression
Amitriptyline is one of the drugs confirmed to prolong (including agranulocytosis, leukopenia, and thrombo-
the QT interval and is accepted as having a risk of cytopenia), eosinophilia, purpura
causing torsade de pointes. In terms of epinephrine, it Hepatic: Hepatic failure, hepatitis (rare; including
is not known what effect vasoconstrictors in the local altered liver function and jaundice)
anesthetic regimen will have in patients with a known Hypersensitivity: Tongue edema
history of congenital prolonged QT interval or in patients Neuromuscular & skeletal: Lupus-like syndrome,
taking any medication that prolongs the QT interval. tremor, weakness
Until more information is obtained, it is suggested that Ophthalmic: Accommodation disturbance, blurred
the clinician consult with the physician prior to the use of vision, increased intraocular pressure, mydriasis
a vasoconstrictor in suspected patients, and that the Otic: Tinnitus
vasoconstrictor (epinephrine, mepivacaine and levonor- Postmarketing and/or case reports: Angle-closure glau-
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used coma, neuroleptic malignant syndrome (rare; Stevens,
with caution. 2008), serotonin syndrome (rare)
Effects on Dental Treatment Key adverse event(s) Mechanism of Action Increases the synaptic concen-
related to dental treatment: Xerostomia and changes in tration of serotonin and/or norepinephrine in the central
salivation (normal salivary flow resumes upon discon- nervous system by inhibition of their reuptake by the
tinuation), stomatitis, peculiar taste, and black tongue. presynaptic neuronal membrane pump.
Patients may experience orthostatic hypotension as Pharmacodynamics/Kinetics
they stand up after treatment; especially if lying in Onset of Action Individual responses may vary, how-
dental chair for extended periods of time. Use caution ever 4 to 8 weeks of treatment are needed before
with sudden changes in position during and after dental determining if a patient with depression is partially or
treatment. Amitriptyline is the most anticholinergic and non-responsive; similarly 8 to 12 weeks are required
sedating of the antidepressants; has pronounced for an adequate migraine prophylaxis trial (APA 2010;
effects on the cardiovascular system. Long-term treat- Prinsheim 2012); desired therapeutic effect (for anal-
ment with TCAs such as amitriptyline increases the risk gesia) may take as long as 1 to 3 weeks.
of caries by reducing salivation and salivary buffer Half-life Elimination ~13 to 36 hours (Schulz 1985)
capacity. In a study by Rundergren, et al, pathological Time to Peak Serum: ~2 to 5 hours (Schulz 1985)
alterations were observed in the oral mucosa of 72% of Pregnancy Risk Factor C
58 patients; 55% had new carious lesions after taking Pregnancy Considerations
TCAs for a median of 51/2 years. Current research is Adverse events have been observed in some animal
investigating the use of the salivary stimulant pilocar- reproduction studies. Amitriptyline crosses the human
pine (Salagen®) to overcome the xerostomia from placenta; CNS effects, limb deformities, and develop-
amitriptyline. mental delay have been noted in case reports (causal
Effects on Bleeding May cause thrombocytopenia relationship not established). Tricyclic antidepressants
Adverse Reactions Anticholinergic effects may be may be associated with irritability, jitteriness, and con-
pronounced; moderate to marked sedation can occur vulsions (rare) in the neonate (Yonkers 2009). Crying,
(tolerance to these effects usually occurs). constipation, problems with urinating, and nausea may
also occur in neonates exposed during pregnancy
Frequency not defined.
(Larsen 2015).
Cardiovascular: Atrioventricular conduction disturb-
ance, cardiac arrhythmia, cardiomyopathy (rare), cer- The ACOG recommends that therapy for depression
ebrovascular accident, ECG changes (nonspecific), during pregnancy be individualized; treatment should
edema, facial edema, heart block, hypertension, myo- incorporate the clinical expertise of the mental health
cardial infarction, orthostatic hypotension, palpitations, clinician, obstetrician, primary health care provider, and
syncope, tachycardia pediatrician (ACOG 2008). According to the American
Central nervous system: Anxiety, ataxia, cognitive dys- Psychiatric Association (APA), the risks of medication
function, coma, confusion, delusions, disorientation, treatment should be weighed against other treatment
dizziness, drowsiness, drug withdrawal (nausea, options and untreated depression. For women who
headache, malaise, irritability, restlessness, dream discontinue antidepressant medications during preg-
and sleep disturbance, mania [rare], and hypomania nancy and who may be at high risk for postpartum
[rare]), dysarthria, EEG pattern changes, excitement, depression, the medications can be restarted following
extrapyramidal reaction (including abnormal delivery (APA 2010). Treatment algorithms have been
113
AMITRIPTYLINE
developed by the ACOG and the APA for the manage- 1% to 10%:
ment of depression in women prior to conception and Cardiovascular: Palpitations (≤5%, dose related),
during pregnancy (Yonkers 2009). Tricyclic antidepres- flushing (≤3%, dose related, more frequent in
sants are not the preferred therapy for depression in females)
pregnant women but may be helpful when agitation is Central nervous system: Fatigue (5%), dizziness (1%
also present. If a TCA is needed, amitriptyline is one of to 3%, dose related), male sexual disorder (≤2%),
the preferred agents. Maternal serum concentrations drowsiness (1%)
should be monitored during pregnancy (Larsen 2015; Dermatologic: Pruritus (≤2%), skin rash (≤2%)
Yonkers 2009). Migraine prophylaxis should be avoided Gastrointestinal: Nausea (3%), abdominal pain (2%)
during pregnancy; if needed, amitriptyline may be used Neuromuscular & skeletal: Muscle cramps (≤2%),
if other agents are ineffective or contraindicated (Pring- weakness (≤2%)
sheim 2012). Respiratory: Dyspnea (≤2%)
Pregnant women exposed to antidepressants during dreams, acute interstitial nephritis (Ejaz 2000),
pregnancy are encouraged to enroll in the National angioedema, anorexia, anxiety, arthralgia, atrial fibril-
Pregnancy Registry for Antidepressants (NPRAD). lation, back pain, bradycardia, cardiac arrhythmia,
Women 18 to 45 years of age or their health care chest pain, cholestasis, conjunctivitis, constipation,
providers may contact the registry by calling depersonalization, depression, diaphoresis, diarrhea,
844-405-6185. Enrollment should be done as early in difficulty in micturition, diplopia, dysphagia, epistaxis,
pregnancy as possible. erythema multiforme, erythematous rash, exfoliative
Dental Health Professional Considerations See dermatitis, extrapyramidal reaction, eye pain, female
Local Anesthetic/Vasoconstrictor Precautions sexual disorder, flatulence, gingival hyperplasia, gyne-
comastia, hepatitis, hot flash, hyperglycemia, hyper-
AmLODIPine (am LOE di peen) sensitivity angiitis, hypersensitivity reaction,
hypoesthesia, increased serum transaminases,
Related Information increased thirst, insomnia, jaundice, leukopenia, mac-
Calcium Channel Blockers and Gingival Hyperplasia on ulopapular rash, malaise, myalgia, nervousness, noc-
page 1601 turia, nonthrombocytopenic purpura, orthostatic
Cardiovascular Diseases on page 1442 hypotension, osteoarthritis, pain, pancreatitis, pares-
Brand Names: US Norvasc thesia, peripheral ischemia, peripheral neuropathy,
phototoxicity, purpura, rigors, syncope, tachycardia,
Brand Names: Canada Norvasc
thrombocytopenia, tinnitus, tremor, urinary frequency,
Pharmacologic Category Antianginal Agent; Antihy-
vasculitis, ventricular tachycardia, vertigo, visual dis-
pertensive; Calcium Channel Blocker; Calcium Channel
turbance, vomiting, weight gain, weight loss, xero-
Blocker, Dihydropyridine
stomia
Use Mechanism of Action Inhibits calcium ion from enter-
Chronic stable angina: Treatment of symptomatic ing the "slow channels" or select voltage-sensitive
chronic stable angina. May be used alone or in areas of vascular smooth muscle and myocardium
combination with other antianginal agents. during depolarization, producing a relaxation of coro-
Hypertension: Management of hypertension. nary vascular smooth muscle and coronary vasodila-
Stable coronary artery disease with ongoing ische- tion; increases myocardial oxygen delivery in patients
mic symptoms: To reduce the risk of hospitalization with vasospastic angina. Amlodipine directly acts on
secondary to angina and to reduce the risk of a vascular smooth muscle to produce peripheral arterial
coronary revascularization procedure in patients with vasodilation reducing peripheral vascular resistance
documented coronary artery disease (CAD). and blood pressure.
Vasospastic angina (previously referred to as Prinz- Pharmacodynamics/Kinetics
metal or variant angina): Treatment of confirmed or Onset of Action Antihypertensive effect: Significant
suspected vasospastic angina. May be used alone or reductions in blood pressure at 24 to 48 hours after
in combination with other antianginal agents. first dose; slight increase in heart rate within 10 hours
Local Anesthetic/Vasoconstrictor Precautions of administration may reflect some vasodilating activity
No information available to require special precautions (Donnelly 1993)
Effects on Dental Treatment Key adverse event(s) Duration of Action Antihypertensive effect: At least
related to dental treatment: Rare occurrence of gingival 24 hours (Donnelly 1993); has been shown to extend
hyperplasia with amlodipine than with other calcium to at least 72 hours when discontinued after 6 to 7
channel blockers (usually resolves upon discontinua- weeks of therapy (Biston 1999)
tion); consultation with physician is suggested if gingival Half-life Elimination Terminal (biphasic): 30 to 50
hyperplasia is observed. Rare occurrences of xerosto- hours; increased with hepatic dysfunction
mia, orthostatic hypotension, and erythema multiforme Time to Peak Plasma: 6 to 12 hours
(severe oral ulcerations that respond well to systemic Pregnancy Considerations
steroid therapy). Amlodipine crosses the placenta. Cord blood concen-
Effects on Bleeding No information available to trations were approximately one-third of maternal
require special precautions serum at delivery, and concentrations in the newborn
Adverse Reactions were below the limit of quantification (<0.1 ng/mL) when
>10%: measured in eight infants within 48 hours of delivery
Cardiovascular: Peripheral edema (2% to 11% dose (Morgan 2017). Information related to the use of amlo-
related; female 15%; male 6%; HF patients 27% to dipine in pregnancy is limited (Ahn 2007; Nahapetian
28% [Packer 1996; Packer 2013]) 2008; Vigil-De Gracia 2014; Yu 2015). Due to preg-
Respiratory: Pulmonary edema (HF patients 7% to nancy induced pharmacologic changes, amlodipine
15% [Packer 1996; Packer 2013]) pharmacokinetics may be altered immediately
114
AMOXAPINE
postpartum; large individual patient variability was Local Anesthetic/Vasoconstrictor Precautions

observed (Naito 2015b). Use with caution; epinephrine and levonordefrin have
Untreated chronic maternal hypertension is associated been shown to have an increased pressor response in
with adverse events in the fetus, infant, and mother. If combination with TCAs. Amoxapine is one of the drugs
treatment for hypertension during pregnancy is needed, confirmed to prolong the QT interval and is accepted as
agents other than amlodipine are preferred having a risk of causing torsade de pointes. The risk of
(ACOG 2013). drug-induced torsade de pointes is extremely low when
a single QT interval prolonging drug is prescribed. In
terms of epinephrine, it is not known what effect vaso-
Amlodipine and Olmesartan constrictors in the local anesthetic regimen will have in
(am LOE di peen & olme SAR tan)
patients with a known history of congenital prolonged
Related Information QT interval or in patients taking any medication that
AmLODIPine on page 114 prolongs the QT interval. Until more information is
Olmesartan on page 992 obtained, it is suggested that the clinician consult with
Brand Names: US Azor the physician prior to the use of a vasoconstrictor in
Pharmacologic Category Angiotensin II Receptor suspected patients, and that the vasoconstrictor (epi-
Blocker; Antianginal Agent; Antihypertensive; Calcium nephrine, mepivacaine and levonordefrin [Carbocaine®
Channel Blocker; Calcium Channel Blocker, Dihydro- 2% with Neo-Cobefrin®]) be used with caution.
pyridine Effects on Dental Treatment Key adverse event(s)
Use Hypertension: Management of hypertension related to dental treatment: Xerostomia and changes in
(monotherapy or with other antihypertensive agents). salivation (normal salivary flow resumes upon discon-
Local Anesthetic/Vasoconstrictor Precautions tinuation). Long-term treatment with TCAs, such as
No information available to require special precautions amoxapine, increases the risk of caries by reducing
Effects on Dental Treatment Key adverse event(s) salivation and salivary buffer capacity.
related to dental treatment: Patients may experience Effects on Bleeding May cause thrombocytopenia
orthostatic hypotension as they stand up after treat- Adverse Reactions
ment; especially if lying in dental chair for extended
>10%:
periods of time. Use caution with sudden changes in
Central nervous system: Drowsiness (14%)
position during and after dental treatment.
Gastrointestinal: Xerostomia (14%), constipa-
Fewer reports of gingival hyperplasia with amlodipine tion (12%)
than with other CCBs (usually resolves upon discontin- 1% to 10%:
uation); consultation with physician is suggested. Cardiovascular: Edema, palpitations
Effects on Bleeding No information available to Central nervous system: Anxiety, ataxia, confusion,
require special precautions dizziness, EEG pattern changes, excitement, fatigue,
Adverse Reactions Reactions/percentages reported headache, insomnia, nervousness, nightmares, rest-
with combination product; also see individual agents lessness
>10%: Cardiovascular: Peripheral edema (dose related: Dermatologic: Diaphoresis, skin rash
18% to 26%) Endocrine & metabolic: Increased serum prolactin
Frequency not defined (limited to important or life- Gastrointestinal: Increased appetite, nausea
threatening): Anaphylaxis, hypotension, nocturia, Neuromuscular & skeletal: Tremor, weakness
orthostatic hypotension, palpitations, pruritus, skin
Ophthalmic: Blurred vision (7%)
rash, urinary frequency
<1% (Limited to important or life-threatening): Abdomi-
Mechanism of Action
nal pain, accommodation disturbance, agranulocyto-
Amlodipine: Directly acts on vascular smooth muscle to
sis, alopecia, altered serum glucose, angle-closure
produce peripheral arterial vasodilation reducing
peripheral vascular resistance and blood pressure. glaucoma, anorexia, atrial arrhythmia, atrial fibrillation,
Olmesartan: Blocks the vasoconstrictor and aldoster- breast hypertrophy, decreased libido, delayed mictur-
one-secreting effects of angiotensin II. ition, diarrhea, disorientation, eosinophilia, epigastric
Pregnancy Risk Factor D distress, extrapyramidal reaction, fever, flatulence,
Pregnancy Considerations [US Boxed Warning]: galactorrhea, hallucination, heart block, hepatic insuf-
Drugs that act on the renin-angiotensin system ficiency, hepatitis, hypersensitivity reaction, hyperten-
can cause injury and death to the developing fetus. sion, hyperthermia, hypomania, hypotension,
Discontinue as soon as possible once pregnancy is impotence, increased intraocular pressure, increased
detected. See individual agents. libido, jaundice, lack of concentration, lacrimation,
leukopenia, menstrual disease, mydriasis, myocardial
infarction, nasal congestion, neuroleptic malignant
Amoxapine (a MOKS a peen)
syndrome, numbness, painful ejaculation, pancreati-
Related Information tis, paralytic ileus, paresthesia, parotid swelling, pete-
Dentin Hypersensitivity, Acid Erosion, High Caries chia, pruritus, purpura, seizure, SIADH, skin
Index, Management of Alveolar Osteitis, and Xerosto- photosensitivity, syncope, tachycardia, tardive dyski-
mia on page 1548 nesia, testicular swelling, thrombocytopenia, tingling
Vasoconstrictor Interactions With Antidepressants on sensation, tinnitus, unusual taste, urinary frequency,
page 1606 urinary retention, urticaria, vasculitis, vomiting, weight
Pharmacologic Category Antidepressant, Tricyclic gain, weight loss
(Secondary Amine) Mechanism of Action Reduces the reuptake of sero-
Use Major depressive disorder (unipolar): Treatment tonin and norepinephrine. The metabolite, 7-OH-amox-
of unipolar major depression, including depression with apine has significant dopamine receptor blocking
psychotic features activity similar to antipsychotic agents.
115
AMOXAPINE
Pharmacodynamics/Kinetics Use
Onset of Action Antidepressant effect: Usually Ear, nose, and throat infections (pharyngitis/tonsil-
occurs after 1 to 2 weeks, but may require 4 to 6 litis, otitis media):
weeks Immediate release: Treatment of infections due to
Half-life Elimination 8 hours; 8-hydroxyamoxapine beta-lactamase-negative Streptococcus spp. (alpha-
metabolite: 30 hours and beta-hemolytic isolates only), Streptococcus
Time to Peak Serum: ~90 minutes pneumoniae, Staphylococcus spp., or Haemophilus
Pregnancy Risk Factor C influenzae.
Pregnancy Considerations Adverse events were Extended release: Treatment of tonsillitis and/or phar-
observed in some animal reproduction studies. Tricyclic yngitis due to Streptococcus pyogenes in adults and
antidepressants may be associated with irritability, jitt- pediatric patients ≥12 years of age.
eriness, and convulsions (rare) in the neonate (Yonkers, Genitourinary tract infections: Immediate release:
2009). Treatment of infections of the genitourinary tract due
to beta-lactamase-negative Escherichia coli, Proteus
The ACOG recommends that therapy for depression mirabilis, or Enterococcus faecalis.
during pregnancy be individualized; treatment should Helicobacter pylori eradication: Immediate release:
incorporate the clinical expertise of the mental health Eradication of H. pylori to reduce the risk of duodenal
clinician, obstetrician, primary healthcare provider, and ulcer recurrence as a component of combination
pediatrician (ACOG, 2008). According to the American therapy in patients with active or 1-year history of
Psychiatric Association (APA), the risks of medication duodenal ulcer disease.
treatment should be weighed against other treatment Lower respiratory tract infections (including pneu-
options and untreated depression. For women who monia): Immediate release: Treatment of infections of
discontinue antidepressant medications during preg- the lower respiratory tract due to beta-lactamase-neg-
nancy and who may be at high risk for postpartum ative Streptococcus spp. (alpha- and beta-hemolytic
depression, the medications can be restarted following strains only), S. pneumoniae, Staphylococcus spp., or
delivery (APA, 2010). Treatment algorithms have been H. influenzae.
developed by the ACOG and the APA for the manage- Rhinosinusitis, acute bacterial: Immediate release:
ment of depression in women prior to conception and
Treatment of infections due to beta-lactamase-nega-
during pregnancy (Yonkers, 2009).
tive Streptococcus spp. (alpha- and beta-hemolytic
Pregnant women exposed to antidepressants during isolates only), S. pneumoniae, Staphylococcus spp.,
pregnancy are encouraged to enroll in the National or H. influenzae.
Pregnancy Registry for Antidepressants (NPRAD). Skin and skin structure infections: Immediate
Women 18 to 45 years of age or their health care release: Treatment of infections of the skin and skin
providers may contact the registry by calling structure due to beta-lactamase-negative Streptococ-
844-405-6185. Enrollment should be done as early in cus spp. (alpha- and beta-hemolytic strains only),
pregnancy as possible. Staphylococcus spp., or E. coli.
Dental Health Professional Considerations See Local Anesthetic/Vasoconstrictor Precautions
Local Anesthetic/Vasoconstrictor Precautions No information available to require special precautions
Effects on Dental Treatment Prolonged use of pen-
icillins may lead to development of oral candidiasis
Amoxicillin (a moks i SIL in)
Related Information require special precautions
Antibiotic Prophylaxis on page 1502 Adverse Reactions
Bacterial Infections on page 1525 1% to 10%:
Gastrointestinal Disorders on page 1465 Central nervous system: Headache (1%)
Osteonecrosis of the Jaw on page 1486 Gastrointestinal: Diarrhea (2%), nausea (1%), vomit-
ing (1%)
Periodontal Diseases on page 1534
Genitourinary: Vulvovaginal infection (2%)
Related Sample Prescriptions Frequency not defined:
Bacterial Infections and Periodontal Diseases - Sample Cardiovascular: Hypersensitivity angiitis
Prescriptions on page 36 Central nervous system: Agitation, anxiety, behavioral
Prevention of Endocarditis and to Reduce the Risk of changes, confusion, dizziness, insomnia, reversible
Late Infections of Joint Prostheses - Sample Prescrip- hyperactivity, seizure
tions on page 41 Dermatologic: Acute generalized exanthematous pus-
Sinus Infection Treatment - Sample Prescriptions on tulosis, erythematous maculopapular rash, erythema
page 42 multiforme, exfoliative dermatitis, skin rash, Stevens-
Brand Names: US Moxatag [DSC] Johnson syndrome, toxic epidermal necrolysis, urti-
Brand Names: Canada Novamoxin; Pro-Amox-250; caria
Pro-Amox-500 Gastrointestinal: Clostridioides difficile associated
Generic Availability (US) Yes diarrhea, Clostridioides difficile colitis, hemorrhagic
Pharmacologic Category Antibiotic, Penicillin colitis, melanoglossia, mucocutaneous candidiasis,
Dental Use Antibiotic for standard prophylactic regimen staining of tooth
for dental patients who are at risk for infective endo- Genitourinary: Crystalluria
carditis; prophylaxis in total joint replacement patients Hematologic & oncologic: Agranulocytosis, anemia,
undergoing dental procedures; antibiotic used to treat eosinophilia, hemolytic anemia, immune thrombocy-
orofacial infections. Useful (as amoxicillin or amoxicillin/ topenia, leukopenia, thrombocytopenia
clavulanic acid) in combination with metronidazole in Hepatic: Cholestatic hepatitis, cholestatic jaundice,
addition to scaling and root planing in the treatment of hepatitis (acute cytolytic), increased serum alanine
periodontitis associated with the presence of Actino- aminotransferase, increased serum aspartate ami-
bacillus actinomycetemcomitans (AA). notransferase
116
AMOXICILLIN
Hypersensitivity: Anaphylaxis biological weapon-related event and 7 to 10 days

Immunologic: Serum sickness-like reaction after naturally acquired infection. Note: Patients
<1%, postmarketing, and/or case reports: Abdomi- with cutaneous lesions of the head or neck or
nal pain extensive edema should be treated with a paren-
Dental Usual Dosage Oral: teral regimen recommended for systemic involve-
Children >3 months and <40 kg: Prophylaxis against ment (CDC [Hendricks 2014]).
infective endocarditis: 50 mg/kg 30-60 minutes before Asplenia, prophylaxis against bacterial infection
procedure. Note: American Heart Association (AHA) in select high-risk patients (off-label use): Oral:
guidelines now recommend prophylaxis only in Based on expert opinion: 500 mg twice daily. Dura-
patients undergoing invasive procedures and in whom tion varies based on patient-specific factors (Paster-
underlying cardiac conditions may predispose to a nack 2018).
higher risk of adverse outcomes should infection Bronchiectasis (off-label use):
occur. Treatment of pulmonary exacerbations in patients
Adults: without beta-lactamase-positive Haemophilus
Periodontitis (aggressive) (in combination with metro- influenzae or Pseudomonas aeruginosa: Oral:
nidazole) associated with presence of Actinobacillus 500 mg 3 times daily (Barker 2018; Finegold
actinomycetemcomitans (AA): 500 mg every 8 hours 1981) or 1 g 3 times daily (Prigogine 1988) for up
for 10 days used in addition to scaling and root to 14 days (Barker 2018; ERS [Polverino 2017]).
planing (Varela 2011). In aggressive periodontitis, Prevention of pulmonary exacerbations: Oral:
greatest benefit is seen after 3 months of therapy. 500 mg twice daily; dosing based on expert opinion
No benefit was seen after 6 months of therapy (Barker 2018). Note: Recommended for patients
(Varela 2011). with ≥3 exacerbations per year who are not colon-
Prophylaxis against infective endocarditis: 2 g 30-60 ized with P. aeruginosa and not candidates for long-
minutes before procedure. Note: American Heart term macrolide therapy (Barker 2018; ERS [Polver-
Association (AHA) guidelines now recommend pro- ino 2017]).
phylaxis only in patients undergoing invasive proce- Endocarditis, prophylaxis (dental or invasive res-
dures and in whom underlying cardiac conditions piratory tract procedures) (off-label use): Oral:
may predispose to a higher risk of adverse outcomes 2 g 30 to 60 minutes before procedure. Note: Only
should infection occur. recommended for patients with cardiac conditions
Orofacial infection: 250-500 mg every 8 hours or associated with the highest risk of an adverse out-
500-875 mg twice daily come from endocarditis and who are undergoing a
Prophylaxis in total joint replacement patients under- procedure likely to result in bacteremia with an
going dental procedures which produce bacteremia: organism that has the potential ability to cause
2 g 1 hour prior to procedure endocarditis (AHA [Wilson 2007]).
Note: In general, patients with prosthetic joint implants Helicobacter pylori eradication: Oral:
do not require prophylactic antibiotics prior to dental Clarithromycin triple regimen: Amoxicillin 1 g twice
procedures. In planning an invasive oral procedure, daily in combination with clarithromycin 500 mg
dental consultation with the patient's orthopedic sur- twice daily, plus a standard-dose or double-dose
geon may be advised to review the risks of infection. proton pump inhibitor; continue regimen for 14
Dosing days. Note: Avoid use in patients with risk factors
Adult & Geriatric Note: Unless otherwise specified, for macrolide resistance (eg, prior macrolide expo-
all dosing recommendations based on immediate- sure or local clarithromycin resistance rates ≥15%,
release product formulations. which is assumed in the United States) (ACG [Chey
Usual dosage range: 2017]; Fallone 2016).
Immediate release: Oral: 500 mg to 1 g every 8 to Concomitant regimen: Amoxicillin 1 g twice daily in
12 hours combination with clarithromycin 500 mg twice daily,
Extended release: 775 mg once daily either metronidazole or tinidazole 500 mg twice
Actinomycosis (off-label use): Note: For initial ther- daily, plus a standard-dose proton pump inhibitor
apy of mild infections or step-down therapy following twice daily; continue regimen for 10 to 14 days
parenteral treatment of severe infections. (ACG [Chey 2017])
Oral: 500 mg 3 to 4 times daily or 1 g 3 times daily Sequential regimen (alternative regimen): Amoxicillin
(Martin 1984; Paulo 2018; Sharkaway 2018; Shi- 1 g twice daily plus a standard-dose proton pump
kino 2015); higher doses of 4 to 6 g/day in divided inhibitor twice daily for 5 to 7 days; followed by
doses have been utilized in case reports (Moghimi clarithromycin 500 mg twice daily, either metroni-
2013; Valour 2014). Optimal duration of therapy is dazole or tinidazole 500 mg twice daily, plus a
unknown; some experts suggest 2 to 12 months, standard-dose proton pump inhibitor twice daily
depending on severity of infection and response to for 5 to 7 days; some experts prefer the 10-day
therapy (Sharkaway 2018). regimen due to the lack of data showing superiority
Anthrax (alternative agent for penicillin-suscepti- of the 14-day sequential regimen in North America
ble strains) (off-label use): Note: Consult public (ACG [Chey 2017]; Crowe 2018).
health officials for event-specific recommendations. Hybrid regimen (alternative regimen): Amoxicillin 1 g
A high index of suspicion for emergent beta-lactam twice daily, plus a standard-dose proton pump
resistance during therapy is warranted (Wil- inhibitor twice daily for 7 days; followed by amox-
son 2018). icillin 1 g twice daily, clarithromycin 500 mg twice
Inhalational exposure postexposure prophylaxis: daily, either metronidazole or tinidazole 500 mg
Oral: 1 g every 8 hours for 60 days. Note: Anthrax twice daily, plus a standard-dose proton pump
vaccine should also be administered to exposed inhibitor twice daily for 7 days (ACG [Chey 2017]).
individuals (CDC [Hendricks 2014]). Levofloxacin triple regimen (salvage regimen):
Cutaneous, without systemic involvement: Oral: 1 g Amoxicillin 1 g twice daily in combination with a
every 8 hours; duration is 60 days following standard-dose proton pump inhibitor twice daily
117
AMOXICILLIN
plus levofloxacin 500 mg once daily; continue regi- In uncomplicated acute bacterial rhinosinusitis, ini-
men for 10 to 14 days (ACG [Chey 2017]). tial observation and symptom management without
High-dose dual therapy (salvage regimen): Amoxicil- antibiotic therapy is appropriate in most patients
lin 750 mg 4 times daily or 1 g 3 times daily; in (AAO-HNS [Rosenfeld 2015]; ACG/CDC [Har-
combination with a standard-dose or double-dose ris 2016]).
proton pump inhibitor 3 to 4 times daily for 14 days Skin and soft tissue infection:
(ACG [Chey 2017]). Erysipelas, mild: Oral: 500 mg 3 times daily or
Lyme disease (Borrelia spp. infection) (off-label 875 mg twice daily for 5 days, with extension to
use): 14 days for slow response, severe infection, or
Early localized (eg, erythema migrans): Oral: 500 mg immunosuppression (Spelman 2018; manufactur-
3 times daily for 14 to 21 days (IDSA er's labeling).
[Wormser 2006])
Erysipeloid, localized cutaneous: Oral: 500 mg 3
Early disseminated, carditis (initial therapy for mild
times daily for 7 to 10 days (IDSA [Stevens 2014])
disease [first-degree atrioventricular block with PR
Streptococcal pharyngitis (group A): Oral: 500 mg
interval <300 msec] or step-down therapy after
initial parenteral treatment for more severe disease twice daily or 1 g once daily for 10 days (AHA
once PR interval <300 msec): Oral: 500 mg 3 times [Gerber 2009]; IDSA [Shulman 2012])
daily for 14 to 21 days (Hu 2018; IDSA [Wormser Extended release: 775 mg once daily for 10 days
2006]); for step-down therapy, some experts prefer Manufacturer’s labeling. Dosing in the prescribing
a total antibiotic duration of 21 to 28 days information may not reflect current clinical practice:
(Hu 2018). Oral: Immediate release: 250 mg every 8 hours
Early disseminated, mild neurologic involvement Urinary tract infection: Note: Not recommended for
(isolated facial nerve palsy [no evidence of menin- empiric therapy given decreased efficacy compared
gitis]) (alternative agent): Oral: 500 mg 3 times to first-line agents and high prevalence of resistance
daily for 14 to 21 days (IDSA [Wormser 2006]). (IDSA/ESCMID [Gupta 2011]).
Late disease, arthritis without neurologic involve- Cystitis due to Enterococcus spp.: Oral: 500 mg
ment: Oral: 500 mg 3 times daily for 28 days (IDSA every 8 hours or 875 mg every 12 hours for 5 days
[Wormser 2006]) (Cole 2015; Hooton 2018a; Murray 2018; Swami-
Otitis media: Limited data: Oral: 500 mg every 8 nathan 2010).
hours or 875 mg every 12 hours (WHO 2001; man- Asymptomatic group B Streptococcus bacteriuria in
ufacturer's labeling). Some experts treat for 5 to 7 pregnancy: Oral: 500 mg every 8 hours or 875 mg
days for mild to moderate infection and 10 days for every 12 hours for 3 to 7 days (Hooton 2018b; IDSA
severe infection (Limb 2019). [Nicolle 2005]). Note: Some experts recommend a
Note: Some experts recommend amoxicillin/clavula- treatment threshold of ≥104 CFU per mL (Puo-
nate over amoxicillin alone because of concern for polo 2018).
decreased penicillin susceptibility in Streptococcus
Renal Impairment: Adult
pneumoniae and other otopathogens (Limb 2019).
Oral:
Periodontitis, generalized aggressive (off-label
use): Oral: 250 to 500 mg every 8 hours in combi- Immediate-release: Note: Avoid immediate-release
nation with metronidazole for 10 to 14 days; used in 875 mg tablet in patients with GFR <30 mL/minute.
addition to periodontal debridement (Rabelo 2015; GFR ≥30 mL/minute: No dosage adjustment nec-
Silva-Senem 2013; Wilder 2018) essary.
Pneumonia, community-acquired (CAP), outpa- GFR 10 to 30 mL/minute: 250 to 500 mg every 12
tient empiric therapy: Oral: 1 g 3 times daily as hours
part of an appropriate combination regimen. Duration GFR <10 mL/minute: 250 to 500 mg every 24 hours
is for a minimum of 5 days and varies based on Hemodialysis: Moderately dialyzable (20% to 50%);
disease severity and response to therapy; patients ~30% removed by 3-hour hemodialysis: 250 to
should be afebrile for ≥48 hours and clinically stable 500 mg every 24 hours; administer after dialysis
before therapy is discontinued (IDSA/ATS [Man- on dialysis days (Aronoff 2007)
dell 2007]) Extended-release:
Prosthetic joint infection (off-label use): Note: For CrCl ≥30 mL/minute: There are no dosage adjust-
chronic antimicrobial suppression of prosthetic joint ments provided in the manufacturer's labeling
infection caused by beta-hemolytic streptococci, (has not been studied).
penicillin-susceptible Enterococcus spp., or Cutibac- CrCl <30 mL/minute: Not recommended
terium spp. (following pathogen-specific IV therapy in Hemodialysis: Not recommended.
patients undergoing 1-stage exchange or debride- Hepatic Impairment: Adult There are no dosage
ment with retention of prosthesis). adjustments provided in the manufacturer's labeling.
Oral: 500 mg 3 times daily (IDSA [Osmon 2013];
Pediatric
Siqueria 2015); duration depends on patient-spe-
cific factors (Berbari 2018). Note: Unless otherwise specified, all pediatric dosing
Rhinosinusitis, acute bacterial: Note: For initial recommendations based on immediate release prod-
therapy of nonsevere infection in patients without uct formulations (oral suspension, chewable tablet,
risk factors for pneumococcal resistance or poor tablet, and capsule).
outcome (eg, age ≥65 years, recent hospitalization General dosing, susceptible infection:
or antibiotic use, immunocompromising condition, Mild to moderate infection:
residence in a region with high rates of resistance) Infants ≤3 months: Oral: 25 to 50 mg/kg/day in
(Patel 2018). divided doses every 8 hours (Red Book [AAP
Oral: 500 mg every 8 hours or 875 mg every 12 2015]). Note: Manufacturer's labeling recom-
hours for 5 to 7 days (AAO-HNS [Rosenfeld mends a maximum daily dose of 30 mg/kg/day
2015]; Garbutt 2012; Lindbaek 1996; Patel 2018). divided into 2 doses per day for this age group.
118
AMOXICILLIN
Infants >3 months, Children, and Adolescents: The Diagnosis and Management of Acute Otitis
AAP recommendations (Red Book [AAP 2015]): Media (AAP [Lieberthal 2013]); however, some
Oral: 25 to 50 mg/kg/day in divided doses experts suggest a maximum daily dose of
every 8 hours; maximum dose: 500 mg/dose 4,000 mg/day for high-dose amoxicillin therapy
Manufacturer's labeling: Oral: 20 to 40 mg/kg/ (Bradley 2015).
day in divided doses every 8 hours (maximum Peritonitis (peritoneal dialysis), prophylaxis for
dose: 500 mg/dose) or 25 to 45 mg/kg/day in patients requiring invasive dental procedures:
divided doses every 12 hours (maximum dose: Infants, Children, and Adolescents: Oral: 50 mg/kg
875 mg/dose) administered 30 to 60 minutes before dental pro-
Severe infection (as step-down therapy): Infants, cedure; maximum dose: 2,000 mg/dose (ISPD
Children, and Adolescents: Oral: 80 to [Warady 2012])
100 mg/kg/day in divided doses every 8 hours; Pneumonia, community-acquired: Infants ≥3
maximum dose: 500 mg/dose for most indications months, Children, and Adolescents (IDSA [Bradley
(Red Book [AAP 2015]) 2011]):
Anthrax: Empiric therapy for presumed bacterial pneumonia:
Cutaneous, without systemic involvement: Infants, Oral: 90 mg/kg/day in divided doses every 12
Children, and Adolescents: Oral: 75 mg/kg/day in hours; maximum daily dose: 4,000 mg/day
3 divided doses. Maximum dose: 1,000 mg/dose. Group A Streptococcus, mild infection or step-down
Duration of therapy: 7 to 10 days for naturally therapy: Oral: 50 to 75 mg/kg/day in divided
acquired infection, up to 60 days for biological doses every 12 hours; maximum daily dose:
weapon-related exposure (AAP [Bradley 2014]). 4,000 mg/day
Inhalational, postexposure prophylaxis: Infants, Haemophilus influenzae, mild infection or step-
Children, and Adolescents: Oral: 75 mg/kg/day down therapy: Oral: 75 to 100 mg/kg/day in div-
in divided doses every 8 hours for 60 days after ided doses every 8 hours; maximum daily dose:
exposure; maximum dose: 1,000 mg/dose (AAP 4,000 mg/day
[Bradley 2014]). Streptococcus pneumonia (penicillin MIC ≤2
Catheter (peritoneal dialysis), exit-site or tunnel mcg/mL); mild infection or step-down therapy:
infection: Infants, Children, and Adolescents: Oral: Oral: 90 mg/kg/day in divided doses every 12
10 to 20 mg/kg once daily; maximum dose: hours or 45 mg/kg/day in divided doses every 8
1,000 mg/dose (ISPD [Warady 2012]) hours; maximum daily dose: 4,000 mg/day
Endocarditis, prophylaxis: Note: AHA guidelines
Pneumococcal infection prophylaxis for ana-
(Baltimore 2015) limit the use of prophylactic anti-
tomic or functional asplenia [eg, sickle cell
biotics to patients at the highest risk for infective
disease (SCD)] (Price 2007; Red Book [AAP
endocarditis (IE) or adverse outcomes (eg, pros-
2015]):
thetic heart valves, patients with previous IE, unre-
Before 2 months of age (or as soon as SCD is
paired cyanotic congenital heart disease, repaired
diagnosed or asplenia occurs) through 5 years of
congenital heart disease with prosthetic material or
age: Oral: 20 mg/kg/day in divided doses every 12
device during first 6 months after procedure,
hours; maximum dose: 250 mg/dose
repaired congenital heart disease with residual
Children ≥6 years and Adolescents: Oral: 250 mg
defects at the site or adjacent to site of prosthetic
patch or device, heart transplant recipients with every 12 hours; Note: The decision to discontinue
cardiac valvulopathy): penicillin prophylaxis after 5 years of age in chil-
Dental or oral procedures or respiratory tract pro- dren who have not experienced invasive pneumo-
cedures (eg, tonsillectomy, adenoidectomy): coccal infection and have received recommended
Infants, Children, and Adolescents: Oral: pneumococcal immunizations is patient and clini-
50 mg/kg 30 to 60 minutes before procedure; cian dependent.
maximum dose: 2,000 mg/dose (AHA [Wil- Rhinosinusitis, acute bacterial; uncomplicated:
son 2007]) Note: AAP guidelines recommend amoxicillin as
H. pylori eradication: Children and Adolescents: first-line empiric therapy for pediatric patients 1 to
Oral: 50 mg/kg/day in 2 divided doses for 10 to 14 18 years with uncomplicated cases and where
days. Note: Duration dependent on regimen used; resistance is not suspected; however, the IDSA
maximum daily dose: 2,000 mg/day. Administer in guidelines consider amoxicillin/clavulanate as the
combination with a proton pump inhibitor or bismuth preferred therapy (IDSA [Chow 2012]; AAP [Wald
subsalicylate and at least one other antibiotic (clar- 2013]):
ithromycin and/or metronidazole) (NASPGHAN/ Low dose: Children ≥2 years and Adolescents:
ESPGHAN [Koletzko 2011]). Oral: 45 mg/kg/day in divided doses every 12
Lyme disease: Infants, Children, and Adolescents: hours; Note: Only use for uncomplicated, mild to
Oral: 50 mg/kg/day in divided doses every 8 hours; moderate infections in children who do not attend
maximum dose: 500 mg/dose (Halperin 2007; daycare and who have not received antibiotics
IDSA [Wormser 2006]) within the last month (AAP [Wald 2013]).
Otitis media, acute (AOM): Infants ≥2 months and High dose (use reserved for select patients; see
Children: Oral: 80 to 90 mg/kg/day in divided doses Note): Children ≥2 years and Adolescents: Oral:
every 12 hours; variable duration of therapy, if <2 80 to 90 mg/kg/day in divided doses every 12
years of age or severe symptoms (any age): 10-day hours; maximum dose: 2,000 mg/dose; Note:
course; if 2 to 5 years of age with mild to moderate Should only use for mild to moderate infections
symptoms: 7-day course; ≥6 years of age with mild in children who do not attend daycare and who
to moderate symptoms: 5- to 7-day course; some have not received antibiotics within the last month
experts recommend initiating with 90 mg/kg/day and live in communities with a high prevalence of
(AAP [Lieberthal 2013]; Red Book [AAP 2015]); a nonsusceptible S. pneumoniae resistance (AAP
maximum dose is not provided in the Guidelines for [Wald 2013]).
119
AMOXICILLIN
Tonsillopharyngitis; Group A streptococcal Contraindications

infection, treatment and primary prevention of Serious hypersensitivity to amoxicillin (eg, anaphylaxis,
rheumatic fever: Stevens-Johnson syndrome) or to other beta-lactams,
Immediate release (oral suspension, chewable tab- or any component of the formulation
lets, tablets, capsules): Children and Adolescents Canadian labeling: Additional contraindications (not in
3 to 18 years: Oral: 50 mg/kg once daily or US labeling): Infectious mononucleosis (suspected or
25 mg/kg twice daily for 10 days; maximum daily confirmed)
dose: 1,000 mg/day (AHA [Gerber 2009]; IDSA Warnings/Precautions In patients with renal impair-
[Shulman 2012]) ment, doses and/or frequency of administration should
Extended release tablets: Children ≥12 years and be modified in response to the degree of renal impair-
Adolescents: Oral: 775 mg once daily for 10 days; ment; dosage adjustment recommended in patients
Note: Patient must be able to swallow tablet with GFR <30 mL/minute. Avoid extended release
whole. 775 mg tablet and immediate release 875 mg tablet in
UTI, prophylaxis (hydronephrosis, vesicoureteral patients with GFR <30 mL/minute or patients requiring
reflux): Infants ≤2 months: Oral: 10 to 15 mg/kg hemodialysis. A high percentage of patients with infec-
once daily; some suggest administration in the tious mononucleosis develop an erythematous rash
evening (drug resides in bladder longer); Note: during amoxicillin therapy; avoid use in these patients.
Due to resistance, amoxicillin should not be used Serious and occasionally severe or fatal hypersensitiv-
for prophylaxis after 2 months of age (Belarmino ity (anaphylactic) reactions have been reported in
2006; Greenbaum 2006; Mattoo 2007). patients on penicillin therapy, including amoxicillin,
Renal Impairment: Pediatric especially with a history of beta-lactam hypersensitivity
There are no dosage adjustments provided in the (including severe reactions with cephalosporins) and/or
manufacturer's labeling; however, the following a history of sensitivity to multiple allergens. Prolonged
guidelines have been used by some clinicians use may result in fungal or bacterial superinfection,
(Aronoff 2007): Oral: including C. difficile-associated diarrhea (CDAD) and
Immediate release: Infants, Children, and Adoles- pseudomembranous colitis; CDAD has been observed
cents: >2 months postantibiotic treatment. Potentially signifi-
Mild to moderate infection: Dosing based on 25 to
cant interactions may exist, requiring dose or frequency
50 mg/kg/day divided every 8 hours:
adjustment, additional monitoring, and/or selection of
GFR >30 mL/minute/1.73 m2: No adjustment
alternative therapy.
required
GFR 10 to 29 mL/minute/1.73 m2: 8 to 20 mg/kg/ Chewable tablets may contain phenylalanine; see man-
dose every 12 hours ufacturer's labeling.
GFR <10 mL/minute/1.73 m2: 8 to 20 mg/kg/
Benzyl alcohol and derivatives: Some dosage forms
dose every 24 hours
may contain sodium benzoate/benzoic acid; benzoic
Hemodialysis: Moderately dialyzable (20% to
acid (benzoate) is a metabolite of benzyl alcohol; large
50%); ~30% removed by 3-hour hemodialysis:
8 to 20 mg/kg/dose every 24 hours; give after amounts of benzyl alcohol (≥99 mg/kg/day) have been
dialysis associated with a potentially fatal toxicity ("gasping
Peritoneal dialysis: 8 to 20 mg/kg/dose every 24 syndrome") in neonates; the "gasping syndrome" con-
hours sists of metabolic acidosis, respiratory distress, gasping
Severe infection (high dose): Dosing based on 80 respirations, CNS dysfunction (including convulsions,
to 90 mg/kg/day divided every 12 hours: intracranial hemorrhage), hypotension, and cardiovas-
GFR >30 mL/minute/1.73 m2: No adjustment cular collapse (AAP ["Inactive" 1997]; CDC 1982); some
required data suggests that benzoate displaces bilirubin from
GFR 10 to 29 mL/minute/1.73 m2: 20 mg/kg/ protein binding sites (Ahlfors 2001); avoid or use dos-
dose every 12 hours; do not use the 875 mg age forms containing benzyl alcohol derivative with
tablet caution in neonates. See manufacturer's labeling.
GFR <10 mL/minute/1.73 m2: 20 mg/kg/dose Warnings: Additional Pediatric Considerations
every 24 hours; do not use the 875 mg tablet Epstein-Barr virus infection (infectious mononucleosis),
Hemodialysis: Moderately dialyzable (20% to acute lymphocytic leukemia, or cytomegalovirus infec-
50%); ~30% removed by 3-hour hemodialysis: tion increases risk for amoxicillin-induced maculopapu-
20 mg/kg/dose every 24 hours; give after lar rash. Appearance of a rash should be carefully
dialysis evaluated to differentiate a nonallergic amoxicillin rash
Peritoneal dialysis: 20 mg/kg/dose every 24 from a hypersensitivity reaction. Amoxicillin rash occurs
hours in 5% to 10% of children receiving amoxicillin and is a
Extended release: Children ≥12 years and Adoles- generalized dull, red, maculopapular rash, generally
cents: CrCl <30 mL/minute: Not recommended appearing 3 to 14 days after the start of therapy. It
Hepatic Impairment: Pediatric There are no dos- normally begins on the trunk and spreads over most
age adjustments provided in the manufacturer's label- of the body. It may be most intense at pressure areas,
ing. elbows, and knees. A high percentage (43% to 100%)
Mechanism of Action Inhibits bacterial cell wall syn- of patients with infectious mononucleosis have devel-
thesis by binding to one or more of the penicillin-binding oped rash during therapy; amoxicillin-class antibiotics
proteins (PBPs) which in turn inhibits the final trans- are not recommended in these patients.
peptidation step of peptidoglycan synthesis in bacterial Drug Interactions
cell walls, thus inhibiting cell wall biosynthesis. Bacteria Metabolism/Transport Effects None known.
eventually lyse due to ongoing activity of cell wall Avoid Concomitant Use
autolytic enzymes (autolysins and murein hydrolases) Avoid concomitant use of Amoxicillin with any of the
while cell wall assembly is arrested. following: BCG (Intravesical); Cholera Vaccine
120
AMOXICILLIN AND CLAVULANATE
Increased Effect/Toxicity with breastfeeding when used in usual recommended

Amoxicillin may increase the levels/effects of: Metho- doses (WHO 2002). Amoxicillin has been recom-
trexate; Vitamin K Antagonists mended to treat mastitis in breastfeeding women
when penicillin susceptibility is documented (WHO
The levels/effects of Amoxicillin may be increased by:
Acemetacin; Allopurinol; Probenecid 2000) and also for the management of Bacillus anthra-
Decreased Effect cis (Meaney-Delman 2014).
Amoxicillin may decrease the levels/effects of: BCG Dosage Forms: US
(Intravesical); BCG Vaccine (Immunization); Cholera Capsule, Oral:
Vaccine; Lactobacillus and Estriol; Mycophenolate; Generic: 250 mg, 500 mg
Sodium Picosulfate; Typhoid Vaccine Suspension Reconstituted, Oral:
Generic: 125 mg/5 mL (80 mL, 100 mL, 150 mL);
The levels/effects of Amoxicillin may be decreased by: 200 mg/5 mL (50 mL, 75 mL, 100 mL); 250 mg/5
Tetracyclines
mL (80 mL, 100 mL, 150 mL); 400 mg/5 mL (50 mL,
Dietary Considerations Some products may contain
75 mL, 100 mL)
phenylalanine.
Pharmacodynamics/Kinetics Tablet, Oral:
Half-life Elimination Adults: Immediate-release: 61.3 Generic: 500 mg, 875 mg
minutes; Extended-release: 90 minutes Tablet Chewable, Oral:
Time to Peak Capsule; oral suspension: 1 to 2 hours; Generic: 125 mg, 250 mg
Chewable tablet: 1 hour; Extended-release tablet: 3.1
hours Amoxicillin and Clavulanate
Pregnancy Risk Factor B (a moks i SIL in & klav yoo LAN ate)
Pregnancy Considerations Adverse events have not
been observed in animal reproduction studies. Amox- Related Information
icillin crosses the placenta (Muller 2009). Maternal use Amoxicillin on page 116
of amoxicillin has generally not resulted in an increased Bacterial Infections on page 1525
risk of adverse fetal effects; however, a possible asso- Related Sample Prescriptions
ciation with cleft lip with cleft palate has been observed Bacterial Infections and Periodontal Diseases - Sample
in some studies (more data is needed) (Lin 2012; Puhó Prescriptions on page 36
2007). Amoxicillin may be used for the management of Sinus Infection Treatment - Sample Prescriptions on
Bacillus anthracis in pregnant women when penicillin page 42
susceptibility is documented (Meaney-Delman 2014). Brand Names: US Augmentin; Augmentin ES-600;
Amoxicillin is an alternative antibiotic for the treatment
Augmentin XR [DSC]
of chlamydial infections in pregnancy (CDC [Workowski
2015]). Amoxicillin can also be used in the management Brand Names: Canada Amoxi-Clav; Clavulin
of preterm premature rupture of membranes and in Generic Availability (US) Yes
certain situations prior to vaginal delivery in women at Pharmacologic Category Antibiotic, Penicillin
high risk for endocarditis (ACOG 120 2011; ACOG Dental Use Treatment of orofacial infections when beta-
139 2013). lactamase-producing staphylococci and beta-lacta-
mase-producing Bacteroides are present
pharmacokinetic parameters of amoxicillin may be Use
altered (Andrew 2007). Oral ampicillin-class antibiotics Otitis media, acute:
are poorly absorbed during labor. Immediate-release tablets, chewable tablets, oral sus-
Breastfeeding Considerations pension (400/57 mg per 5 mL, 250/62.5 mg per 5
Amoxicillin is excreted in breast milk (Kafetzis 1981). mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5
The relative infant dose (RID) of amoxicillin is 0.15% to mL only): Treatment of otitis media caused by beta-
0.54% when calculated using the highest average lactamase-producing strains of H. influenzae and M.
breast milk concentration located and compared to catarrhalis.
an infant therapeutic dose of 25 to 90 mg/kg/day. In Oral suspension (600/42.9 mg per 5 mL concentra-
general, breastfeeding is considered acceptable when tion): Treatment of acute otitis media, recurrent or
the RID is <10%; when an RID is >25% breastfeeding persistent, caused by S. pneumoniae (penicillin MIC
should generally be avoided (Anderson 2016; Ito = 2 mcg/mL or less), H. influenzae (including beta-
2000). Using the highest average milk concentration lactamase-producing strains), and M. catarrhalis
(0.9 mcg/mL), the estimated daily infant dose via (including beta-lactamase-producing strains) in
breast milk is 0.135 mg/kg/day. This milk concentra- pediatric patients with a history of antibiotic exposure
tion was obtained following maternal administration of for acute otitis media in the preceding 3 months and
a single oral dose of amoxicillin 1,000 mg (Kafet- who are either 2 years or younger or attend day care.
zis 1981).
Pneumonia:
Self-limiting diarrhea, rash, and somnolence have been
Extended-release tablets only: Treatment of patients
reported in nursing infants exposed to amoxicillin
(Benyamini 2005; Goldstein 2009; Ito 1993); the man- with community-acquired pneumonia (CAP) caused
ufacturer warns of the potential for allergic sensitiza- by confirmed or suspected beta-lactamase-produc-
tion in the infant. In general, antibiotics that are ing pathogens (ie, Haemophilus influenzae, Morax-
present in breast milk may cause non-dose-related ella catarrhalis, Haemophilus parainfluenzae,
modification of bowel flora. Monitor infants for GI Klebsiella pneumoniae, methicillin-susceptible
disturbances, such as thrush or diarrhea (WHO 2002). Staphylococcus aureus) and Streptococcus pneu-
Although the manufacturer recommends that caution be moniae with reduced susceptibility to penicillin (pen-
exercised when administering amoxicillin to breast- icillin minimum inhibitory concentration [MIC] = 2
feeding women, amoxicillin is considered compatible mcg/mL).
121
Limitations of use: Augmentin XR is not indicated for erythema multiforme, exfoliative dermatitis, gastritis,
the treatment of infections caused by S. pneumo- glossitis, hematuria, hemolytic anemia, hemorrhagic
niae with penicillin MIC of 4 mcg/mL or greater colitis, hyperactivity, immune thrombocytopenia,
(limited data). increased serum bilirubin, increased serum transami-
Immediate-release tablets, chewable tablets, oral sus- nases, insomnia, interstitial nephritis, leukopenia, mel-
pension (400/57 mg per 5 mL, 250/62.5 mg per 5 anoglossia, mucocutaneous candidiasis, pruritus,
mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5 pseudomembranous colitis, serum sickness-like reac-
mL only): Treatment of lower respiratory tract infection, Stevens-Johnson syndrome, stomatitis, thrombo-
tion caused by beta-lactamase-producing strains of cytopenia, toxic epidermal necrolysis
H. influenzae and M. catarrhalis. Dental Usual Dosage Orofacial infections: Children
Rhinosinusitis, acute bacterial: >40 kg and Adults: Oral: 250-500 mg every 8 hours or
Extended-release tablets: Treatment of patients with 875 mg every 12 hours
acute bacterial sinusitis caused by confirmed or Dosing
suspected beta-lactamase-producing pathogens (ie, Adult & Geriatric Note: Dose is based on the amox-
H. influenzae, M. catarrhalis, H. parainfluenzae, K. icillin component. Dose and frequency are product
pneumoniae, methicillin-susceptible S. aureus) and specific; not all products are interchangeable. For
S. pneumoniae with reduced susceptibility to pen- adults who have difficulty swallowing the tablets, the
icillin (penicillin MIC = 2 mcg/mL). 125 mg/5 mL or 250 mg/5 mL suspension (in appro-
Limitations of use: Augmentin XR is not indicated for priate amounts) may be given in place of the 500 mg
the treatment of infections caused by S. pneumo- tablet; the 200 mg/5 mL or 400 mg/5 mL suspension
niae with penicillin MIC of 4 mcg/mL or greater (in appropriate amounts) may be given in place of the
(limited data). 875 mg tablet.
Immediate-release tablets, chewable tablets, oral sus- Usual dosing range: Oral: Immediate release:
pension (400/57 mg per 5 mL, 250/62.5 mg per 5
500 mg every 8 to 12 hours or 875 mg every 12
mL, 200/28.5 mg per 5 mL, and 125/31.25 mg per 5
hours; Extended release: 2 g every 12 hours
mL only): Treatment of sinusitis caused by beta-
Bite wound, prophylaxis or treatment (animal or
lactamase-producing strains of H. influenzae and
human bite) (off-label use): Oral: Immediate
M. catarrhalis.
release: 875 mg every 12 hours (IDSA [Stevens
Skin and skin structure infections: Immediate-
2014]). Note: For prophylaxis, duration is 3 to 5 days
release tablets, chewable tablets, oral suspension
(IDSA [Stevens 2014]); for treatment of established
(400/57 mg per 5 mL, 250/62.5 mg per 5 mL,
200/28.5 mg per 5 mL, and 125/31.25 mg per 5 mL infection, duration is typically 5 to 14 days and varies
only): Treatment of skin and skin structure infections based on clinical response and patient-specific fac-
caused by beta-lactamase-producing strains of S. tors (Baddour 2019a; Baddour 2019b).
aureus, Escherichia coli, and Klebsiella spp. Chronic obstructive pulmonary disease (COPD),
Urinary tract infections: Immediate-release tablets, exacerbation (off-label use): Oral: Immediate
chewable tablets, oral suspension (400/57 mg per 5 release: 500 mg every 8 hours or 875 mg every 12
mL, 250/62.5 mg per 5 mL, 200/28.5 mg per 5 mL, hours for 5 to 7 days (GOLD 2018; Llor 2012; Wilson
and 125/31.25 mg per 5 mL only): Treatment of uri- 2012). Note: Some experts reserve for use in
nary tract infections caused by beta-lactamase-pro- patients with complicated COPD (eg, age ≥65 years,
ducing strains of E. coli, Klebsiella spp, and FEV1 <50% predicted, frequent exacerbations, major
Enterobacter spp. comorbidities) (Anzueto 2007; Sethi 2008).
Local Anesthetic/Vasoconstrictor Precautions Diabetic foot infection (off-label use): Note: May be
No information available to require special precautions used alone for mild infections or after clinical
Effects on Dental Treatment Prolonged use of pen- response to parenteral therapy in patients without
icillins may lead to development of oral candidiasis (see risk factors or concern for infection caused by Pseu-
Dental Health Professional Considerations) domonas aeruginosa (IDSA [Lipsky 2012]; Wein-
Effects on Bleeding No information available to trob 2018).
require special precautions Oral: Immediate release: 875 mg every 12 hours
Adverse Reactions (IDSA [Lipsky 2012]; Lipsky 2004; Weintrob
>10%: Gastrointestinal: Diarrhea (3% to 34%; incidence 2018). Duration of therapy should be tailored to
varies upon dose and regimen used) individual clinical circumstances; most patients with
1% to 10%: infection limited to skin and soft tissue respond to 1
Dermatologic: Diaper rash, skin rash, urticaria to 2 weeks of therapy (IDSA [Lipsky 2012]; Wein-
Gastrointestinal: Abdominal distress, loose stools, trob 2018).
nausea, vomiting Intraabdominal infection (off-label use):
Genitourinary: Vaginitis Diverticulitis, acute (for uncomplicated infection
Infection: Candidiasis, vaginal mycosis that meets criteria for outpatient therapy or as
<1%, postmarketing, and/or case reports: Cholestatic step-down therapy after clinical improvement
jaundice, flatulence, headache, hepatic insufficiency, on initial parenteral therapy): Oral:
hepatitis, hepatotoxicity (idiosyncratic) (Chalasani Immediate release: 875 mg every 8 hours (Biondo
2014), increased liver enzymes, increased serum 2014; Mora Lopez 2013)
alkaline phosphatase, prolonged prothrombin time, Extended release: 2 g every 12 hours (Pember-
thrombocythemia, vasculitis (hypersensitivity) ton 2018)
Additional adverse reactions seen with ampicillin- Other intraabdominal infection, step-down ther-
class antibiotics: Acute generalized exanthematous apy (when clinically improved and able to toler-
pustulosis, agitation, agranulocytosis, anaphylaxis, ate oral therapy) : Oral: Immediate release:
anemia, angioedema, anxiety, behavioral changes, 875 mg 2 to 3 times daily (Barshak 2018; Lucasti
confusion, convulsions, crystalluria, dental discolora- 2008; SIS [Mazuski 2017]; SIS/IDSA [Solo-
tion, dizziness, dyspepsia, enterocolitis, eosinophilia, mkin 2010])
122
Duration of therapy is for 4 to 7 days following recent hospitalization, antibiotic use within the past
adequate source control (SIS/IDSA [Solomkin month, immunocompromise, residence in a region
2010]); for uncomplicated appendicitis and divertic- with high rates of penicillin-resistant S. pneumo-
ulitis managed nonoperatively, a longer duration is niae, or failure to respond to initial treatment
necessary (Barshak 2018; Pemberton 2018). (AAO-HNS [Rosenfeld 2015]; IDSA [Chow 2012]).
Neutropenic fever, low-risk cancer patients For initial therapy, the duration is 5 to 7 days; for
(empiric therapy) (off-label use): Oral: Immediate patients who have failed initial therapy and require
release: 500 mg every 8 hours (Freifeld 1999; Kern re-treatment, the duration is 7 to 10 days
1999) or 1 g every 12 hours (Kern 2013). Combine (Patel 2018).
either dosing regimen with oral ciprofloxacin; con- Streptococcus (group A), chronic carriage (off-
tinue until resolution of fever and neutropenia. Note: label use): Oral: Immediate release: 40 mg/kg/day
Avoid in patients who have received fluoroquinolone in divided doses (eg, 875 mg every 12 hours) (max-
prophylaxis. Administer first dose in the health care imum: 2 g/day) for 10 days (IDSA [Shulman 2012];
setting (after blood cultures are drawn); observe Mahakit 2006). Note: Most individuals with chronic
patient for ≥4 hours before discharge (ASCO/IDSA carriage do not require antibiotics (IDSA [Shul-
[Taplitz 2018]; IDSA [Freifeld 2011]). man 2012]).
Odontogenic infection (initial therapy for mild Urinary tract infection (UTI) (alternative agent):
infection or step-down therapy after parenteral Note: Although evidence is limited, some experts
treatment) (off-label use): Oral: Immediate release: recommend the use of amoxicillin/clavulanate in this
875 mg twice daily (Tancawan 2015); continue to setting. Use with caution and only when first-line
complete a total of 7 to 14 days of therapy agents cannot be used (due to decreased efficacy
(Chow 2018) of oral beta-lactams compared to other agents)
Otitis media, acute: Oral: (ESCMID/IDSA [Gupta 2011]; Hooton 2018a).
Immediate release: 875 mg twice daily (Mira 2001) Closely monitor patient.
or 500 mg every 8 hours (WHO 2001) Acute uncomplicated cystitis or acute simple
Extended release: 1 or 2 g twice daily, based on cystitis (infection limited to bladder and no
weight and severity of infection; some experts pre- signs/symptoms of upper tract or systemic
fer the extended release formulation for patients at infection) : Oral: Immediate release: 500 mg twice
high risk of severe infection or resistant S. pneumo- daily (Hooton 2005) for 5 to 7 days (ESCMID/IDSA
niae (Limb 2019). [Gupta 2011]; Hooton 2018a).
Duration: 5 to 7 days for mild to moderate infection Complicated UTI (including pyelonephritis): Oral:
and 10 days for severe infection (Limb 2019). Immediate release: 875 mg twice daily for 10 to 14
Peritonsillar cellulitis or abscess (off-label-use): days (ESCMID/IDSA [Gupta 2011]; Johnson 2018).
Note: For step-down therapy after parenteral treat- Note: Oral therapy should follow appropriate paren-
ment. Limited data available; dosing based on expert teral therapy. For outpatient treatment of mild infec-
opinion. Reserve for use in regions where Staph- tion, a single dose of a long-acting parenteral agent
ylococcus aureus remains susceptible to methicillin is acceptable; for outpatients who are more ill or are
or based upon susceptibility results of isolated patho-
at risk for more severe illness, consider continuing
gens, if available. Oral: Immediate release: 875 mg
parenteral therapy until culture and susceptibility
every 12 hours to complete a total of 14 days of
results are available (ESCMID/IDSA [Gupta 2011];
therapy (Wald 2018).
Hooton 2018b).
Pneumonia:
Aspiration pneumonia (community-acquired
[mild]): Oral: Note: Renally adjusted dose recommendations are
Immediate release: 875 mg twice daily (Bar- based on the amoxicillin 250 mg/clavulanate
tlett 2018) 125 mg and amoxicillin 500 mg/clavulanate 125 mg
Extended release: 2 g twice daily (Bartlett 2018; tablets.
IDSA [Mandell 2007]) CrCl ≥30 mL/minute: No dosage adjustment nec-
Duration of therapy: 5 to 7 days (Bartlett 2018; essary.
IDSA [Mandell 2007]) CrCl 10 to 30 mL/minute: 250 to 500 mg every 12
Community-acquired (CAP), outpatient empiric hours; do not use 875 mg tablet or extended-
therapy: Oral: Extended release: 2 g every 12 release tablets
hours as part of an appropriate combination regi- CrCl <10 mL/minute: 250 to 500 mg every 24 hours;
men. Duration is for a minimum of 5 days and do not use 875 mg tablet or extended-release
varies based on disease severity and response to tablets
therapy; patients should be afebrile for ≥48 hours End-stage renal disease (ESRD) on hemodialysis:
and clinically stable before therapy is discontinued 250 to 500 mg every 24 hours; administer dose
(IDSA [Mandell 2007]) both during and after dialysis. Do not use 875 mg
Rhinosinusitis, acute bacterial: Note: In uncompli- tablet or extended-release tablets.
cated acute bacterial rhinosinusitis, initial observa- Hepatic Impairment: Adult There are no dosage
tion and symptom management without antibiotic adjustments provided in the manufacturer's labeling;
therapy is appropriate in most patients (AAO-HNS use with caution. Use contraindicated in patients with
[Rosenfeld 2015]; Harris 2016). a history of amoxicillin and clavulanate-associated
Standard dose: Oral: Immediate release: 500 mg hepatic dysfunction.
every 8 hours or 875 mg every 12 hours for 5 to Pediatric Note: Dosing based on amoxicillin compo-
7 days (IDSA [Chow 2012]) nent; dose and frequency are product specific; not all
High dose: Oral: Extended release: 2 g every 12 products are interchangeable; using a product with the
hours. Note: Recommended for patients at risk incorrect amoxicillin:clavulanate ratio could result in
for poor outcome or pneumococcal resistance subtherapeutic clavulanic acid concentrations or
based on the following features: age ≥65 years, severe diarrhea.
123
Frequency of dosing generally based on ratio of Rhinosinusitis, acute bacterial:

amoxicillin to clavulanate: Infants ≥3 months: Oral: 45 mg amoxicillin/kg/day
• 2:1 formulations are dosed 3 times daily (amoxicillin divided every 12 hours or 40 mg/kg/day divided
250 mg/clavulanate 125 mg) every 8 hours
• 4:1 formulations are dosed 3 times daily (amoxicillin Children and Adolescents: Oral:
125 mg/clavulanate 31.25 mg; amoxicillin 250 mg/ Standard dose: 45 mg amoxicillin/kg/day divided
clavulanate 62.5 mg; amoxicillin 500 mg/clavula- every 12 hours for 10 to 14 days; usual adult
nate 125 mg) dose: 875 mg amoxicillin/dose (IDSA
• 7:1 formulations are dosed 2 times daily (amoxicillin [Chow 2012])
200 mg/clavulanate 28.5 mg; amoxicillin 400 mg/ High dose: 80 to 90 mg amoxicillin/kg/day divided
clavulanate 57 mg; amoxicillin 875 mg/clavulanate every 12 hours; maximum dose: 2,000 mg/dose
125 mg) Note: Per the manufacturer, amoxicillin (AAP [Wald 2013]; IDSA [Chow 2012]); treatment
875 mg/clavulanate 125 mg should only be used duration variable: 10 to 28 days, some have
in patients ≥40 kg suggested discontinuation of therapy 7 days after
• 14:1 formulations are dosed 2 times daily (amox- resolution of signs and symptoms of infection
icillin 600 mg/clavulanate 42.9 mg) Note: Per the (AAP [Wald 2013]); some experts recommend a
manufacturer, this formulation should only be used duration of 10 to 14 days (IDSA [Chow 2012]).
in patients <40 kg Note: Recommended for patients who live in
• 16:1 formulations (extended release) are dosed 2 areas with high endemic rates of penicillin-non-
times daily (amoxicillin 1,000 mg/clavulanate susceptible S. pneumonia, patients with moderate
62.5 mg) to severe infections, daycare attendance, age <2
General dosing, susceptible infection: Note: Dos- years, recent hospitalization, antibiotic use within
ing determined by formulations amoxicillin:clavula- the past month, patients who are immunocompro-
nate ratio: mised or if initial therapy fails (second-line ther-
Immediate-release formulations (Red Book [AAP apy) (AAP [Wald 2013]; IDSA [Chow 2012]).
2018]): Infants, Children, and Adolescents: Oral: Streptococci, group A; chronic carrier treatment:
4:1 formulation: 20 to 40 mg amoxicillin/kg/day in Children and Adolescents: Oral: 40 mg amoxicillin/
divided doses 3 times daily: maximum daily dose: kg/day in divided doses every 8 hours for 10 days;
1,500 mg/day maximum daily dose: 2,000 mg amoxicillin/day
7:1 formulation: 25 to 45 mg amoxicillin/kg/day in (IDSA [Shulman 2012])
divided doses twice daily: maximum daily dose: Urinary tract infections: Infants ≥2 months and Chil-
1,750 mg/day dren ≤2 years: Oral: 20 to 40 mg amoxicillin/kg/day
14:1 formulation: 90 mg amoxicillin/kg/day in div- in divided doses 3 times daily (AAP 2011)
ided doses twice daily; maximum daily dose: Renal Impairment: Pediatric
4,000 mg/day Infants, Children, and Adolescents: There are no
Extended-release formulation (16:1): Children and dosage adjustments provided in the manufacturer's
Adolescents >40 kg: Oral: 2,000 mg amoxicillin labeling; however, the following guidelines have
every 12 hours been used by some clinicians (Aronoff 2007): Oral:
Impetigo: Infants, Children, and Adolescents: Oral: Mild to moderate infection: Dosing based on 20 to
25 mg amoxicillin/kg/day in divided doses twice 40 mg amoxicillin/kg/day divided every 8 hours or
daily; maximum dose: 875 mg amoxicillin/dose 25 to 45 mg amoxicillin/kg/day divided every 12
(IDSA [Stevens 2014]) hours:
Otitis media, acute: Infants ≥3 months and Children: GFR >30 mL/minute/1.73 m 2 : No adjustment
Oral suspension (600 mg/5 mL): Oral: 90 mg amox- required
icillin/kg/day divided every 12 hours for up to 10 GFR 10 to 29 mL/minute/1.73 m2: 8 to 20 mg
days; recommended for use in children with severe amoxicillin/kg/dose every 12 hours
illness, who have received amoxicillin in the past 30 GFR <10 mL/minute/1.73 m2: 8 to 20 mg amox-
days, who have treatment failure at 48 to 72 hours on icillin/kg/dose every 24 hours
first-line therapy, and when coverage for beta-lacta- Hemodialysis: 8 to 20 mg amoxicillin/kg/dose
mase positive H. influenzae and M. catarrhalis is every 24 hours; give after dialysis
needed. Variable duration of therapy; the manufac- Peritoneal dialysis: 8 to 20 mg amoxicillin/kg/dose
turer suggests 10-day course in all patients; how- every 24 hours
ever, new data suggests a shorter course in some Severe infection (high dose): Dosing based on 80
cases: If <2 years of age or severe symptoms (any to 90 mg amoxicillin/kg/day divided every 12
age): 10-day course; if 2 to 5 years of age with mild hours:
to moderate symptoms: 7-day course; if ≥6 years of CrCl >30 mL/minute/1.73 m2 : No adjustment
age with mild to moderate symptoms: 5- to 7-day required
course (AAP [Lieberthal 2013]). CrCl 10 to 29 mL/minute/1.73 m2: 20 mg amox-
Pneumonia, community-acquired (IDSA/PIDS icillin/kg/dose every 12 hours; do not use the
[Bradley 2011]): Infants ≥3 months, Children, and 875 mg tablet
Adolescents: CrCl <10 mL/minute/1.73 m2: 20 mg amoxicillin/
Empiric therapy: Oral: 90 mg amoxicillin/kg/day in kg/dose every 24 hours; do not use the 875 mg
divided doses twice daily; maximum daily dose: tablet
4,000 mg/day Hemodialysis: 20 mg amoxicillin/kg/dose every 24
H. influenzae, beta-lactamase positive strains, mild hours; give after dialysis; do not use the 875 mg
infection, or step-down therapy: Oral: tablet
Standard dose: 45 mg amoxicillin/kg/day in divided Peritoneal dialysis: 20 mg amoxicillin/kg/dose
doses 3 times daily every 24 hours; do not use the 875 mg tablet
High dose: 90 mg amoxicillin/kg/day in divided Hepatic Impairment: Pediatric There are no dos-
doses twice daily age adjustments provided in the manufacturer's
124
labeling; use with caution. Use contraindicated in Drug Interactions

patients with a history of amoxicillin and clavulanate- Metabolism/Transport Effects None known.
associated hepatic dysfunction. Avoid Concomitant Use
Mechanism of Action Clavulanic acid binds and inhib- Avoid concomitant use of Amoxicillin and Clavulanate
its beta-lactamases that inactivate amoxicillin resulting with any of the following: BCG (Intravesical); Cholera
in amoxicillin having an expanded spectrum of activity. Vaccine
Amoxicillin inhibits bacterial cell wall synthesis by bind- Increased Effect/Toxicity
ing to one or more of the penicillin-binding proteins Amoxicillin and Clavulanate may increase the levels/
(PBPs) which in turn inhibits the final transpeptidation effects of: Methotrexate; Vitamin K Antagonists
step of peptidoglycan synthesis in bacterial cell walls,
The levels/effects of Amoxicillin and Clavulanate may
thus inhibiting cell wall biosynthesis. Bacteria eventually
be increased by: Acemetacin; Allopurinol; Probenecid
lyse due to ongoing activity of cell wall autolytic
Decreased Effect
enzymes (autolysins and murein hydrolases) while cell
Amoxicillin and Clavulanate may decrease the levels/
wall assembly is arrested.
effects of: BCG (Intravesical); BCG Vaccine (Immuni-
Contraindications zation); Cholera Vaccine; Lactobacillus and Estriol;
Hypersensitivity to amoxicillin, clavulanic acid, other Mycophenolate; Sodium Picosulfate; Typhoid Vaccine
beta-lactam antibacterial drugs (eg, penicillins, ceph-
alosporins), or any component of the formulation; The levels/effects of Amoxicillin and Clavulanate may
history of cholestatic jaundice or hepatic dysfunction be decreased by: Tetracyclines
with amoxicillin/clavulanate potassium therapy Dietary Considerations May be taken with meals or
Augmentin XR: Additional contraindications: Severe on an empty stomach; take with meals to increase
renal impairment (creatinine clearance <30 mL/ absorption and decrease GI upset; may mix with milk,
minute) and hemodialysis patients formula, or juice. Extended release tablets should be
taken with food. Some products may contain sodium.
Canadian labeling: Additional contraindications (not in Some products contain phenylalanine. All dosage forms
US labeling): Suspected or confirmed mononucleosis contain potassium.
Warnings/Precautions Hypersensitivity reactions, Pharmacodynamics/Kinetics
including anaphylaxis (some fatal), have been reported. Half-life Elimination Clavulanic acid: 1 hour
Prolonged use may result in fungal or bacterial super- Time to Peak Clavulanic acid: Serum: 1.5 hours
infection, including C. difficile-associated diarrhea Pregnancy Risk Factor B
(CDAD) and pseudomembranous colitis; CDAD has
Pregnancy Considerations Both amoxicillin and
been observed >2 months postantibiotic treatment. clavulanic acid cross the placenta (Weber 1984). Oral
Although rarely fatal, hepatic dysfunction (eg, choles- ampicillin-class antibiotics are poorly absorbed during
tatic jaundice, hepatitis) has been reported. Patients at labor.
highest risk include those with serious underlying dis-
Breastfeeding Considerations
ease or concomitant medications. Hepatic toxicity is
Amoxicillin is present in breast milk following adminis-
usually reversible. Monitor liver function tests at regular tration amoxicillin/clavulanate (Weber 1984).
intervals in patients with hepatic impairment. High per- The relative infant dose (RID) of amoxicillin following
centage of patients with infectious mononucleosis have administration of amoxicillin/clavulanate is 0.02% to
developed rash during therapy; ampicillin class anti- 0.07% when calculated using the highest average
biotics not recommended in these patients. Incidence breast milk concentration located and compared to
of diarrhea is higher than with amoxicillin alone. Due to an infant therapeutic dose of 25 to 90 mg/kg/day. In
differing content of clavulanic acid, not all formulations general, breastfeeding is considered acceptable when
are interchangeable; use of an inappropriate product for the RID is <10% (Anderson 2016; Ito 2000).
a specific dosage could result in either diarrhea (which Using the highest average milk concentration (0.12
may be severe) or subtherapeutic clavulanic acid con- mcg/mL), the estimated daily infant dose via breast
centrations leading to decreased clinical efficacy. Low milk is 0.018 mg/kg/day. This milk concentration was
incidence of cross-allergy with cephalosporins exists. obtained 4 to 6 hours following maternal administra-
Monitor renal, hepatic, and hematopoietic function if tion of oral amoxicillin/clavulanate 250 mg/125 mg
therapy extends beyond approved duration times. (Takase 1982).
Some products contain phenylalanine. Potentially sig- Constipation, diarrhea, restlessness, and rash have
nificant drug-drug interactions may exist, requiring dose been reported in breastfeeding infants exposed to
or frequency adjustment, additional monitoring, and/or amoxicillin and clavulanate; reversible elevations in
selection of alternative therapy. AST and ALT have been noted in one infant (Benya-
Warnings: Additional Pediatric Considerations mini 2005). The manufacturer warns of the potential
Epstein-Barr virus infection (infectious mononucleosis), for allergic sensitization in the infant. In general, anti-
acute lymphocytic leukemia, or cytomegalovirus infec- biotics that are present in breast milk may cause non-
tion increase risk for penicillin-induced maculopapular dose-related modification of bowel flora. Monitor
rash. Appearance of a rash should be carefully eval- infants for GI disturbances, such as thrush and diar-
uated to differentiate a nonallergic ampicillin rash from a rhea (WHO 2002).
hypersensitivity reaction; rash occurs in 5% to 10% of Although the manufacturer recommends that caution be
children and is a generalized dull red, maculopapular exercised when administering amoxicillin and clavula-
rash, generally appearing 3 to 14 days after the start of nate to breastfeeding women, amoxicillin/clavulanate
therapy. It normally begins on the trunk and spreads is considered compatible with breastfeeding when
over most of the body. It may be most intense at used in usual recommended doses (WHO 2002).
pressure areas, elbows, and knees. A high percentage Dosage Forms: US
(43% to 100%) of patients with infectious mononucleo- Suspension Reconstituted, Oral:
sis have developed rash during therapy; ampicillin-class Augmentin: Amoxicillin 250 mg and clavulanate potas-
antibiotics are not recommended in these patients. sium 62.5 mg per 5 mL (75 mL, 100 mL, 150 mL);
125
Amoxicillin 125 mg and clavulanate potassium Use

31.25 mg per 5 mL (75 mL, 100 mL, 150 mL) Attention-deficit/hyperactivity disorder: Treatment
Augmentin ES-600: Amoxicillin 600 mg and clavula- of ADHD
nate potassium 42.9 mg per 5 mL (75 mL, 125 mL, Exogenous obesity (immediate-release tablet only):
200 mL) Short-term treatment of exogenous obesity as an
Generic: Amoxicillin 200 mg and clavulanate potas- adjunct to caloric restriction for patients refractory to
sium 28.5 mg per 5 mL (50 mL, 75 mL, 100 mL); alternative therapy (eg, repeated diets, group pro-
Amoxicillin 250 mg and clavulanate potassium grams, other drugs)
62.5 mg per 5 mL (75 mL, 100 mL, 150 mL); Amox- Narcolepsy (immediate-release tablet only): Treat-
icillin 400 mg and clavulanate potassium 57 mg per ment of narcolepsy
5 mL (50 mL, 75 mL, 100 mL); Amoxicillin 600 mg Local Anesthetic/Vasoconstrictor Precautions
and clavulanate potassium 42.9 mg per 5 mL (75 Use vasoconstrictor with caution in patients taking
mL, 125 mL, 200 mL) amphetamine. Amphetamines enhance the sympatho-
Tablet, Oral: mimetic response of epinephrine and norepinephrine
Augmentin: Amoxicillin 500 mg and clavulanate potas- leading to potential hypertension and cardiotoxicity.
sium 125 mg Effects on Dental Treatment Key adverse event(s)
Generic: Amoxicillin 250 mg and clavulanate potas- related to dental treatment: Amphetamines cause
sium 125 mg, Amoxicillin 500 mg and clavulanate tachycardia, increases in blood pressure, and palpita-
potassium 125 mg, Amoxicillin 875 mg and clavula- tions. Consider monitoring blood pressure prior to using
nate potassium 125 mg local anesthetic with a vasoconstrictor. Symptoms asso-
Tablet Chewable, Oral: ciated with bruxism have been observed in some
Generic: Amoxicillin 200 mg and clavulanate potas- patients.
sium 28.5 mg, Amoxicillin 400 mg and clavulanate Effects on Bleeding No information available to
potassium 57 mg require special precautions
Tablet Extended Release 12 Hour, Oral: Adverse Reactions As reported in children and adults
Generic: Amoxicillin 1000 mg and clavulanate potas- unless otherwise noted.
sium 62.5 mg 1% to 10%:
Dosage Forms: Canada Note: Also refer to Dosage Gastrointestinal: Upper abdominal pain (children: 4%)
Forms. Respiratory: Allergic rhinitis (children: 4%), epistaxis
Powder for suspension, oral: (children: 4%)
Clavulin: Frequency not defined:
125: Amoxicillin 125 mg and clavulanate potassium Cardiovascular: Increased blood pressure, palpita-
31.25 mg per 5 mL tions, Raynaud's phenomenon, tachycardia
200: Amoxicillin 200 mg and clavulanate potassium Central nervous system: Dizziness, dysphoria, eupho-
28.5 mg per 5 mL ria, exacerbation of Gilles de la Tourette's syndrome,
250: Amoxicillin 250 mg and clavulanate potassium headache, insomnia, overstimulation, psychosis,
62.5 mg per 5 mL restlessness, tics (including exacerbation), vocal tics
400: Amoxicillin 400 mg and clavulanate potassium (exacerbation)
57 mg per 5 mL Dermatologic: Urticaria
Tablet, oral: Endocrine & metabolic: Change in libido, growth sup-
Clavulin: pression (children), weight loss (children)
500: Amoxicillin 500 mg and clavulanate potassium Gastrointestinal: Anorexia, constipation, diarrhea, dys-
125 mg geusia, gastrointestinal disease, vomiting, xero-
875: Amoxicillin 875 mg and clavulanate potassium stomia
125 mg Genitourinary: Erectile dysfunction (frequent or pro-
Dental Health Professional Considerations In longed erections), impotence
maxillary sinus, anterior nasal cavity, and deep neck Neuromuscular & skeletal: Dyskinesia, rhabdomyoly-
infections, beta-lactamase-producing staphylococci and sis, tremor
beta-lactamase-producing Bacteroides usually are <1%, postmarketing, and/or case reports: Mania,
present. In these situations, antibiotics that resist the peripheral vascular disease
beta-lactamase enzyme are indicated. Amoxicillin and Mechanism of Action Amphetamines are noncate-
clavulanic acid is administered orally for moderate cholamine sympathomimetic amines that promote
infections. Ampicillin sodium and sulbactam sodium release of catecholamines (primarily dopamine and
(Unasyn®) is administered parenterally for more severe norepinephrine) from their storage sites in the presy-
infections. naptic nerve terminals. A less significant mechanism
may include their ability to block the reuptake of cat-
Amphetamine (am FET a meen) echolamines by competitive inhibition. The anorexi-
genic effect is probably secondary to the CNS-
Related Information stimulating effect; the site of action is probably the
Dentin Hypersensitivity, Acid Erosion, High Caries hypothalamic feeding center.
Index, Management of Alveolar Osteitis, and Xerosto- Pharmacodynamics/Kinetics
mia on page 1548 Duration of Action Oral:
Management of the Chemically Dependent Patient on Immediate-release tablet: Evekeo: 4 to 6 hours
page 1511 (Jain 2017)
Brand Names: US Adzenys ER; Adzenys XR-ODT; Extended-release orally-disintegrating tablet: Adzenys
Dyanavel XR; Evekeo XR-ODT: 10 to 12 hours
Pharmacologic Category Central Nervous System Half-life Elimination Oral:
Stimulant Immediate-release tablet: 12 hours (de la Torre 2004)
126
AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX
Immediate-release orally-disintegrating tablet: Evekeo

ODT: Adults: d-amphetamine 10 hours and l-amphet- Amphotericin B Cholesteryl Sulfate
amine 11.7 hours Complex
Extended-release orally-disintegrating tablet: Adzenys (am foe TER i sin bee kole LES te ril SUL fate KOM plecks)
XR-ODT:
Brand Names: US Amphotec [DSC]
Children 6 to 12 years: d-amphetamine 9 to 10 hours
Pharmacologic Category Antifungal Agent, Paren-
and l-amphetamine 10 to 11 hours
teral
Adults: d-amphetamine 11 hours and l-amphetamine
Use Treatment of invasive aspergillosis in patients who
14 hours
have failed amphotericin B deoxycholate treatment, or
Extended-release suspension:
who have renal impairment or experience unacceptable
Adzenys ER: toxicity which precludes treatment with amphotericin B
Children 6 to 12 years: d-amphetamine 12.7 hours deoxycholate in effective doses.
(mean) and l-amphetamine 15.3 hours Local Anesthetic/Vasoconstrictor Precautions
Adults: d-amphetamine 11.4 hours and l-amphet- No information available to require special precautions
amine 14.1 hours Effects on Dental Treatment No significant effects or
Dyanavel XR: complications reported
Children: d-amphetamine 10.43 ± 2.01 hours and l- Effects on Bleeding No information available to
amphetamine 12.14 ± 3.15 hours require special precautions
Adults: d-amphetamine 12.36 ± 2.95 hours and l- Adverse Reactions Amphotericin B colloidal disper-
amphetamine 15.12 ± 4.4 hours sion has an improved therapeutic index compared to
Time to Peak Oral: conventional amphotericin B, and has been used safely
Immediate-release tablet: Within 4 hours (de la in patients with amphotericin B-related nephrotoxicity;
Torre 2004) however, continued decline of renal function has
Immediate-release orally-disintegrating tablet: Evekeo occurred in some patients.
ODT: Median time d-amphetamine and l-amphet-
>10%:
amine 3.5 hours (with water) and 3 hours (without Cardiovascular: Hypotension, tachycardia
water); increased with food in adults Central nervous system: Chills
Extended-release orally-disintegrating tablet: Adzenys Endocrine & metabolic: Hypokalemia
XR-ODT: Median time d-amphetamine 5 hours (7 Gastrointestinal: Vomiting
hours with food) and l-amphetamine ~5.25 hours Hepatic: Hyperbilirubinemia
(7.75 hours with food) Renal: Increased serum creatinine
Extended-release suspension: Miscellaneous: Fever
Adzenys ER suspension: d-amphetamine and l- 5% to 10%:
amphetamine: 5 hours (median) with or with- Cardiovascular: Chest pain, facial edema, hyper-
out food tension
Dyanavel XR suspension: Central nervous system: Abnormality in thinking,
Children: Median time d-amphetamine 3.9 hours drowsiness, headache, insomnia
and l-amphetamine 4.5 hours Dermatologic: Diaphoresis, pruritus, skin rash
Adults: 4 (2 to 7) hours Endocrine & metabolic: Hyperglycemia, hypocalce-
Pregnancy Considerations mia, hypomagnesemia, hypophosphatemia
Information related to use of amphetamine in preg- Gastrointestinal: Abdominal pain, diarrhea, enlarge-
nancy is limited (Maurovich-Horvat 2013). The majority ment of abdomen, hematemesis, nausea, stomatitis,
xerostomia
of human data are based on illicit amphetamine/meth-
Hematologic & oncologic: Anemia, hemorrhage,
amphetamine exposure and not from therapeutic mater-
thrombocytopenia
nal use (Golub 2005). Use of amphetamines during
Hepatic: Abnormal hepatic function tests, increased
pregnancy may lead to an increased risk of premature serum alkaline phosphatase, jaundice
birth and low birth weight; newborns may experience Neuromuscular & skeletal: Back pain, muscle rigidity,
symptoms of withdrawal. Behavioral problems may also tremor
occur later in childhood (LaGasse 2012). Newborns Respiratory: Dyspnea, epistaxis, hypoxia, increased
should be monitored for agitation, irritability, excessive cough, rhinitis
drowsiness, or feeding difficulties <5%, postmarketing, and/or case reports: Acidosis,
Data collection to monitor pregnancy outcomes follow- atrial arrhythmia, cardiac arrest, cardiac failure, gas-
trointestinal hemorrhage, hepatic failure, injection site
ing exposure to amphetamine is ongoing. Healthcare
reaction, oliguria, pain at injection site, pleural effu-
providers are encouraged to enroll females exposed to
sion, renal failure, seizure, syncope, ventricular
amphetamine during pregnancy in the National Preg-
arrhythmia
nancy Registry for Psychostimulants (1-866-961-2388
Mechanism of Action Binds to ergosterol altering cell
and/or https://womensmentalhealth.org/clinical-and-
membrane permeability in susceptible fungi and caus-
research-programs/pregnancyregistry/othermedica- ing leakage of cell components with subsequent cell
tions/). death. Proposed mechanism suggests that amphoter-
Product Availability Evekeo ODT: FDA approved icin causes an oxidation-dependent stimulation of mac-
January 2019; anticipated availability is currently rophages (Lyman, 1992).
unknown. Information pertaining to this product within Pharmacodynamics/Kinetics
the monograph is pending revision. Consult the pre- Half-life Elimination ~28 hours; prolonged with
scribing information for additional information. higher doses
Controlled Substance C-II Pregnancy Risk Factor B
127
AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX
Pregnancy Considerations Adverse events were not exfoliation of skin, hearing loss, hemorrhagic gastro-
observed in animal reproduction studies. Amphotericin enteritis, hepatitis, hypersensitivity pneumonitis,
crosses the placenta and enters the fetal circulation. increased liver enzymes, jaundice, leukoencephalop-
Amphotericin B is recommended for the treatment of athy, leukopenia, maculopapular rash, melena, neph-
serious systemic fungal diseases in pregnant women; rogenic diabetes insipidus, oliguria, peripheral
refer to current guidelines (IDSA [Pappas 2016]; King neuropathy, pruritus, pulmonary edema, renal failure,
1998; Pilmis 2015). renal tubular acidosis, shock, Stevens-Johnson syn-
Product Availability Amphotec has been discontinued drome, thrombocytopenia, tinnitus, toxic epidermal
in the US for more than 1 year. necrolysis, ventricular fibrillation, vertigo (transient),
visual disturbance, wheezing
Mechanism of Action Binds to ergosterol altering cell
Amphotericin B (Conventional) membrane permeability in susceptible fungi and caus-
(am foe TER i sin bee con VEN sha nal)
ing leakage of cell components with subsequent cell
Related Information death. Proposed mechanism suggests that amphoter-
Fungal Infections on page 1538 icin causes an oxidation-dependent stimulation of mac-
Brand Names: Canada Fungizone rophages (Lyman 1992).
Pharmacologic Category Antifungal Agent, Paren- Pharmacodynamics/Kinetics
teral Half-life Elimination
Use Premature neonates (GA: 27.4 ± 5 weeks): 14.8 hours
Life-threatening fungal infections: Treatment of (range: 5 to 82 hours) (Baley 1990)
patients with progressive, potentially life-threatening Infants and Children (4 months to 14 years): 18.1 ± 6.6
fungal infections: Aspergillosis, cryptococcosis (toru- hours (range: 11.9 to 40.3 hours) (Benson 1989)
losis), North American blastomycosis, systemic candi- Adults: Biphasic: Initial: 15 to 48 hours; Terminal:
diasis, coccidioidomycosis, histoplasmosis, 15 days
zygomycosis (including mucormycosis due to suscep- Time to Peak Within 1 hour following a 4- to 6-hour
tible species of the genera Absidia, Mucor, and Rhi- dose
zopus), and infections due to related susceptible Pregnancy Risk Factor B
species of Conidiobolus, Basidiobolus, and sporotri- Pregnancy Considerations Adverse events were not
chosis. observed in animal reproduction studies. Amphotericin
Leishmaniasis: Alternative treatment in patients with crosses the placenta and enters the fetal circulation.
American (New World) mucocutaneous leishmaniasis Amphotericin B is recommended for the treatment of
Local Anesthetic/Vasoconstrictor Precautions serious systemic fungal diseases in pregnant women.
No information available to require special precautions Refer to current guidelines (IDSA [Pappas 2016]; King
Effects on Dental Treatment No significant effects or 1998; Pilmis 2015).
Effects on Bleeding No information available to Amphotericin B (Lipid Complex)
require special precautions (am foe TER i sin bee LIP id KOM pleks)
Adverse Reactions
Systemic: Brand Names: US Abelcet
>10%: Brand Names: Canada Abelcet
Cardiovascular: Hypotension Pharmacologic Category Antifungal Agent, Paren-
Central nervous system: Chills, headache (less fre- teral
quent with I.T.), malaise, pain (less frequent with I.T.) Use Fungal infection (invasive): Treatment of invasive
Endocrine & metabolic: Hypokalemia, hypomagne- fungal infection in patients who are refractory to or
semia intolerant of conventional amphotericin B (amphotericin
Gastrointestinal: Anorexia, diarrhea, epigastric pain, B deoxycholate) therapy
heartburn, nausea (less frequent with I.T.), stomach Local Anesthetic/Vasoconstrictor Precautions
cramps, vomiting (less frequent with I.T.) No information available to require special precautions
Hematologic & oncologic: Anemia (normochromic-nor- Effects on Dental Treatment No significant effects or
mocytic) complications reported
Local: Pain at injection site (with or without phlebitis or Effects on Bleeding No information available to
thrombophlebitis [incidence may increase with require special precautions
peripheral infusion of admixtures]) Adverse Reactions Nephrotoxicity and infusion-
Renal: Renal function abnormality (including azote- related hyperpyrexia, rigor, and chilling are reduced
mia, renal tubular acidosis, nephrocalcinosis relative to amphotericin deoxycholate.
[>0.1 mg/mL]), renal insufficiency >10%:
Respiratory: Tachypnea Central nervous system: Chills (18%)
Miscellaneous: Fever Renal: Increased serum creatinine (11%)
1% to 10%: Miscellaneous: Fever (14%), multi-organ failure (11%)
Cardiovascular: Flushing, hypertension 1% to 10%:
Central nervous system: Arachnoiditis, delirium, neu- Cardiovascular: Hypotension (8%), cardiac arrest
ralgia (lumbar; especially with intrathecal therapy), (6%), hypertension (5%), chest pain (3%)
paresthesia (especially with intrathecal therapy) Central nervous system: Headache (6%), pain (5%)
Genitourinary: Urinary retention Dermatologic: Skin rash (4%)
Hematologic & oncologic: Leukocytosis Endocrine & metabolic: Hypokalemia (5%)
<1% (Limited to important or life-threatening): Acute Gastrointestinal: Nausea (9%), vomiting (8%), diar-
hepatic failure, agranulocytosis, anuria, blood coagu- rhea (6%), abdominal pain (4%), gastrointestinal
lation disorder, bone marrow depression, broncho- hemorrhage (4%)
spasm, cardiac arrest, cardiac arrhythmia, cardiac Hematologic & oncologic: Thrombocytopenia (5%),
failure, convulsions, diplopia, dyspnea, eosinophilia, anemia (4%), leukopenia (4%)
128
AMPHOTERICIN B (LIPOSOMAL)
Hepatic: Hyperbilirubinemia (4%) experience orthostatic hypotension as they stand up

Infection: Sepsis (7%), infection (5%) after treatment; especially if lying in dental chair for
Renal: Renal failure (5%) extended periods of time. Use caution with sudden
Respiratory: Respiratory failure (8%), dyspnea (6%), changes in position during and after dental treatment
respiratory tract disease (4%) (see Dental Health Professional Considerations).
<1%, postmarketing, and/or case reports: Acute hepatic Effects on Bleeding No information available to
failure, anaphylactoid reaction, anuria, asthma, blood require special precautions
coagulation disorder, brain disease, bronchospasm, Adverse Reactions Percentage of adverse reactions
cardiac arrhythmia, cardiomyopathy, cerebrovascular is dependent upon population studied and may vary
accident, cholangitis, cholecystitis, deafness, dysuria, with respect to premedications and underlying illness.
eosinophilia, erythema multiforme, exfoliative derma- Incidence of decreased renal function and infusion-
titis, extrapyramidal reaction, hearing loss, hemato- related events are lower than rates observed with
logic disease, hemoptysis, hepatic sinusoidal amphotericin B deoxycholate.
obstruction syndrome (formerly known as hepatic >10%:
veno-occlusive disease), hepatitis, hepatomegaly, Cardiovascular: Hypertension (8% to 20%), tachycar-
hepatotoxicity, hypercalcemia, hyperkalemia, hyper- dia (9% to 19%), peripheral edema (15%), edema
sensitivity reaction, hypocalcemia, hypomagnesemia, (12% to 14%), hypotension (7% to 14%), chest pain
increased blood urea nitrogen, increased serum trans- (8% to 12%), localized phlebitis (9% to 11%)
aminases, injection site reaction, jaundice, leukocyto- Central nervous system: Chills (29% to 48%), insom-
sis, myasthenia, myocardial infarction, oliguria, nia (17% to 22%), headache (9% to 20%), pain
peripheral neuropathy, pleural effusion, pulmonary (14%), anxiety (7% to 14%), confusion (9% to 13%)
edema, pulmonary embolism, renal insufficiency, renal Dermatologic: Skin rash (5% to 25%), pruritus (11%)
tubular acidosis, seizure, shock, tachycardia, throm- Endocrine & metabolic: Hypokalemia (31% to 51%),
bophlebitis, ventricular fibrillation, vertigo (transient), hypomagnesemia (15% to 50%), hyperglycemia (8%
visual impairment to 23%), hypocalcemia (5% to 18%), hyponatremia
Mechanism of Action Binds to ergosterol altering cell (9% to 12%), hypervolemia (8% to 12%)
membrane permeability in susceptible fungi and caus- Gastrointestinal: Nausea (16% to 40%), vomiting (11%
ing leakage of cell components with subsequent cell to 32%), diarrhea (11% to 30%), abdominal pain (7%
death. Proposed mechanism suggests that amphoter- to 20%), constipation (15%), anorexia (10% to 14%)
icin causes an oxidation-dependent stimulation of mac- Genitourinary: Nephrotoxicity (14% to 47%), hematu-
rophages. ria (14%)
Pharmacodynamics/Kinetics Hematologic & oncologic: Anemia (27% to 48%),
Half-life Elimination 173 hours following multiple leukopenia (15% to 17%), thrombocytopenia (6%
doses to 13%)
Pregnancy Risk Factor B Hepatic: Increased serum alkaline phosphatase (7%
Pregnancy Considerations Adverse events were not to 22%), hyperbilirubinemia (≤18%), increased
observed in animal reproduction studies. Amphotericin serum ALT (15%), increased serum AST (13%),
crosses the placenta and enters the fetal circulation. abnormal hepatic function tests (not specified) (4%
Amphotericin B is recommended for the treatment of to 13%)
serious, systemic fungal diseases in pregnant women, Hypersensitivity: Transfusion reaction (9% to 18%)
refer to current guidelines (IDSA [Pappas 2016]; King Infection: Sepsis (7% to 14%), infection (11% to 13%)
1998; Pilmus 2015). Neuromuscular & skeletal: Weakness (6% to 13%),
back pain (12%)
Amphotericin B (Liposomal) Renal: Increased serum creatinine (18% to 40%),
(am foe TER i sin bee lye po SO mal) increased blood urea nitrogen (7% to 21%)
Respiratory: Dyspnea (18% to 23%), pulmonary dis-
Brand Names: US AmBisome ease (14% to 18%), cough (2% to 18%), epistaxis
Brand Names: Canada AmBisome (9% to 15%), pleural effusion (13%), rhinitis (11%)
Pharmacologic Category Antifungal Agent, Paren- Miscellaneous: Infusion related reactions (4% to 21%;
teral fever [7% to 24%], chills [6% to 24%], vomiting [4%
Use to 16%], nausea [8% to 14%], dyspnea [5% to 10%],
Cryptococcal meningitis in HIV-infected patients: tachycardia [2% to 10%], hypertension [2% to 9%],
Treatment of cryptococcal meningitis in HIV-infected vasodilation [5%], hypotension [4%], hyperventilation
patients. [1%], hypoxia [≤1%])
Fungal infections, empiric therapy: Empiric treat- 2% to 10%:
ment in febrile neutropenic patients with presumed Cardiovascular: Atrial fibrillation, bradycardia, cardiac
fungal infection. arrest, cardiac arrhythmia, cardiomegaly, facial
Fungal infections, systemic therapy: Treatment of edema, flushing, heart valve disease, orthostatic
systemic infections caused by Aspergillus sp, Candida hypotension, vascular disorder, vasodilatation
sp, and/or Cryptococcus sp in patients refractory to Central nervous system: Dizziness (7% to 9%), abnor-
conventional amphotericin B deoxycholate therapy or mality in thinking, agitation, coma, depression,
when renal impairment or unacceptable toxicity pre- drowsiness, dysesthesia, dystonia, hallucination,
cludes the use of the deoxycholate formulation. malaise, nervousness, paresthesia, rigors, seizure
Leishmaniasis (visceral): Treatment of visceral leish- Dermatologic: Diaphoresis (7%), alopecia, cellulitis,
maniasis. dermal ulcer, dermatological reaction, maculopapu-
Local Anesthetic/Vasoconstrictor Precautions lar rash, skin discoloration, urticaria, vesiculobullous
No information available to require special precautions dermatitis, xeroderma
Effects on Dental Treatment Key adverse event(s) Endocrine & metabolic: Hypernatremia (4%), acidosis,
related to dental treatment: Facial swelling, mucositis, hyperchloremia, hyperkalemia, hypermagnesemia,
stomatitis, and ulcerative stomatitis; Patients may hyperphosphatemia, hypophosphatemia, increased
129
AMPHOTERICIN B (LIPOSOMAL)
lactate dehydrogenase, increased nonprotein of the amphotericin B liposomes. Amphotericin B, lip-

nitrogen osomal contains true liposomes that are <100 nm in
Gastrointestinal: Gastrointestinal hemorrhage (10%), diameter.
aphthous stomatitis, dyspepsia, dysphagia, enlarge-
ment of abdomen, eructation, fecal incontinence,
flatulence, gingival hemorrhage, hematemesis, hem-
Ampicillin (am pi SIL in)
orrhoids, hiccups, increased serum amylase, intesti- Related Information
nal obstruction, mucositis, rectal disease, stomatitis, Antibiotic Prophylaxis on page 1502
xerostomia
Brand Names: Canada Ampicillin for Injection
Genitourinary: Dysuria, toxic nephrosis, urinary incon-
Generic Availability (US) Yes
tence, vaginal hemorrhage
Hematologic & oncologic: Blood coagulation disorder, Pharmacologic Category Antibiotic, Penicillin
bruise, decreased prothrombin time, hemophthal- Dental Use IV or IM administration for the prevention of
mos, hemorrhage, hypoproteinemia, increased pro- infective endocarditis in patients not allergic to penicillin
thrombin time, oral hemorrhage, petechia, purpura and unable to take oral amoxicillin; IV or IM adminis-
Hepatic: Hepatic injury, hepatic sinusoidal obstruction tration for prophylaxis in total joint replacement patients
syndrome (formerly known as hepatic veno-occlu- (hip replacement, knee replacement) not allergic to
sive disease), hepatomegaly penicillin and unable to take oral medications under-
Hypersensitivity: Delayed hypersensitivity, hypersen- going dental procedures
sitivity reaction Use
Immunologic: Graft versus host disease Oral:
Infection: Herpes simplex infection Genitourinary tract infections: Treatment of genito-
Local: Inflammation at injection site urinary tract infections caused by Escherichia coli,
Neuromuscular & skeletal: Arthralgia, myalgia, neck Proteus mirabilis, enterococci, Shigella, Salmonella
pain, ostealgia, tremor typhosa and other Salmonella, and nonpenicillinase-
Ophthalmic: Conjunctivitis, dry eyes producing N. gonorrhoeae. Note: Ampicillin is not
Renal: Acute renal failure, renal failure, renal function recommended by the CDC as a first-line agent in the
abnormality treatment of gonorrhea (CDC, 2010).
Respiratory: Hypoxia (6% to 8%), asthma, atelectasis, GI tract infections: Treatment of GI tract infections
dry nose, flu-like symptoms, hemoptysis, hyperventi- caused by Shigella, S. typhosa and other Salmo-
lation, pharyngitis, pneumonia, pulmonary edema, nella, E. coli, P. mirabilis, and enterococci. Note:
respiratory alkalosis, respiratory failure, respiratory Ampicillin is not recommended as a first-line agent
insufficiency, sinusitis for Shigellosis, Salmonellosis (nontyphoid), or Sal-
Miscellaneous: Procedural complication (8% to 10%) monella enterica species (typhoid fever) due to
Postmarketing and/or case reports: Agranulocytosis, development of resistance (CDC, 2014).
angioedema, bronchospasm, cyanosis, erythema, Respiratory tract infections: Treatment of respira-
hemorrhagic cystitis, hypoventilation, rhabdomyolysis tory tract infections caused by nonpenicillinase-pro-
Mechanism of Action Binds to ergosterol altering cell ducing H. influenzae and staphylococci, and
membrane permeability in susceptible fungi and caus- streptococci, including Streptococcus pneumoniae.
ing leakage of cell components with subsequent cell Injection:
death. Proposed mechanism suggests that amphoter- Gastrointestinal infections: Treatment of GI infec-
icin causes an oxidation-dependent stimulation of mac- tions caused by S. typhi (typhoid fever), other Sal-
rophages (Lyman 1992). monella species and Shigella species (dysentery).
Pharmacodynamics/Kinetics Note: Ampicillin is not recommended as a first-line
Half-life Elimination 7 to 10 hours (following a single agent for Shigellosis, Salmonellosis (nontyphoid), or
24-hour dosing interval); Terminal half-life: 100 to 153 S. enterica species (typhoid fever) due to develop-
hours (following multiple dosing up to 49 days) ment of resistance (CDC, 2014).
Pregnancy Risk Factor B Meningitis, bacterial: Treatment of bacterial menin-
Pregnancy Considerations Adverse events were not gitis caused by E. coli, group B streptococci, and
observed in animal reproduction studies. Amphotericin other gram-negative bacteria (N. meningitidis).
crosses the placenta and enters the fetal circulation. Respiratory tract infections: Treatment of respira-
Amphotericin B is recommended for the treatment of tory tract infections caused by S. pneumoniae,
serious systemic fungal diseases in pregnant women; Staphylococcus aureus (penicillinase and nonpeni-
refer to current guidelines (IDSA [Pappas 2016]; King cillinase producing), H. influenzae, and group A beta-
1998; Pilmis 2015). hemolytic streptococci.
Dental Health Professional Considerations Septicemia and endocarditis: Treatment of septice-
Amphotericin B, liposomal is a true single bilayer lip- mia and endocarditis caused by susceptible gram-
osomal drug delivery system. Liposomes are closed, positive organisms, including Streptococcus species,
spherical vesicles created by mixing specific propor- penicillin G-susceptible staphylococci, and entero-
tions of amphophilic substances such as phospholipids cocci; gram-negative sepsis caused by E. coli, P.
and cholesterol so that they arrange themselves into mirabilis, and Salmonella species.
multiple concentric bilayer membranes when hydrated Urinary tract infections: Treatment of urinary tract
in aqueous solutions. Single bilayer liposomes are then infections caused by E. coli and P. mirabilis.
formed by microemulsification of multilamellar vesicles Local Anesthetic/Vasoconstrictor Precautions
using a homogenizer. Amphotericin B, liposomal con- No information available to require special precautions
sists of these unilamellar bilayer liposomes with ampho- Effects on Dental Treatment Key adverse event(s)
tericin B intercalated within the membrane. Due to the related to dental treatment: Oral candidiasis, glossitis,
nature and quantity of amphophilic substances used, sore mouth, and stomatitis.
and the lipophilic moiety in the amphotericin B mole- Effects on Bleeding No information available to
cule, the drug is an integral part of the overall structure require special precautions
130
AMPICILLIN
Adverse Reactions Frequency not defined. Enterococcus, native or prosthetic valve (penicillin-
Central nervous system: Brain disease (penicillin- susceptible/aminoglycoside-resistant strains): 2 g
induced), glossalgia, seizure, sore mouth every 4 hours with concomitant ceftriaxone for 6
Dermatologic: Erythema multiforme, exfoliative derma- weeks
titis, skin rash, urticaria Enterococcus, native or prosthetic valve (penicillin-
Note: Appearance of a rash should be carefully susceptible/gentamicin-resistant/streptomycin-sus-
evaluated to differentiate (if possible) nonallergic ceptible strains): 2 g every 4 hours with concom-
ampicillin rash from hypersensitivity reaction. Inci- itant streptomycin for 4 to 6 weeks (4 weeks for
dence is higher in patients with viral infection, Sal- native valve and symptoms present <3 months; ≥6
monella infection, lymphocytic leukemia, or patients weeks for native valve and symptoms present ≥3
that have hyperuricemia. months or prosthetic valve).
Gastrointestinal: Diarrhea, enterocolitis, glossitis, mela- HACEK organisms, native or prosthetic valve (off-
noglossia, nausea, oral candidiasis, pseudomembra- label use): 2 g every 4 hours for 4 weeks (native
nous colitis, stomatitis, vomiting valve) or 6 weeks (prosthetic valve).
Hematologic & oncologic: Agranulocytosis, anemia, Listeria monocytogenes: 2 g every 4 hours, in com-
eosinophilia, hemolytic anemia, immune thrombocyto- bination with an aminoglycoside (eg, gentamicin)
penia, leukopenia (Gelfand 2018; Lorber 1997)
Hepatic: Increased serum AST Viridans group streptococcus (VGS) and S. bovis:
Hypersensitivity: Anaphylaxis Native valve: Highly penicillin-susceptible (MIC
Immunologic: Serum sickness-like reaction ≤0.12 mcg/mL): 2 g every 4 hours for 4 weeks
Renal: Interstitial nephritis (rare) (monotherapy) or for 2 weeks with concomitant
Respiratory: Stridor gentamicin
Miscellaneous: Fever Native valve: Relatively penicillin-resistant (MIC
<1%, postmarketing, and/or case reports: Dysgeusia >0.12 to <0.5 mcg/mL): 2 g every 4 hours for 4
(Syed 2016) weeks with concomitant gentamicin for the first 2
weeks
Dental Usual Dosage
Prosthetic valve: Highly penicillin-susceptible (MIC
Infective endocarditis prophylaxis: IM, IV: Dental, oral,
≤0.12 mcg/mL): 2 g every 4 hours for 6 weeks
or respiratory tract procedures:
(with or without concomitant gentamicin for the
Infants and Children: 50 mg/kg within 30 to 60 minutes
first 2 weeks)
prior to procedure in patients not allergic to penicillin
Prosthetic valve: Relatively or fully penicillin-resist-
and unable to take oral amoxicillin.
ant (MIC >0.12 mcg/mL): 2 g every 4 hours with
Adults: 2 g within 30 to 60 minutes prior to procedure
concomitant gentamicin for 6 weeks
in patients not allergic to penicillin and unable to take
Endocarditis, prophylaxis (off-label use):
oral amoxicillin. Dental, oral, or respiratory tract procedures: IM, IV:
Note: Intramuscular injections should be avoided in 2 g within 30 to 60 minutes prior to procedure in
patients who are receiving anticoagulant therapy. In patients not allergic to penicillin and unable to take
these circumstances, orally administered regimens oral amoxicillin. IM injections should be avoided in
should be given whenever possible. Intravenously patients who are receiving anticoagulant therapy. In
administered antibiotics should be used for patients these circumstances, orally administered regimens
who are unable to tolerate or absorb oral medica- should be given whenever possible. Intravenously
tions. administered antibiotics should be used for patients
Note: American Heart Association (AHA) guidelines who are unable to tolerate or absorb oral medica-
now recommend prophylaxis only in patients under- tions. Note: American Heart Association (AHA)
going invasive procedures and in whom underlying guidelines now recommend prophylaxis only in
cardiac conditions may predispose to a higher risk of patients undergoing invasive procedures and in
adverse outcomes should infection occur. whom underlying cardiac conditions may predis-
Prophylaxis in total joint replacement patient: Adults: pose to a higher risk of adverse outcomes should
IM, IV: 2 g 1 hour prior to the procedure infection occur (Wilson 2007).
Note: In general, patients with prosthetic joint implants Genitourinary and gastrointestinal tract procedures:
do not require prophylactic antibiotics prior to dental IM, IV: Note: Routine prophylaxis for GI/GU proce-
procedures. In planning an invasive oral procedure, dures is no longer recommended by the AHA.
dental consultation with the patient's orthopedic sur- Consider only in patients with the highest risk of
geon may be advised to review the risks of infection. adverse outcome from endocarditis (eg, prosthetic
Dosing heart valve, previous endocarditis, some categories
Adult & Geriatric of congenital heart disease, cardiac valvulopathy in
Usual dosage range: cardiac transplant patients) who have an estab-
Oral: 250 to 500 mg every 6 hours lished GI or GU enterococcal infection or for those
IM, IV: 1 to 2 g every 4 to 6 hours or 50 to 250 mg/kg/ already receiving antibiotic therapy to prevent a
day in divided doses (maximum: 12 g/day) wound infection or sepsis associated with a GI or
Endocarditis, treatment (off-label dose) (AHA GU procedure in which enterococcal coverage is
[Baddour 2015]): IV: desired (Wilson 2007).
Enterococcus, native or prosthetic valve (penicillin/ High-risk patients: 2 g within 30 minutes prior to
gentamicin-susceptible strains): 2 g every 4 hours procedure, followed by ampicillin 1 g (or amoxicil-
with concomitant ceftriaxone for 6 weeks or 2 g lin 1 g orally) 6 hours later; must be used in
every 4 hours with concomitant gentamicin for 4 combination with gentamicin (Dajani 1997).
to 6 weeks (4 weeks for native valve and symptoms Moderate-risk patients: 2 g within 30 minutes prior
present <3 months; 6 weeks for native valve and to procedure (Dajani 1997).
symptoms present ≥3 months or for prosthetic Genitourinary or gastrointestinal infections: Oral,
valve) IM, IV: 500 mg every 6 hours
131
AMPICILLIN
Group B streptococcus (maternal dose for neo- 2 g every 12 to 24 hours (administer after hemo-
natal prophylaxis) (off-label use): IV: 2 g initial dialysis on dialysis days) (Heintz 2009). Note:
dose, then 1 g every 4 hours until delivery Dosing dependent on the assumption of 3 times/
(CDC 2010)
week, complete IHD sessions.
Meningitis, bacterial: Pathogen specific therapy (eg,
Peritoneal dialysis (PD): IV: 250 mg every 12 hours
Enterococcus spp [ampicillin susceptible], Haemo-
philus influenzae [beta-lactamase negative], Listeria (Aronoff, 2007)
monocytogenes, Neisseria meningitidis [penicillin Continuous renal replacement therapy (CRRT)
MIC <0.1 mcg/mL], Streptococcus agalactiae, Strep- (Heintz, 2009): Drug clearance is highly dependent
tococcus pneumoniae [penicillin MIC ≤0.06 on the method of renal replacement, filter type, and
mcg/mL]): IV: 2 g every 4 hours. Use in combination
with gentamicin for susceptible Enterococcus spp; flow rate. Appropriate dosing requires close mon-
addition of an aminoglycoside may be considered itoring of pharmacologic response, signs of adverse
for L. monocytogenes or S. agalactiae (IDSA [Tunkel reactions due to drug accumulation, as well as drug
2004]; IDSA [Tunkel 2017]). concentrations in relation to target trough (if appro-
Mild to moderate infections: Oral: 250 to 500 mg priate). The following are general recommendations
every 6 hours only (based on dialysate flow/ultrafiltration rates of
Osteomyelitis, native vertebral (off-label use): 1 to 2 L/hour and minimal residual renal function)
Enterococcus spp (penicillin-susceptible): IV: 12 g
continuous infusion every 24 hours or 2 g every 4 and should not supersede clinical judgment: IV:
hours for 6 weeks; the addition of an aminoglycoside CVVH: Loading dose of 2 g followed by 1 to 2 g
for 4 to 6 weeks is recommended in patients with every 8 to 12 hours
infective endocarditis (IDSA [Berbari 2015]) CVVHD: Loading dose of 2 g followed by 1 to 2 g
Prosthetic joint infection, Enterococcus spp (pen- every 8 hours
icillin-susceptible) (off-label use): IV: 12 g contin-
CVVHDF: Loading dose of 2 g followed by 1 to 2 g
uous infusion every 24 hours or 2 g every 4 hours for
4 to 6 weeks; consider addition of aminoglycoside every 6 to 8 hours
(Osmon, 2013). Hepatic Impairment: Adult There are no dosage
Prophylaxis in total joint replacement patients adjustments provided in the manufacturer’s labeling.
undergoing dental procedures which produce Pediatric
bacteremia (off-label use): Note: In general,
General dosing, susceptible infection (Red Book
patients with prosthetic joint implants do not require
prophylactic antibiotics prior to dental procedures. In [AAP 2015]): Infants, Children, and Adolescents:
planning an invasive oral procedure, dental consul- Mild to moderate infection:
tation with the patient's orthopedic surgeon may be Oral: 50 to 100 mg/kg/day divided every 6 hours;
advised to review the risks of infection (Solle- maximum daily dose: 4,000 mg/day
cito 2015).
IM, IV: 100 to 150 mg/kg/day divided every 6
IM, IV: 2 g 1 hour prior to procedure (ADA/
AAOS 2003). hours; maximum daily dose: 4,000 mg/day
Respiratory tract infections: Severe infection: IM, IV: 200 to 400 mg/kg/day
Oral: 250 mg 4 times daily divided every 6 hours; maximum daily dose: 12
IM, IV: 250 to 500 mg every 6 hours g/day
Sepsis: IM, IV: Note: administer doses IV initially; IM Community-acquired pneumonia (CAP) (IDSA/
may be used later in therapy course: 150 to PIDS [Bradley 2011]): Infants >3 months, Children,
200 mg/kg/day divided every 3 to 4 hours (range: 6
to 12 g/day) and Adolescents: Note: May consider addition of
Surgical (perioperative) prophylaxis in liver trans- vancomycin or clindamycin to empiric therapy if
plantation (off-label use): IV: 2 g within 60 minutes community-acquired MRSA suspected. In children
prior to surgical incision in combination with cefotax- ≥5 years, a macrolide antibiotic should be added if
ime. Doses may be repeated in 2 hours if procedure atypical pneumonia cannot be ruled out.
is lengthy or if there is excessive blood loss (Brat-
zler 2013). Empiric treatment or S. pneumoniae (MICs for
Urinary tract infections (ampicillin-susceptible penicillin ≤2 mcg/mL) or H. influenzae (beta-lacta-
Enterococcus; off-label use): IV: 1 to 2 g every 4 mase negative) in fully immunized patients: IV:
to 6 hours with or without an aminoglycoside 150 to 200 mg/kg/day divided every 6 hours
(Heintz 2010) Group A Streptococcus: IV: 200 mg/kg/day divided
Renal Impairment: Adult every 6 hours
There are no dosage adjustments provided in the S. pneumoniae (MICs for penicillin ≥4 mcg/mL): IV:
manufacturer’s labeling; however, the following
adjustments have been recommended (Aronoff 300 to 400 mg/kg/day divided every 6 hours
2007): Endocarditis:
CrCl >50 mL/minute: Administer every 6 hours Treatment: Children and Adolescents: IV: 200 to
CrCl 10 to 50 mL/minute: Administer every 6 to 12 300 mg/kg/day divided every 4 to 6 hours; max-
hours
imum daily dose: 12 g/day; use in combination
CrCl <10 mL/minute: Administer every 12 to 24 hours
End-stage renal disease (ESRD) on intermittent with other antibiotics for at least 4 weeks; some
hemodialysis (IHD) (administer after hemodialysis organisms may require longer duration (AHA [Bal-
on dialysis days): Dialyzable (20% to 50%): IV: 1 to timore 2015])
132
AMPICILLIN
Prophylaxis: Note: AHA guidelines (Baltimore transpeptidation step of peptidoglycan synthesis in

2015) limit the use of prophylactic antibiotics to bacterial cell walls, thus inhibiting cell wall biosynthesis.
patients at the highest risk for infective endocardi- Bacteria eventually lyse due to ongoing activity of cell
tis (IE) or adverse outcomes (eg, prosthetic heart wall autolytic enzymes (autolysins and murein hydro-
valves, patients with previous IE, unrepaired cya- lases) while cell wall assembly is arrested.
notic congenital heart disease, repaired congen- Contraindications Hypersensitivity (eg, anaphylaxis)
ital heart disease with prosthetic material or to ampicillin, any component of the formulation, or other
device during first 6 months after procedure, penicillins; infections caused by penicillinase-producing
repaired congenital heart disease with residual organisms
defects at the site or adjacent to site of prosthetic
Warnings/Precautions Dosage adjustment may be
patch or device, and heart transplant recipients
necessary in patients with renal impairment. Serious
with cardiac valvulopathy):
Dental or oral procedures or respiratory tract and occasionally severe or fatal hypersensitivity (ana-
procedures (eg, tonsillectomy, adenoidectomy): phylactoid) reactions have been reported in patients on
Infants, Children, and Adolescents: IV, IM: penicillin therapy, especially with a history of beta-
50 mg/kg within 30 to 60 minutes before proce- lactam hypersensitivity, history of sensitivity to multiple
dure; maximum dose: 2,000 mg/dose. Intramus- allergens, or previous IgE-mediated reactions (eg, ana-
cular (IM) injections should be avoided in phylaxis, angioedema, urticaria). Serious anaphylactoid
patients who are receiving anticoagulant ther- reactions require emergency treatment and airway
apy. In these circumstances, orally administered management. Appropriate treatments must be readily
regimens should be used whenever possible. available. Use with caution in asthmatic patients.
Intravenously (IV) administered antibiotics Appearance of any rash should be carefully evaluated
should be used for patients who are unable to to differentiate a nonallergic ampicillin rash from a
tolerate or absorb oral medications (Wil- hypersensitivity reaction. High percentage of patients
son 2007). with infectious mononucleosis have developed rash
Intra-abdominal infection, complicated: Infants, during therapy with ampicillin; ampicillin-class antibiot-
Children, and Adolescents: IV: 200 mg/kg/day div- ics not recommended in these patients This rash (gen-
ided every 6 hours; maximum single dose: eralized maculopapular and pruritic) usually appears 7
2,000 mg; maximize doses if undrained abdominal to 10 days after initiation and usually resolves within a
abscesses (IDSA [Solomkin 2010]) week of discontinuation. It is not known whether these
Meningitis: Infants, Children, and Adolescents: IV: patients are truly allergic to ampicillin. Ampicillin rash
200 to 400 mg/kg/day divided every 6 hours; max- occurs in 5% to 10% of children receiving ampicillin and
imum daily dose: 12 g/day (Red Book [AAP 2015]; is a generalized dull red, maculopapular rash, generally
IDSA [Tunkel 2004])
appearing 3 to 14 days after the start of therapy. It
Peritonitis (CAPD) Limited data available: Infants,
normally begins on the trunk and spreads over most
Children, and Adolescents: Intraperitoneal: 125 mg
of the body. It may be most intense at pressure areas,
p e r l i t e r o f d i a l y s a t e f o r 2 w e e k s (I S P D
[Warady 2012]) elbows, and knees. Prolonged use may result in fungal
Surgical prophylaxis: Infants, Children, and Ado- or bacterial superinfection, including Clostridium diffi-
lescents: IV: 50 mg/kg 30 to 60 minutes prior to cile-associated diarrhea (CDAD) and pseudomembra-
procedure; may repeat in 2 hours if lengthy proce- nous colitis; CDAD has been observed >2 months
dure or excessive blood loss; maximum single postantibiotic treatment.
dose: 2,000 mg (ASHP/IDSA [Bratzler 2013]; Red Drug Interactions
Book [AAP 2015]) Metabolism/Transport Effects None known.
Renal Impairment: Pediatric Avoid Concomitant Use
Infants, Children, and Adolescents: There are no Avoid concomitant use of Ampicillin with any of the
dosage adjustments provided in the manufacturer’s following: BCG (Intravesical); Cholera Vaccine
labeling; however, the following adjustments have Increased Effect/Toxicity
been recommended (Aronoff 2007). Note: Renally Ampicillin may increase the levels/effects of: Metho-
adjusted dose recommendations are based on IM, trexate; Vitamin K Antagonists
IV doses of 100 to 200 mg/kg/day divided every 6
hours: IM, IV: The levels/effects of Ampicillin may be increased by:
GFR 30 to 50 mL/minute/1.73 m2: 35 to 50 mg/kg/ Acemetacin; Allopurinol; Probenecid
dose every 6 hours Decreased Effect
GFR 10 to 29 mL/minute/1.73 m2: 35 to 50 mg/kg/ Ampicillin may decrease the levels/effects of: Atenolol;
dose every 8 to 12 hours BCG (Intravesical); BCG Vaccine (Immunization);
GFR <10 mL/minute/1.73 m2: 35 to 50 mg/kg/dose Cholera Vaccine; Lactobacillus and Estriol; Mycophe-
every 12 hours nolate; Sodium Picosulfate; Typhoid Vaccine
Intermittent hemodialysis: 35 to 50 mg/kg/dose
every 12 hours The levels/effects of Ampicillin may be decreased by:
Peritoneal dialysis (PD): 35 to 50 mg/kg/dose every Chloroquine; Lanthanum; Tetracyclines
12 hours Food Interactions Food decreases ampicillin absorp-
Continuous renal replacement therapy (CRRT): 35 tion rate; may decrease ampicillin serum concentration.
to 50 mg/kg/dose every 6 hours Management: Take at equal intervals around-the-clock,
Hepatic Impairment: Pediatric There are no dos- preferably on an empty stomach (30 minutes before or
age adjustments provided in the manufacturer’s label- 2 hours after meals). Maintain adequate hydration,
ing. unless instructed to restrict fluid intake.
Mechanism of Action Inhibits bacterial cell wall syn- Dietary Considerations Take on an empty stomach
thesis by binding to one or more of the penicillin-binding 30 minutes before or 2 hours after meals. Some prod-
proteins (PBPs) which in turn inhibits the final ucts may contain sodium.
133
AMPICILLIN
Pharmacodynamics/Kinetics infections where beta-lactamase-producing staphylo-

Half-life Elimination cocci and beta-lactamase-producing Bacteroides are
Neonates: present
PNA 2 to 7 days: 4 hours Use Bacterial infections: Treatment of susceptible
PNA 8 to 14 days: 2.8 hours bacterial infections involved with skin and skin struc-
PNA 15 to 30 days: 1.7 hours ture, intra-abdominal infections, gynecological infec-
Children and Adults: 1 to 1.8 hours (Bergan 1978) tions; spectrum is that of ampicillin plus organisms
Anuric patients: 8 to 20 hours producing beta-lactamases such as S. aureus, H. influ-
Time to Peak Serum concentration: Oral: Within 1 to 2 enzae, E. coli, Klebsiella, Acinetobacter, Enterobacter,
hours and anaerobes
Pregnancy Risk Factor B Local Anesthetic/Vasoconstrictor Precautions
Pregnancy Considerations Adverse events have not No information available to require special precautions
been observed in animal reproduction studies. Ampicil- Effects on Dental Treatment Prolonged use of pen-
lin crosses the placenta, providing detectable concen- icillins may lead to development of oral candidiasis (see
trations in the cord serum and amniotic fluid (Bolognese Dental Health Professional Considerations)
1968; Fisher 1967; MacAulay 1966). Maternal use of Effects on Bleeding No information available to
ampicillin has generally not resulted in an increased risk require special precautions
of birth defects (Aselton 1985; Czeizel 2001b; Heinonen Adverse Reactions Also see Ampicillin.
1977; Jick 1981; Puhó 2007). Ampicillin is recom- >10%: Local: Pain at injection site (IM; 16%)
mended for use in pregnant women for the manage- 1% to 10%:
ment of preterm prelabor rupture of membranes Cardiovascular: Thrombophlebitis (3%), phlebitis (1%)
(PROM) and for the prevention of early-onset group B Dermatologic: Skin rash (<2%)
streptococcal (GBS) disease in newborns. Ampicillin Gastrointestinal: Diarrhea (3%)
may also be used in certain situations prior to vaginal Local: Pain at injection site (IV; 3%)
delivery in women at high risk for endocarditis (ACOG <1%, postmarketing, and/or case reports: Abdominal
120 2011; ACOG 188 2018; ACOG 485 2011; CDC distention, abdominal pain, acute generalized exan-
[RR-10] 2010). thematous pustulosis, agranulocytosis, anaphylactic
shock, anaphylaxis, anemia, angioedema, basophilia,
The volume of distribution of ampicillin is increased
candidiasis, casts in urine (hyaline), chest pain, chills,
during pregnancy and the half-life is decreased. As a
cholestasis, cholestatic hepatitis, cholestatic jaundice,
result, serum concentrations in pregnant patients are
Clostridioides (formerly Clostridium) difficile-associ-
approximately 50% of those in nonpregnant patients
ated diarrhea, constriction of the pharynx, convul-
receiving the same dose. Higher doses may be needed
sions, decreased hematocrit, decreased hemoglobin,
during pregnancy. Although oral absorption is not
decreased neutrophils, decreased red blood cells,
altered during pregnancy, oral ampicillin is poorly
decreased serum albumin, decreased serum total
absorbed during labor (Philipson 1977; Philipson
protein, dermatitis, dizziness, drowsiness, dyspepsia,
1978; Wasz-Höckert 1970).
dyspnea, dysuria, edema, eosinophilia, epistaxis,
Breastfeeding Considerations Ampicillin is present erythema, erythema multiforme, erythrocyturia, exfo-
in breast milk. The manufacturer recommends that
liative dermatitis, facial swelling, fatigue, flatulence,
caution be exercised when administering ampicillin to
gastritis, glossitis, hairy tongue, headache, hemolytic
breastfeeding women. Due to the low concentrations in
anemia, hepatic insufficiency, hepatitis, hyperbilirubi-
human milk, minimal toxicity would be expected in the nemia, hypersensitivity reaction, immune thrombocy-
breastfed infant. Nondose-related effects could include topenia, increased blood urea nitrogen, increased
modification of bowel flora and allergic sensitization. lactate dehydrogenase, increased liver enzymes,
Dosage Forms: US increased monocytes, increased serum alkaline phos-
Capsule, Oral: phatase, increased serum ALT, increased serum AST,
Generic: 500 mg increased serum creatinine, injection site reaction,
Solution Reconstituted, Injection: interstitial nephritis, jaundice, leukopenia, lymphocyto-
Generic: 125 mg (1 ea); 250 mg (1 ea); 500 mg (1 penia, lymphocytosis (abnormal), malaise, melena,
ea); 1 g (1 ea); 2 g (1 ea) mucous membrane bleeding, nausea, positive direct
Solution Reconstituted, Injection [preservative free]: Coombs test, pruritus, pseudomembranous colitis,
Generic: 125 mg (1 ea); 250 mg (1 ea); 500 mg (1 sedation, Stevens-Johnson syndrome, stomatitis, sub-
ea); 1 g (1 ea); 2 g (1 ea); 10 g (1 ea) sternal pain, thrombocythemia, thrombocytopenia,
Solution Reconstituted, Intravenous: toxic epidermal necrolysis, urinary retention, urticaria,
Generic: 1 g (1 ea); 2 g (1 ea) vomiting
Solution Reconstituted, Intravenous [preservative Dental Usual Dosage Severe orofacial infections:
free]: Adults: IM, IV: 1000 to 2000 mg ampicillin (1500 to
Generic: 2 g (1 ea); 10 g (1 ea) 3000 mg Unasyn) every 6 hours (maximum: 8 g ampi-
cillin/day, 12 g Unasyn)
Ampicillin and Sulbactam Dosing
(am pi SIL in & SUL bak tam) Adult & Geriatric Unasyn (ampicillin/sulbactam) is a
combination product. Note: Dosage recommenda-
Related Information tions are expressed as grams of ampicillin/sulbac-
Ampicillin on page 130 tam combination.
Brand Names: US Unasyn Susceptible infections: IM, IV: 1.5 to 3 g every 6
Generic Availability (US) Yes hours (maximum: 12 g ampicillin/sulbactam daily)
Pharmacologic Category Antibiotic, Penicillin Acute bacterial rhinosinusitis, severe infection
Dental Use Parenteral beta-lactamase-resistant anti- requiring hospitalization (off-label use): IV: 1.5
biotic combination to treat more severe orofacial to 3 g every 6 hours for 5 to 7 days (Chow 2012)
134
AMPICILLIN AND SULBACTAM
Amnionitis, cholangitis, diverticulitis, endomyo- on dialysis days): 1.5 to 3 g every 12 to 24 hours

metritis (with doxycycline), endophthalmitis, epi- (Heintz 2009). Note: Dosing dependent on the
didymitis/orchitis, liver abscess (with assumption of 3 times weekly, complete IHD ses-
metronidazole), or peritonitis: IV: 3 g every 6 sions.
hours Continuous renal replacement therapy (CRRT): Drug
Bite wounds (animal/human) (off-label use): IV: 1.5 clearance is highly dependent on the method of renal
to 3 g every 6 hours (human bites) or every 6 to 8 replacement, filter type, and flow rate. Appropriate
hours (animal bites) (IDSA [Stevens 2014]) dosing requires close monitoring of pharmacologic
Endocarditis, treatment (off-label use): Enterococ- response, signs of adverse reactions due to drug
cus (native or prosthetic valve; beta-lactamase pro- accumulation, as well as drug levels in relation to
ducing strains resistant to penicillin/susceptible to target trough (if appropriate). The following are gen-
aminoglycoside and vancomycin): IV: 3 g every 6 eral recommendations only (based on dialysate flow/
hours with a concomitant aminoglycoside for 6 ultrafiltration rates of 1 to 2 L/hour and minimal
weeks (AHA [Baddour 2015]) residual renal function) and should not supersede
Intravascular catheter-associated bloodstream clinical judgment (Heintz 2009; Trotman 2005):
infection, Acinetobacter spp (off-label use) (IDSA CVVH: Initial: 3 g; maintenance: 1.5 to 3 g every 8 to
2009): IV: 3 g every 6 hours 12 hours
Orbital cellulitis: IV: 3 g every 6 hours CVVHD: Initial: 3 g; maintenance: 1.5 to 3 g every 8
Osteomyelitis (diabetic foot) (Lipsky 2004): IV: 3 g hours
every 6 hours CVVHDF: Initial: 3 g; maintenance: 1.5 to 3 g every
Pelvic inflammatory disease (alternative to pre- 6 to 8 hours
ferred therapy): IV: 3 g every 6 hours with doxycy- Hepatic Impairment: Adult There is no dosage
cline oral or IV; transition from parenteral to oral adjustment provided in the manufacturer’s labeling.
therapy can usually be initiated within 24 to 48 hours Pediatric Note: Unasyn (ampicillin/sulbactam) is a
of clinical improvement for a total treatment duration combination product formulated in a 2:1 ratio (eg,
of 14 days; if tubo-ovarian abscess is present, at each 3 g vial contains 2 g of ampicillin and 1 g of
least 24 hours of inpatient observation is recom- sulbactam); review dosing units carefully. Dosage
mended (CDC [Workowski 2015). recommendations are expressed as either mg of the
Peritonitis associated with CAPD: Intraperitoneal: ampicillin component or as total grams of the ampi-
Intermittent: 3 g added to one exchange every 12 cillin/sulbactam combination within the dosing field;
hours; allow to dwell for at least 6 hours (Blackwell review dosing units in each indication carefully.
1990; Li 2010) General dosing, susceptible infection: Infants, Chil-
Continuous: Loading dose: 1.5 g per liter of dialy- dren, and Adolescents:
sate; maintenance dose: 150 mg per liter of dialy- Mild to moderate infection: IV: 100 to 200 mg ampi-
sate (Li 2010) cillin/kg/day divided every 6 hours; maximum dose:
Pneumonia, community-acquired (off-label use): 2,000 mg ampicillin/dose (Red Book [AAP 2018]);
IV: 1.5 to 3 g every 6 hours for ≥5 days (Geckler may also be administered IM (Bradley 2018)
1994; Majcher-Peszynska 2014; Mandell 2007; Severe infection (eg, meningitis, resistant Strepto-
Rossoff 1995). Note: In ICU patients, use in combi- coccus pneumonia): IV: 200 to 400 mg ampicillin/
nation with azithromycin or a fluoroquinolone (Man- kg/day divided every 6 hours; maximum dose:
dell 2007). 2,000 mg ampicillin/dose (Bradley 2018; Red Book
Pneumonia, hospital-acquired or ventilator-asso- [AAP 2018]); may also be administered IM (Brad-
ciated due to Acinetobacter (off-label use): IV: 3 g ley 2018)
every 6 hours (Zalts 2016); duration of therapy is 7 Endocarditis, treatment: Children and Adolescents:
days (may consider shorter or longer duration IV: 200 to 300 mg ampicillin/kg/day divided every 4
depending on rate of clinical improvement) to 6 hours; maximum dose: 2,000 mg ampicillin/
(Kalil 2016) dose; may use in combination with gentamicin, van-
Surgical (perioperative) prophylaxis (off-label comycin, and/or rifampin (optional; dependent upon
use): IV: 3 g within 60 minutes prior to surgical organism) for at least 4 to 6 weeks; some organisms
incision. Doses may be repeated in 2 hours if proce- may require longer duration (AHA [Baltimore 2015])
dure is lengthy or if there is excessive blood loss Intra-abdominal infection, complicated: Infants,
(Bratzler 2013). Children, and Adolescents: IV: 200 mg ampicillin/
Surgical site infections (intestinal or GI tract) (off- kg/day divided every 6 hours; Note: Due to high
label use): IV: 3 g every 6 hours; in combination with rates of E. coli resistance, not recommended for
gentamicin or tobramycin (IDSA [Stevens 2014]) the treatment of community-acquired intra-abdomi-
Urinary tract infections, pyelonephritis: IV: 3 g nal infections (IDSA [Solomkin 2010])
every 6 hours for 14 days Pelvic inflammatory disease: Adolescents: IV: 3 g
Renal Impairment: Adult Note: Estimation of renal ampicillin/sulbactam every 6 hours with doxycycline
function for the purpose of drug dosing should be done (CDC [Workowski 2015])
using the Cockcroft-Gault formula. Dosage recom- Rhinosinusitis, severe infection requiring hospi-
mendations are expressed as grams of ampicillin/ talization: Children and Adolescents: IV: 200 to
sulbactam combination: 400 mg ampicillin/kg/day divided every 6 hours for
CrCl ≥30 mL/minute/1.73 m2: No dosage adjustment 10 to 14 days; maximum dose: 2,000 mg ampicillin/
necessary. dose (IDSA [Chow 2012])
CrCl 15 to 29 mL/minute/1.73 m2: 1.5 to 3 g every 12 Skin and skin structure infection: Children and
hours Adolescents: IV: 200 mg ampicillin/kg/day divided
CrCl 5 to 14 mL/minute/1.73 m2: 1.5 to 3 g every 24 every 6 hours for up to 14 days; maximum dose:
hours 2,000 mg ampicillin/dose
End stage renal disease (ESRD) on intermittent Surgical prophylaxis: Children and Adolescents: IV:
hemodialysis (IHD) (administer after hemodialysis 50 mg ampicillin/kg/dose within 60 minutes prior to
135
AMPICILLIN AND SULBACTAM
procedure; may repeat in 2 hours if lengthy proce- Decreased Effect

dure or excessive blood loss; maximum dose: Ampicillin and Sulbactam may decrease the levels/
2,000 mg ampicillin/dose (Bratzler 2013) effects of: Atenolol; BCG (Intravesical); BCG Vaccine
Renal Impairment: Pediatric (Immunization); Cholera Vaccine; Lactobacillus and
Children and Adolescents: IV: Estriol; Mycophenolate; Sodium Picosulfate; Typhoid
CrCl ≥30 mL/minute/1.73 m2: No dosage adjustment Vaccine
required. The levels/effects of Ampicillin and Sulbactam may be
CrCl 15 to 29 mL/minute/1.73 m2: Administer every decreased by: Chloroquine; Lanthanum; Tetracyclines
12 hours. Dietary Considerations Some products may contain
CrCl 5 to 14 mL/minute/1.73 m2: Administer every 24 sodium.
hours. Pharmacodynamics/Kinetics
Hepatic Impairment: Pediatric There are no dos- Half-life Elimination Sulbactam: Children 1 to 12
age adjustments provided in the manufacturer’s label- years (normal renal function): Mean range: ~0.7 to
ing. 0.9 hours (Nahata 1999); Adults (normal renal func-
Mechanism of Action Inhibits bacterial cell wall syn- tion): 1 to 1.3 hours; Note: Elimination kinetics of both
thesis by binding to one or more of the penicillin-binding ampicillin and sulbactam are similarly affected in
proteins (PBPs) which in turn inhibits the final trans- patients with renal impairment, therefore, the blood
peptidation step of peptidoglycan synthesis in bacterial concentration ratio is expected to remain constant
cell walls, thus inhibiting cell wall biosynthesis. Bacteria regardless of renal function.
eventually lyse due to ongoing activity of cell wall Pregnancy Considerations
autolytic enzymes (autolysins and murein hydrolases) Both ampicillin and sulbactam cross the placenta.
while cell wall assembly is arrested. The addition of
sulbactam, a beta-lactamase inhibitor, to ampicillin
pharmacokinetic properties of ampicillin/sulbactam may
extends the spectrum of ampicillin to include some
be altered (Chamberlain 1993). Ampicillin/sulbactam
beta-lactamase-producing organisms.
may be considered for prophylactic use prior to cesar-
Contraindications Hypersensitivity (eg, anaphylaxis ean delivery (consult current recommendations) (ACOG
or Stevens-Johnson syndrome) to ampicillin, sulbac- 199 2018).
tam, or to other beta-lactam antibacterial drugs (eg,
penicillins, cephalosporins), or any component of the
Ampicillin and sulbactam are present in breast milk.
formulations; history of cholestatic jaundice or hepatic A review article notes the exposure of ampicillin and
dysfunction associated with ampicillin/sulbactam sulbactam to a breastfeeding infant would be ~1% to
Warnings/Precautions Dosage adjustment may be 2% of a typical adult dose (Foulds 1986).
necessary in patients with renal impairment. Serious The manufacturer recommends that caution be used if
and occasionally severe or fatal hypersensitivity (ana- administering to breastfeeding women. Ampicillin is
phylactic) reactions have been reported in patients on considered compatible with breastfeeding when used
penicillin therapy, especially with a history of beta- in usual recommended doses. In general, antibiotics
lactam hypersensitivity, history of sensitivity to multiple that are present in breast milk may cause nondose-
allergens. Patients with a history of penicillin hyper- related modification of bowel flora. Monitor infants for
sensitivity have experienced severe reactions when GI disturbances (WHO 2002).
treated with cephalosporins. Before initiating therapy, Also refer to the Ampicillin monograph.
carefully investigate previous penicillin, cephalosporin, Dosage Forms: US
or other allergen hypersensitivity. If an allergic reaction Solution Reconstituted, Injection:
occurs, discontinue and institute appropriate therapy. Unasyn: 3 g: Ampicillin 2 g and sulbactam 1 g (1 ea);
Hepatitis and cholestatic jaundice have been reported 15 g: Ampicillin 10 g and sulbactam 5 g (1 ea); 1.5 g:
(including fatalities). Toxicity is usually reversible. Mon- Ampicillin 1 g and sulbactam 0.5 g (1 ea)
itor hepatic function at regular intervals in patients with Generic: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g (1
hepatic impairment. High percentage of patients with ea); 15 g: Ampicillin 10 g and sulbactam 5 g (1 ea);
infectious mononucleosis have developed rash during 3 g: Ampicillin 2 g and sulbactam 1 g (1 ea)
therapy with ampicillin; ampicillin-class antibacterials Solution Reconstituted, Injection [preservative free]:
are not recommended in these patients. Appearance Generic: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g (1
of a rash should be carefully evaluated to differentiate a ea); 15 g: Ampicillin 10 g and sulbactam 5 g (1 ea);
nonallergic ampicillin rash from a hypersensitivity reac- 3 g: Ampicillin 2 g and sulbactam 1 g (1 ea)
tion. Prolonged use may result in fungal or bacterial Solution Reconstituted, Intravenous:
superinfection, including C. difficile-associated diarrhea Generic: 1.5 g: Ampicillin 1 g and sulbactam 0.5 g (1
(CDAD) and pseudomembranous colitis; CDAD has ea); 15 g: Ampicillin 10 g and sulbactam 5 g (1 ea);
been observed >2 months postantibiotic treatment. 3 g: Ampicillin 2 g and sulbactam 1 g (1 ea)
Drug Interactions Solution Reconstituted, Intravenous [preservative
Metabolism/Transport Effects None known. free]:
Avoid Concomitant Use Generic: 15 g: Ampicillin 10 g and sulbactam 5 g
Avoid concomitant use of Ampicillin and Sulbactam (1 ea)
with any of the following: BCG (Intravesical); Cholera Dental Health Professional Considerations In
Vaccine maxillary sinus, anterior nasal cavity, and deep neck
Increased Effect/Toxicity infections, beta-lactamase-producing staphylococci and
Ampicillin and Sulbactam may increase the levels/ beta-lactamase-producing Bacteroides usually are
present. In these situations, antibiotics that resist the
effects of: Methotrexate; Vitamin K Antagonists
beta-lactamase enzyme should be administered. Amox-
The levels/effects of Ampicillin and Sulbactam may be icillin and clavulanic acid is administered orally for
increased by: Acemetacin; Allopurinol; Probenecid moderate infections. Ampicillin sodium and sulbactam
136
ANAGRELIDE
sodium (Unasyn) is administered parenterally for more reduce associated symptoms (including thrombohemor-
severe infections. rhagic events)
Amyl Nitrite (AM il NYE trite)
Pharmacologic Category Antianginal Agent; Anti- related to dental treatment: Patients may experience
dote; Vasodilator orthostatic hypotension as they stand up after treat-
Local Anesthetic/Vasoconstrictor Precautions ment; especially if lying in dental chair for extended
No information available to require special precautions periods of time. Use caution with sudden changes in
Effects on Dental Treatment Key adverse event(s) position during and after dental treatment.
related to dental treatment: Patients may experience Effects on Bleeding Anagrelide causes dose-related
orthostatic hypotension as they stand up after treat- reduction in platelet production and could affect normal
ment; especially if lying in dental chair for extended clotting; hemorrhage has been reported. Medical con-
periods of time. Use caution with sudden changes in sult is suggested for patients under active treatment
position during and after dental treatment. with anagrelide.
Effects on Bleeding No information available to Adverse Reactions
require special precautions Frequency not always defined; reactions similar in adult
and pediatric patients unless otherwise noted.
Cardiovascular: Palpitations (26%), edema (21%),
Cardiovascular: Cerebral ischemia, facial flushing,
peripheral edema (9%), chest pain (8%), tachycardia
hypotension, orthostatic hypotension, shock, syncope,
(8%), angina pectoris (1% to <5%), cardiac arrhyth-
tachycardia, vasodilatation
mia (1% to <5%), cardiac failure (1% to <5%), hyper-
Central nervous system: Dizziness, headache, tension (1% to <5%), orthostatic hypotension (1% to
increased intracranial pressure, restlessness <5%), syncope (1% to <5%), vasodilatation (1% to
Dermatologic: Dermatitis, diaphoresis, pallor, skin irri- <5%), atrial fibrillation, cardiomegaly, cardiomyop-
tation athy, cerebrovascular accident, complete atrioven-
Gastrointestinal: Fecal incontinence, nausea, vomiting tricular block, decreased diastolic pressure
Genitourinary: Urinary incontinence (pediatric patients), increased heart rate (pediatric
Hematologic & oncologic: Hemolytic anemia, methemo- patients), myocardial infarction, pericardial effusion,
globinemia systolic hypotension (pediatric patients)
Neuromuscular & skeletal: Weakness Central nervous system: Headache (44%), dizziness
Ophthalmic: Eye irritation, increased intraocular (15%), pain (15%), malaise (6%), paresthesia (6%),
pressure amnesia (1% to <5%), chills (1% to <5%), confusion
Mechanism of Action Relaxes vascular smooth (1% to <5%), depression (1% to <5%), drowsiness
muscle; decreases venous ratios and arterial blood (1% to <5%), insomnia (1% to <5%), migraine (1% to
pressure; reduces left ventricular work; decreases myo- <5%), nervousness (1% to <5%), fatigue (pediatric
cardial O2 consumption. When used for cyanide poison- patients)
ing, amyl nitrite promotes the formation of Dermatologic: Skin rash (8%), pruritus (6%), alopecia
methemoglobin which competes with cytochrome oxi- (1% to <5%)
dase for the cyanide ion. Cyanide combines with meth- Gastrointestinal: Diarrhea (26%), nausea (17%),
emoglobin to form cyanomethemoglobin, thereby abdominal pain (16%), flatulence (10%), vomiting
freeing the cytochrome oxidase and allowing aerobic (10%), anorexia (8%), dyspepsia (5%), constipation
metabolism to continue. (1% to <5%), gastritis (1% to <5%), gastrointestinal
Pharmacodynamics/Kinetics hemorrhage (1% to <5%), pancreatitis
Onset of Action Angina: Within 30 seconds Hematologic & oncologic: Anemia (1% to <5%), bruise
Duration of Action Angina: 3-15 minutes; Pharma- (1% to <5%), hemorrhage (1% to <5%), thrombocy-
cologic provocation of latent left ventricular outflow topenia (1% to <5%)
tract (LVOT) gradient in hypertrophic cardiomyopathy Hepatic: Increased liver enzymes (1% to <5%)
(HCM): ~30 seconds (Reagan, 2005) Neuromuscular & skeletal: Weakness (23%), back
Half-life Elimination Amyl nitrite: <1 hour; Methemo- pain (6%), arthralgia (1% to <5%), myalgia (1% to
globin: 1 hour <5%), muscle cramps (pediatric patients)
Pregnancy Risk Factor C Ophthalmic: Diplopia (1% to <5%), visual field defect
Pregnancy Considerations Animal reproduction (1% to <5%)
studies have not been conducted. Because amyl nitrite Otic: Tinnitus (1% to <5%)
significantly decreases systemic blood pressure and Renal: Hematuria (1% to <5%), renal failure (1%)
therefore blood flow to the fetus, use is contraindicated Respiratory: Dyspnea (12%), cough (6%), epistaxis
in pregnancy (per manufacturer). In addition, fetal (1% to <5%), flu-like symptoms (1% to <5%), pneu-
monia (1% to <5%), pleural effusion, pulmonary
hemoglobin may be more susceptible methemoglobin
hypertension, pulmonary fibrosis, pulmonary infil-
conversion (Valenzuela, 1986).
trates
Anagrelide (an AG gre lide) <1%, postmarketing, and/or case reports: Eosinophilic
pneumonitis, hepatotoxicity, hypersensitivity pneumo-
Brand Names: US Agrylin nitis, increased serum ALT (>3 x ULN), increased
Brand Names: Canada Agrylin serum AST (>3 x ULN), interstitial nephritis, interstitial
Pharmacologic Category Antiplatelet Agent; Phos- pneumonitis, leukocytosis, prolonged Q-T interval on
phodiesterase-3 Enzyme Inhibitor ECG, skin photosensitivity (pediatric patients), tor-
Use Thrombocythemia: Treatment of thrombocythemia sades de pointes, ventricular tachycardia
secondary to myeloproliferative disorders to reduce Mechanism of Action Anagrelide appears to inhibit
elevated platelets and the risk of thrombosis and to cyclic nucleotide phosphodiesterase and the release of
137
ANAGRELIDE
arachidonic acid from phospholipase, possibly by inhib- Hematologic & oncologic: Eosinophilia (RA: 9%),
iting phospholipase A2. It also causes a dose-related decreased white blood cell count (RA: 8%), change
reduction in platelet production, which results from in platelet count (RA; decreased: 2%
decreased megakaryocyte hypermaturation (disrupts Frequency not defined:
the postmitotic phase of maturation). Dermatologic: Skin rash (NOMID)
Pharmacodynamics/Kinetics Endocrine & metabolic: Hypercholesterolemia (RA)
Onset of Action Initial: Within 7 to 14 days; complete Respiratory: Upper respiratory tract infection (NOMID)
response (platelets ≤600,000/mm3): 4 to 12 weeks <1%, postmarketing, and/or case reports: Hepatitis
Duration of Action 6 to 24 hours; upon discontinua- (noninfectious), hypersensitivity reaction (including
tion, platelet count begins to rise within 4 days anaphylaxis, angioedema, pruritus, skin rash, urtica-
Half-life Elimination Anagrelide: 1.5 hours, similar ria), increased serum transaminases, metastases
data reported in pediatric patients 7 to 14 years; 3- (malignant lymphoma, malignant melanoma), oppor-
hydroxy anagrelide: 2.5 hours tunistic infection, thrombocytopenia (including severe)
Time to Peak Serum: 1 hour, similar data reported in Mechanism of Action Antagonist of the interleukin-1
pediatric patients 7 to 14 years (IL-1) receptor. Endogenous IL-1 is induced by inflam-
Pregnancy Considerations matory stimuli and mediates a variety of immunological
Data regarding use of anagrelide during pregnancy is responses, including degradation of cartilage (loss of
limited (Alkindi 2005; Birgegård 2018; Cornet 2017; proteoglycans) and stimulation of bone resorption.
Doubek 2004; Sobas 2009; Wright 2001).
Half-life Elimination Terminal: 4 to 6 hours; Severe
Thrombocythemia is associated with an increased risk renal impairment (CrCl <30 mL/minute): ~7 hours;
for adverse pregnancy outcomes including miscarriage, ESRD: 9.7 hours (Yang 2003)
stillbirth, and preeclampsia. When treatment for essen- Time to Peak SubQ: 3 to 7 hours
tial thrombocythemia is needed during pregnancy, other Pregnancy Considerations Information related to the
agents are currently preferred (Tefferi 2018). use of anakinra during pregnancy is limited (İlgen 2017;
Götestam Skorpen 2016; Makol 2011; Ostensen 2011;
Anakinra (an a KIN ra)
Youngstein 2017). Until additional information is avail-
able, anakinra should be discontinued prior to concep-
Related Information tion if possible; use may continue when other treatment
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis options are not effective (Götestam Skorpen 2016).
on page 1484 Women exposed to anakinra during pregnancy may
Brand Names: US Kineret contact the Organization of Teratology Information
Brand Names: Canada Kineret Services (OTIS), Rheumatoid Arthritis and Pregnancy
Pharmacologic Category Antirheumatic, Disease Study at 1-877-311-8972.
Modifying; Interleukin-1 Receptor Antagonist
Use Anastrozole (an AS troe zole)
Neonatal-onset multisystem inflammatory disease:
Treatment of neonatal-onset multisystem inflamma- Brand Names: US Arimidex
tory disease (NOMID). Brand Names: Canada Arimidex
Rheumatoid arthritis: Reduction in signs and symp- Pharmacologic Category Antineoplastic Agent, Aro-
toms and slowing the progression of structural dam- matase Inhibitor
age of moderately to severely active rheumatoid Use Breast cancer:
arthritis (RA) in patients 18 years and older who have First-line treatment of locally-advanced or metastatic
failed 1 or more disease-modifying antirheumatic breast cancer (hormone receptor-positive or unknown)
drugs (DMARDs). in postmenopausal women
Local Anesthetic/Vasoconstrictor Precautions Adjuvant treatment of early hormone receptor-positive
No information available to require special precautions breast cancer in postmenopausal women
Effects on Dental Treatment No significant effects or Treatment of advanced breast cancer in postmeno-
complications reported pausal women with disease progression following
Effects on Bleeding No information available to tamoxifen therapy
>10%: Effects on Dental Treatment Key adverse event(s)
Central nervous system: Headache (12% to 14%) related to dental treatment: Xerostomia (normal salivary
Gastrointestinal: Vomiting (NOMID: 14%) flow resumes upon discontinuation).
Immunologic: Antibody development (RA: 49%; neu- Effects on Bleeding No information available to
tralizing: 2%; no correlation of antibody development require special precautions
and adverse effects) Adverse Reactions
Infection: Infection (RA: 39%; serious infection: 2% to >10%:
3%; including cellulitis, pneumonia, and bone and Cardiovascular: Vasodilatation (25% to 36%), ische-
joint infections) mic heart disease (4%; 17% in patients with preex-
Local: Injection site reaction (RA: 71%; mild: 73%; isting ischemic heart disease), hypertension (2% to
moderate: 24%; severe: 2% to 3%; NOMID: 16%; 13%), angina pectoris (2%; 12% in patients with
mild: 76%; moderate: 24%) preexisting ischemic heart disease), edema (7%
Neuromuscular & skeletal: Arthralgia (NOMID: 12%) to 11%)
Respiratory: Nasopharyngitis (NOMID: 12%) Central nervous system: Fatigue (19%), mood disor-
Miscellaneous: Fever (NOMID: 12%) der (19%), headache (9% to 18%), pain (11% to
1% to 10%: 17%), depression (2% to 13%)
Gastrointestinal: Nausea (RA: 8%), diarrhea (RA: 7%) Dermatologic: Skin rash (6% to 11%)
138
ANDEXANET ALFA
Endocrine & metabolic: Hot flash (12% to 36%) Pharmacodynamics/Kinetics

Gastrointestinal: Gastrointestinal distress (29% to Onset of Action Onset of estradiol reduction: 70%
34%), nausea (11% to 20%), vomiting (8% to 13%) reduction after 24 hours; 80% after 2 weeks of therapy
Neuromuscular & skeletal: Weakness (13% to 19%), Duration of Action Duration of estradiol reduction: 6
arthritis (17%), arthralgia (2% to 15%), back pain days
(10% to 12%), ostealgia (6% to 12%), osteoporo- Half-life Elimination ~50 hours
sis (11%) Time to Peak Plasma: ~2 hours without food; 5 hours
Respiratory: Pharyngitis (6% to 14%), dyspnea (8% to with food
11%), increased cough (7% to 11%) Pregnancy Considerations
1% to 10%: Based on the mechanism of action and information from
Cardiovascular: Peripheral edema (5% to 10%), chest animal reproduction studies, anastrozole may cause
pain (5% to 7%), venous thrombosis (2% to 4%; fetal harm if exposure occurs during pregnancy.
including pulmonary embolism, thrombophlebitis, ret-
Evaluate pregnancy status prior to therapy. Females of
inal vein thrombosis), myocardial infarction (1%)
reproductive potential should use effective contracep-
Central nervous system: Insomnia (2% to 10%), dizzi-
tion during therapy and for at least 3 weeks after the last
ness (5% to 8%), paresthesia (5% to 7%), anxiety
anastrozole dose.
(2% to 6%), confusion (2% to 5%), drowsiness (2%
to 5%), malaise (2% to 5%), nervousness (2% to
5%), carpal tunnel syndrome (3%), hypertonia (3%), Andexanet Alfa (an DEX a net AL fa)
cerebrovascular insufficiency (2%), lethargy (1%)
Dermatologic: Alopecia (2% to 5%), pruritus (2% to Brand Names: US Andexxa
5%), diaphoresis (1% to 5%) Pharmacologic Category Antidote
Endocrine & metabolic: Hypercholesterolemia (9%), Use Reversal of anticoagulation from apixaban or
increased serum cholesterol (9%), weight gain (2% rivaroxaban: Reversal of anticoagulation in patients
to 9%), increased gamma-glutamyl transferase (2% treated with apixaban or rivaroxaban experiencing life-
to 5%), weight loss (2% to 5%) threatening or uncontrolled bleeding
Gastrointestinal: Constipation (7% to 9%), diarrhea Local Anesthetic/Vasoconstrictor Precautions
(7% to 9%), abdominal pain (6% to 9%), anorexia No information available to require special precautions
(5% to 8%), dyspepsia (7%), gastrointestinal disease Effects on Dental Treatment No significant effects or
(7%), xerostomia (4% to 6%) complications reported
Genitourinary: Mastalgia (2% to 8%), urinary tract Effects on Bleeding FDA has issued a black box
infection (2% to 8%), pelvic pain (5% to 7%), vulvo- warning on the possibility of andexanet alfa induc-
vaginitis (6%), vaginal dryness (1% to 5%), vaginal ing thromboembolic events as a reversal agent to
hemorrhage (1% to 5%), vaginal discharge (4%), apixaban (Eliquis) and rivaroxaban (Xarelto). It is
vaginitis (4%), leukorrhea (2% to 3%) anticipated its use will be in a medical emergency
and not in the dental setting.
Hematologic & oncologic: Lymphedema (10%), breast
neoplasm (5%), neoplasm (5%), anemia (2% to 5%), Adverse Reactions
leukopenia (2% to 5%), tumor flare (3%) >10%:
Immunologic: Antibody development (6% to 17%)
Hepatic: Increased serum alkaline phosphatase (2%
Miscellaneous: Infusion related reaction (18%)
to 5%), increased serum ALT (2% to 5%), increased
1% to 10%:
serum AST (2% to 5%)
Cardiovascular: Deep vein thrombosis (6%), ischemic
Infection: Infection (2% to 9%)
stroke (5%), acute myocardial infarction (3%), pul-
Neuromuscular & skeletal: Bone fracture (1% to 10%),
monary embolism (3%), cardiogenic shock (2%),
arthrosis (7%), myalgia (2% to 6%), neck pain (2% to
cardiac failure (1%)
5%), pathological fracture (2% to 5%)
Genitourinary: Urinary tract infection (≥5%)
Ophthalmic: Cataract (6%) Respiratory: Pneumonia (≥5%), acute respiratory fail-
Respiratory: Flu-like symptoms (2% to 7%), sinusitis ure (1%)
(2% to 6%), bronchitis (2% to 5%), rhinitis (2% to 5%) Frequency not defined: Cardiovascular: Arterial throm-
Miscellaneous: Accidental injury (2% to 10%), cyst boembolism, venous thromboembolism
(5%), fever (2% to 5%) <1%, postmarketing, and/or case reports: Coronary
<1%, postmarketing, and/or case reports: Anaphylaxis, thrombosis, intracardiac thrombus, nonsustained ven-
angioedema, cerebral infarction, cerebral ischemia, tricular tachycardia
decreased bone mineral density, dermal ulcer, endo- Mechanism of Action Andexanet alfa binds and
metrial carcinoma, erythema multiforme, hepatitis, sequesters the FXa inhibitors rivaroxaban and apixa-
hepatomegaly, hypercalcemia, hypersensitivity angii- ban. In addition, andexanet alfa inhibits the activity of
tis (including anaphylactoid purpura [IgA vasculitis]), Tissue Factor Pathway Inhibitor (TFPI), increasing tis-
increased serum bilirubin, jaundice, joint stiffness, sue factor-initiated thrombin generation.
pulmonary embolism, retinal thrombosis, skin blister, Pharmacodynamics/Kinetics
skin lesion, Stevens-Johnson syndrome, tenosynovitis Onset of Action Rapid (Lu 2013)
(stenosing), urticaria Half-life Elimination Note: Clinical trials have shown
Mechanism of Action Anastrozole is a potent and that when andexanet alfa is administered to patients
selective nonsteroidal aromatase inhibitor. By inhibiting taking apixaban or rivaroxaban, anti-factor Xa activity
aromatase, the conversion of androstenedione to increases to placebo levels ~2 hours after completion
estrone, and testosterone to estradiol, is prevented, of the infusion (Connolly 2016; Siegel 2015). However,
thereby decreasing tumor mass or delaying progression elevation of tissue factor-initiated thrombin generation
in patients with tumors responsive to hormones. Anas- above pretreatment baseline occurs within 2 minutes
trozole causes an 85% decrease in estrone sulfate after administration and is sustained above placebo
levels. for at least 22 hours after administration.
139
ANDEXANET ALFA
Pharmacokinetic half-life: related reaction, prolonged prothrombin time, pruritus,

Generation 1 product: Low dose: 4.3 (range: 3.3 to right bundle branch block, rigors, seizure, sinus
11.9) hours; High dose: 4 (range: 2 to 5.7) hours arrhythmia, skin rash, thrombocytopenia, thrombo-
Generation 2 product: Low dose: 3.3 (range: 2.3 to 4) phlebitis, urticaria, ventricular premature contractions,
hours; High dose: 2.7 (range: 1.9 to 3.4) hours visual disturbance
Pharmacodynamic half-life: ~1 hour (Siegal 2015). Mechanism of Action Noncompetitive inhibitor of 1,3-
Pregnancy Considerations Animal reproduction beta-D-glucan synthase resulting in reduced formation
studies have not been conducted. of 1,3-beta-D-glucan, an essential polysaccharide com-
prising 30% to 60% of Candida cell walls (absent in
mammalian cells); decreased glucan content leads to
Anidulafungin (ay nid yoo la FUN jin)
osmotic instability and cellular lysis
Related Information Pharmacodynamics/Kinetics
Half-life Elimination Terminal: 40-50 hours
Fungal Infections on page 1538
Pregnancy Considerations Adverse effects were
Brand Names: US Eraxis
observed in animal reproduction studies. Other agents
Brand Names: Canada Eraxis are currently preferred for the treatment of Candida
Pharmacologic Category Antifungal Agent, Paren- infections in pregnant women (IDSA [Pappas 2016]).
teral; Echinocandin
Use Treatment of candidemia, esophageal candidiasis,
and other forms of Candida infections (intra-abdominal Antihemophilic Factor (Human)
abscess and peritonitis) (an tee hee moe FIL ik FAK tor HYU man)
Local Anesthetic/Vasoconstrictor Precautions Brand Names: US Hemofil M; Koate; Koate-DVI;
No information available to require special precautions Monoclate-P
Effects on Dental Treatment No significant effects or Brand Names: Canada Hemofil M
complications reported Pharmacologic Category Antihemophilic Agent;
Effects on Bleeding No information available to Blood Product Derivative
require special precautions Use Hemophilia A: Control and prevention of bleeding
Adverse Reactions episodes in patients with hemophilia A (classic hemo-
>10%: philia); perioperative management of hemophilia A.
Cardiovascular: Hypotension (15%), hypertension Limitations of use: Not indicated for the treatment of von
(12%), peripheral edema (11%) Willebrand disease.
Central nervous system: Insomnia (15%) Local Anesthetic/Vasoconstrictor Precautions
Endocrine & metabolic: Hypokalemia (≤25%), hypo- No information available to require special precautions
magnesemia (12%) Effects on Dental Treatment No significant effects or
Gastrointestinal: Nausea (7% to 24%), diarrhea (9% to complications reported
18%), vomiting (7% to 18%) Effects on Bleeding Following large doses, an
Genitourinary: Urinary tract infection (15%) increased bleeding tendency has rarely been reported.
Hepatic: Increased serum alkaline phosphatase (12%) Mild thrombocytopenia has been reported. Due to
Infection: Bacteremia (18%) underlying hemophilia and complications of thrombotic
Respiratory: Dyspnea (12%) events, a medical consultation is warranted.
Miscellaneous: Fever (9% to 18%) Adverse Reactions <1%, postmarketing, and/or case
2% to 10%: reports: Acute hemolytic anemia, anaphylaxis (rare),
Cardiovascular: Deep vein thrombosis (10%), chest blurred vision, chest tightness, chills, drowsiness, fever,
pain (5%) headache, hemorrhagic diathesis, hypersensitivity
Central nervous system: Confusion (8%), headache reaction (rare), increased factor VIII inhibitors,
(8%), depression (6%) increased serum fibrinogen, jitteriness, lethargy, nau-
Dermatologic: Decubitus ulcer (5%) sea, pain at injection site, stomach discomfort, tingling
Endocrine & metabolic: Hypoglycemia (7%), dehydra- sensation, urticaria, vasomotor symptoms (with rapid
tion (6%), hyperglycemia (6%), hyperkalemia (6%) infusion), vomiting
Gastrointestinal: Constipation (8%), dyspepsia (7%), Mechanism of Action Protein (factor VIII) in normal
abdominal pain (6%), oral candidiasis (5%) plasma which is necessary for clot formation and main-
Hematologic & oncologic: Anemia (8% to 9%), leuko- tenance of hemostasis; activates factor X in conjunction
cytosis (5% to 8%), thrombocythemia (6%) with activated factor IX; activated factor X converts
Hepatic: Increased serum transaminases (≤5%) prothrombin to thrombin, which converts fibrinogen to
Infection: Sepsis (7%) fibrin, and with factor XIII forms a stable clot
Neuromuscular & skeletal: Back pain (5%) Pharmacodynamics/Kinetics
Renal: Increased serum creatinine (5%) Half-life Elimination Mean: 14.8 to 17.5 hours
Respiratory: Pleural effusion (10%), cough (7%), Pregnancy Considerations Pregnant hemophilia A
pneumonia (6%), respiratory distress (6%) carriers may have an increased bleeding risk following
<2%, postmarketing, and/or case reports: Anaphylactic abortion, invasive procedures, miscarriage, and deliv-
shock, anaphylaxis, angioedema, atrial fibrillation, ery; close surveillance is recommended. Factor VIII
blood coagulation disorder, blurred vision, broncho- levels should be monitored at the first antenatal visit,
spasm, cholestasis, clostridium infection, diaphoresis, once or twice during the third trimester, prior to surgical
dizziness, ECG abnormality (including ECG changes or invasive procedures, and at delivery. Although factor
– prolonged Q-T interval), erythema, eye pain, flush- VIII concentrations increase in pregnant patients, factor
ing, hepatic insufficiency, hepatic necrosis, hepatitis, VIII replacement is recommended if concentrations are
hot flash, increased amylase, increased blood urea <0.5 IU/mL and any of the following occur: need for
nitrogen, increased creatine phosphokinase, invasive procedures (including delivery), spontaneous
increased gamma-glutamyl transferase, increased miscarriage, insertion and removal of epidural cathe-
serum bilirubin, increased serum lipase, infusion ters, or active bleeding. Hemostatic factor VIII
140
ANTIHEMOPHILIC FACTOR (RECOMBINANT [FC FUSION PROTEIN])
concentrations should be maintained for at least 3 to 5 Hepatic: Increased liver enzymes (in patients previ-
days following invasive procedures or postpartum. If a ously exposed to factor VIII products: 1%)
replacement product is indicated, a recombinant prod- Hypersensitivity: Hypersensitivity reaction (2%)
uct is preferred (NHF 2017; RCOG [Pavord 2017]; WFH Local: Injection site reaction (1% to 7%)
[Srivastava 2013]). Neuromuscular & skeletal: Weakness (5% to 7%),
back pain (≤3%; more common in children)
Otic: Otic infection (≤5%)
Antihemophilic Factor (Recombinant) Respiratory: Pharyngolaryngeal pain (9%), upper res-
(an tee hee moe FIL ik FAK tor ree KOM be nant)
piratory tract infection (9%), nasal congestion (8%),
Brand Names: US Advate; Afstyla; Helixate FS; rhinorrhea (5%)
Kogenate FS; Kogenate FS Bio-Set [DSC]; Kovaltry; Miscellaneous: Limb injury (10%)
Novoeight; Nuwiq; Recombinate; Xyntha; Xyntha Solo- <1%, postmarketing, and/or case reports: Anaphylaxis,
fuse angioedema, cold extremities, cyanosis, dysgeusia,
Brand Names: Canada Advate; Afstyla; Helixate FS; edema, epistaxis, erythema, facial edema, facial flush-
Kogenate FS; Kovaltry; Nuwiq; Xyntha; Xyntha Solo- ing, fatigue, feeling hot, flushing, hematoma, hot flash,
fuse; Zonovate hyperhidrosis, hypotension, inflammation at injection
Pharmacologic Category Antihemophilic Agent site, joint swelling, laryngeal edema, limb pain, loss of
Use consciousness, maculopapular rash, malaise, myal-
gia, pain at injection site, pallor, paresthesia, restless-
Hemophilia A:
ness, tachycardia, tremor, vertigo, xerostomia
Control and prevention of bleeding episodes: Pre-
vention and control of bleeding episodes in adults Mechanism of Action Factor VIII replacement, neces-
sary for clot formation and maintenance of hemostasis.
and children with hemophilia A.
It activates factor X in conjunction with activated factor
Perioperative management: Surgical prophylaxis in
IX; activated factor X converts prothrombin to thrombin,
adults and children with hemophilia A.
which converts fibrinogen to fibrin, and with factor XIII
Routine prophylaxis to prevent or reduce the fre-
forms a stable clot.
quency of bleeding: Routine prophylactic treatment
to prevent or reduce the frequency of bleeding epi-
sodes in adults and children with hemophilia A.
Advate: Children <12 years: 8.7 to 11.2 hours; Ado-
Routine prophylaxis to prevent bleeding episodes
lescents and Adults: 12 hours
and joint damage (Helixate FS, Kogenate FS):
Afstyla: Children <12 years: 10.2 to 10.4 hours; Chil-
Routine prophylactic treatment to reduce the fre- dren ≥12 years and Adolescents: 14.3 hours; Adults:
quency of bleeding episodes and the risk of joint 14.2 hours
damage in children without preexisting joint damage. Helixate FS, Kogenate FS: Children: 10.7 hours;
Limitations of use: Not indicated for the treatment of von Adults: 13.7 to 14.6 hours
Willebrand disease. Kovaltry: Children <12 years: ~12 hours; Children ≥12
Local Anesthetic/Vasoconstrictor Precautions years, Adolescents, and Adults: ~14 hours
No information available to require special precautions Novoeight: Children <12 years: 7.7 to 10 hours; Ado-
Effects on Dental Treatment Key adverse event(s) lescents and Adults: 11 to 12 hours
related to dental treatment: Taste perversion. Nuwiq: Children ≤12 years: 11.9 to 13.1 hours; Ado-
Effects on Bleeding Following large doses, an lescents and Adults: 17.1 hours
increased bleeding tendency has rarely been reported. Recombinate: Adults: 14.6 ± 4.9 hours
Mild thrombocytopenia has been reported. Due to Xyntha, Xyntha Solofuse: Children and Adolescents:
underlying hemophilia and complications of thrombotic 6.9 to 8.3 hours; Adults: 11 to 17 hours
events, a medical consultation is warranted. Pregnancy Considerations Pregnant hemophilia A
Adverse Reactions Actual frequency may vary by carriers may have an increased bleeding risk following
product. abortion, invasive procedures, miscarriage, and deliv-
>10%: ery; close surveillance is recommended. Factor VIII
Central nervous system: Headache (7% to 26%) levels should be monitored at the first antenatal visit,
Dermatologic: Pruritus (≤16%), skin rash (≤16%), urti- once or twice during the third trimester, prior to surgical
caria (≤16%) or invasive procedures, and at delivery. Although factor
Gastrointestinal: Nausea (6% to 13%), vomiting (7% VIII concentrations increase in pregnant patients, factor
to 12%) VIII replacement is recommended if concentrations are
Hematologic & oncologic: Increased factor VIII inhib- <0.5 IU/mL and any of the following occur: need for
itors (≤43%) invasive procedures (including delivery), spontaneous
Local: Catheter infection (18% to 19%) miscarriage, insertion and removal of epidural cathe-
Neuromuscular & skeletal: Arthralgia (8% to 25%) ters, or active bleeding. Hemostatic factor VIII concen-
Respiratory: Cough (11% to 19%), nasopharyngi- trations should be maintained for at least 3 to 5 days
tis (17%) following invasive procedures or postpartum. If a
Miscellaneous: Fever (≤43%; in patients previously replacement product is indicated, a recombinant prod-
exposed to factor VIII products: <1%) uct is preferred (NHF 2017; RCOG [Pavord 2017]; WFH
1% to 10%: [Srivastava 2013]).
Cardiovascular: Chest discomfort (1%), palpitations
(1%), sinus tachycardia (1%) Antihemophilic Factor (Recombinant
Central nervous system: Pain (8%), procedural pain
(5%), insomnia (3%), chills (≤1%), dizziness (≤1%) [Fc Fusion Protein])
(an tee hee moe FIL ik FAK tor ree KOM be nant eff see FYOO zhun
Dermatologic: Allergic dermatitis (1%) PRO teen)
Gastrointestinal: Diarrhea (5% to 8%), abdominal dis-
tress (2%), abdominal pain (2%), dyspepsia (2%) Brand Names: US Eloctate
Hematologic & oncologic: Lymphadenopathy (1%) Brand Names: Canada Eloctate
141
ANTIHEMOPHILIC FACTOR (RECOMBINANT [FC FUSION PROTEIN])
Pharmacologic Category Antihemophilic Agent Use

Use Hemophilia A: Hemophilia A:
Control and prevention of bleeding episodes: For Alphanate: Treatment and prevention of bleeding in
the prevention and control of bleeding episodes in adult and pediatric patients with factor VIII deficiency
adults and children with hemophilia A. due to hemophilia A (classical hemophilia).
Perioperative management: For surgical prophylaxis Humate-P: Treatment and prevention of bleeding in
in adults and children with hemophilia A. adults with hemophilia A (classical hemophilia).
Routine prophylaxis to prevent or reduce the fre- von Willebrand disease:
quency of bleeding: For routine prophylactic treat- Alphanate: Surgical and/or invasive procedures in
ment to prevent or reduce the frequency of bleeding adult and pediatric patients with von Willebrand
episodes in adults and children with hemophilia A. disease when desmopressin is either ineffective or
Limitation of use: Not indicated for the treatment of von contraindicated
Willebrand disease. Limitations of use: Not indicated for patients with
Local Anesthetic/Vasoconstrictor Precautions severe von Willebrand disease (type 3) undergoing
No information available to require special precautions major surgery.
Effects on Dental Treatment No significant effects or Humate-P: Treatment of spontaneous or trauma-
complications reported induced bleeding, as well as prevention of excessive
Effects on Bleeding Following large doses, an bleeding during and after surgery in adult and pedia-
increased bleeding tendency has rarely been reported. tric patients with severe von Willebrand disease,
Mild thrombocytopenia has been reported. Due to including mild or moderate von Willebrand disease
underlying hemophilia and complications of thrombotic where use of desmopressin is known or suspected to
events, a medical consultation is warranted. be inadequate.
Limitations of use: Safety and efficacy of prophylactic
Adverse Reactions
dosing to prevent spontaneous bleeding have not
<1%, postmarketing, and/or case reports: Antibody
been conducted in patients with von Willebrand
development (neutralizing), arthralgia, back pain, bra-
disease.
dycardia, chest pain, cough, dizziness, dysgeusia,
Wilate: On demand treatment and control of bleeding
feeling hot, headache, hot flash, hypersensitivity reac-
episodes, and perioperative management of bleed-
tion, hypertension, joint swelling, lower abdominal
ing in adult and pediatric patients with von Willebrand
pain, malaise, myalgia, procedural hypotension, sen-
disease.
sation of cold, skin rash, venous pain (postinjection)
Mechanism of Action Factor VIII replacement, neces- No information available to require special precautions
sary for clot formation and maintenance of hemostasis.
It activates factor X in conjunction with activated factor
IX; activated factor X converts prothrombin to thrombin,
which converts fibrinogen to fibrin, and with factor XIII
Effects on Bleeding Following large doses, an
increased bleeding tendency has rarely been reported.
forms a stable clot.
Pharmacodynamics/Kinetics Mild thrombocytopenia has been reported. Due to
underlying hemophilia and complications of thrombotic
Half-life Elimination Children <12 years: 12.7 to 14.9
events, a medical consultation is warranted.
hours; Children ≥12 years, Adolescents, and Adults:
16.4 to 19.7 hours Adverse Reactions Frequency not always defined.
Cardiovascular: Facial edema (>5%), peripheral edema
Pregnancy Considerations Pregnant hemophilia A
(1%), vasodilatation (1%), chest pain, orthostatic
carriers may have an increased bleeding risk following
hypotension, phlebitis, pulmonary embolism (large
abortion, invasive procedures, miscarriage, and deliv-
doses), subdural hematoma, thrombophlebitis
ery; close surveillance is recommended. Factor VIII
Central nervous system: Chills (>5%), fatigue (>5%),
levels should be monitored at the first antenatal visit,
pain (>5%), paresthesia (3% to >5%), dizziness (1%),
once or twice during the third trimester, prior to surgical
cerebral hemorrhage, drowsiness, headache,
or invasive procedures, and at delivery. Although factor
insomnia
VIII concentrations increase in pregnant patients, factor
Dermatologic: Skin rash (>5%), pruritus (1% to >5%),
VIII replacement is recommended if concentrations are
urticaria (1% to >5%), diaphoresis
<0.5 IU/mL and any of the following occur: need for
Endocrine & metabolic: Hypermenorrhea
invasive procedures (including delivery), spontaneous
Gastrointestinal: Nausea (24%; postoperative), consti-
miscarriage, insertion and removal of epidural cathe-
pation, gastrointestinal hemorrhage, sore throat, vom-
ters, or active bleeding. Hemostatic factor VIII concen-
iting
trations should be maintained for at least 3 to 5 days
Genitourinary: Urinary retention, urinary tract infection
following invasive procedures or postpartum. If a Hematologic & oncologic: Hemorrhage (30%; postop-
replacement product is indicated, a recombinant prod- erative), anemia, decreased hematocrit (moderate),
uct is preferred (NHF 2017; RCOG [Pavord 2017]; WFH increased factor VIII inhibitors
[Srivastava 2013]). Hepatic: Increased serum ALT
Hypersensitivity: Anaphylaxis, hypersensitivity reac-
Antihemophilic Factor/von Willebrand tion (2%)
Infection: Parvovirus B19 seroconversion (3%; not
Factor Complex (Human) accompanied by clinical signs of disease), infection,
(an tee hee moe FIL ik FAK tor von WILL le brand FAK tor KOM plex
HYU man) sepsis
Local: Pain at injection site
Brand Names: US Alphanate/VWF Complex/Human; Neuromuscular & skeletal: Arthralgia (>5%), limb pain
Humate-P; Wilate (1%), back pain
Brand Names: Canada Humate-P; Wilate Renal: Pyelonephritis
Pharmacologic Category Antihemophilic Agent; Respiratory: Respiratory distress (>5%), cough, phar-
Blood Product Derivative yngitis
142
ANTITHROMBIN
Miscellaneous: Postoperative pain (17%), fever (>5%) Use

Postmarketing and/or case reports: Abdominal pain, Hemorrhage in patients with hemophilia: Control
antibody development (neutralizing), cardiorespiratory and prevention of bleeding episodes in patients with
arrest, chest discomfort, chest tightness, dyspnea, hemophilia A and B with inhibitors.
edema, flushing, hemolysis, hypervolemia, lethargy, Perioperative bleeding management in patients
parotid gland enlargement, seizure, shock, tachycar- with hemophilia: Perioperative bleeding manage-
dia, thromboembolic complications, venous thrombo- ment in patients with hemophilia A and B with inhib-
sis (femoral) itors.
Mechanism of Action Factor VIII and von Willebrand Routine prophylaxis of bleeding events in patients
factor (VWF), obtained from pooled human plasma, are with hemophilia: Routine prophylaxis to prevent or
used to replace endogenous factor VIII and VWF in reduce the frequency of bleeding episodes in patients
patients with hemophilia or von Willebrand disease. with hemophilia A and B with inhibitors.
Factor VIII in conjunction with activated factor IX, Local Anesthetic/Vasoconstrictor Precautions
activates factor X which converts prothrombin to throm- No information available to require special precautions
bin and fibrinogen to fibrin. VWF promotes platelet Effects on Dental Treatment No significant effects or
aggregation and adhesion to damaged vascular endo-
thelium and acts as a stabilizing carrier protein for factor Effects on Bleeding Due to underlying hemophilia and
complications of thrombotic events, a medical consulta-
VIII. (Circulating levels of functional VWF are measured
tion is warranted.
as ristocetin cofactor activity [VWF:RCo]).
Pharmacodynamics/Kinetics Adverse Reactions Frequency not defined.
Cardiovascular: Cerebrovascular accident (embolic/
Onset of Action Shortening of bleeding time: Imme-
thrombotic stroke), chest discomfort, chest pain,
diate; maximum effect: 1 to 2 hours
decreased blood pressure, flushing, hypertension,
Duration of Action von Willebrand disease: Short- hypotension, myocardial infarction, pulmonary embo-
ening of bleeding time: <6 hours postinfusion; pres- lism, tachycardia, thromboembolism, thrombosis
ence of VWF multimers detected in the plasma: ≥24 (arterial thrombosis, venous thrombosis)
hours (Alphanate) Central nervous system: Chills, dizziness, drowsiness,
Half-life Elimination headache, hypoesthesia (including facial), malaise,
Factor VIII coagulant activity (FVIII:C): Range: 8 to 28 paresthesia
hours in patients with hemophilia A Dermatologic: Pruritus, skin rash, urticaria
VWF:RCo: Range (in patients with von Willebrand Gastrointestinal: Abdominal distress, diarrhea, dysgeu-
disease): Alphanate: 4 to 16 hours; Humate: 3 to sia, nausea, vomiting
34 hours; Wilate: 6 to 49 hours Hematologic & oncologic: Disseminated intravascular
Pregnancy Considerations Pregnant hemophilia A coagulation
carriers and those with von Willebrand disease may Hypersensitivity: Angioedema, hypersensitivity reaction
have an increased bleeding risk following abortion, (including anaphylaxis)
invasive procedures, miscarriage, and delivery; close Immunologic: Antibody development (anamnestic
surveillance is recommended. Factor VIII concentra- response)
tions may increase in pregnant patients; changes in Local: Pain at injection site
von Willebrand factor levels may vary during pregnancy Miscellaneous: Fever
depending on type. Patients should be monitored at the Respiratory: Bronchospasm, cough, dyspnea,
wheezing
first antenatal visit, once or twice during the third
trimester, prior to surgical or invasive procedures, and Mechanism of Action Multiple interactions of the
components in anti-inhibitor coagulant complex restore
at delivery. Replacement is recommended if concen-
the impaired thrombin generation of hemophilia patients
trations are <0.5 IU/mL and any of the following occur:
with inhibitors. In vitro, anti-inhibitor coagulant complex
need for invasive procedures (including delivery), spon-
shortens the activated partial thromboplastin time of
taneous miscarriage, insertion and removal of epidural plasma containing factor VIII inhibitor.
catheters, or active bleeding. Hemostatic concentra- Pharmacodynamics/Kinetics
tions should be maintained for at least 3 to 5 days Onset of Action Peak thrombin generation: Within 15
following invasive procedures or postpartum. When to 30 minutes (Varadi 2003)
VWF replacement therapy is needed, a recombinant Duration of Action 8 to 12 hours (based on thrombin
product or a product made from a safe plasma source generation) (Varadi 2003)
with viral testing that contains both factor VIII and von Half-life Elimination 4 to 7 hours (based on thrombin
Willebrand factor is recommended. A recombinant generation) (Varadi 2003)
product is one of the preferred agents if prophylaxis or Pregnancy Risk Factor C
treatment is needed for hemophilia A during pregnancy Pregnancy Considerations Animal reproduction
(NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava studies have not been conducted.
2013]).
Antithrombin (an tee THROM bin)
Anti-inhibitor Coagulant Complex
(Human) Brand Names: US Thrombate III
(an TEE in HI bi tor coe AG yoo lant KOM pleks HYU man) Brand Names: Canada Antithrombin III NF; Throm-
bate III
Brand Names: US FEIBA Pharmacologic Category Anticoagulant; Blood Prod-
Brand Names: Canada FEIBA NF uct Derivative
Pharmacologic Category Activated Prothrombin Use
Complex Concentrate (aPCC); Antihemophilic Agent; Treatment and prevention of antithrombin defi-
Blood Product Derivative ciency: Thrombate III: Treatment and prevention of
143
ANTITHROMBIN
thromboembolism and prevention of peri-operative in their third trimester. Pharmacokinetic studies in

and peri-partum thromboembolism in patients with pregnant women using the recombinant product
hereditary antithrombin (AT) deficiency. showed an increase in clearance and volume of
Prevention of thromboembolic events: ATryn: Pre- distribution compared to nonpregnant patients. There-
vention of perioperative and peripartum thromboem- fore, distinct initial dosing recommendations are pro-
bolic events in patients with hereditary antithrombin vided for pregnant women compared to nonpregnant
deficiency. patients.
Limitations of use: Not indicated for treatment of Thrombate III: Adverse events were not observed in
thromboembolic events in patients with hereditary animal reproduction studies. Dosing recommenda-
antithrombin deficiency. tions do not differ for obstetric patients compared to
Local Anesthetic/Vasoconstrictor Precautions nonpregnant patients.
No information available to require special precautions In patients with hereditary antithrombin (AT) deficiency,
Effects on Dental Treatment No significant effects or the risk of thromboembolic events such as VTE is
complications reported increased; pregnancy and delivery further increase
Effects on Bleeding As with all anticoagulant drugs, this risk. These products are specifically indicated for
bleeding is a potential adverse effect of antithrombin use in pregnant women with hereditary AT deficiency
during dental surgery; risk is dependent on multiple to decrease this risk, although use of other agents
variables, including the intensity of anticoagulation may be preferred (Bates 2012).
and patient susceptibility. Medical consult is suggested. Thromboembolism has been reported in children of
It is unlikely that ambulatory patients presenting for women with hereditary AT deficiency; AT concentra-
dental treatment will be taking intravenous anticoagu- tions in neonates of parents with hereditary AT defi-
lant therapy such as antithrombin. ciency should be measured immediately after birth.
Adverse Reactions Plasma AT levels are typically lower in neonates and
1% to 10%: infants than in adults. Low plasma AT concentrations
Cardiovascular: Chest pain (≤2%) in neonates may not be indicative of deficiency; con-
Central nervous system: Dizziness (2%) sultation with a coagulation expert is recommended.
Gastrointestinal: Liver enzyme abnormalities (≤2%)
Genitourinary: Hematuria (≤2%) Antithymocyte Globulin (Equine)
Hematologic & oncologic: Hemorrhage (≥5%), hema- (an te THY moe site GLOB yu lin, E kwine)
toma (≤2%)
Local: Infusion site reaction (≥5%) Brand Names: US Atgam
Neuromuscular & skeletal: Hemarthrosis (≤2%) Brand Names: Canada Atgam
<1%, postmarketing, and/or case reports: Blurred Pharmacologic Category Immune Globulin; Immuno-
vision, chest tightness, chills, dizziness, dyspnea, suppressant Agent; Polyclonal Antibody
fever, gastrointestinal fullness, muscle cramps, nau- Use
sea, unpleasant taste, urticaria Aplastic anemia: Treatment of moderate-to-severe
Mechanism of Action Antithrombin is the primary aplastic anemia in patients not considered suitable
physiologic inhibitor of in vivo coagulation. It is an candidates for bone marrow transplantation
alpha2-globulin. Its principal actions are the inactivation Limitations of use: The usefulness of antithymocyte
of thrombin, plasmin, and other active serine proteases globulin (equine) has not been demonstrated in
of coagulation, including factors IXa, Xa, XIa, and XIIa. patients with aplastic anemia who are suitable candi-
The inactivation of proteases is a major step in the dates for transplantation, or in aplastic anemia secon-
normal clotting process. The strong activation of clotting dary to neoplastic disease, storage disease,
enzymes at the site of every bleeding injury facilitates myelofibrosis, Fanconi syndrome, or in patients with
fibrin formation and maintains normal hemostasis. known prior treatment with myelotoxic agents or radi-
Thrombosis in the circulation would be caused by active ation therapy
serine proteases if they were not inhibited by antithrom- Local Anesthetic/Vasoconstrictor Precautions
bin after the localized clotting process (Schwartz, No information available to require special precautions
1989). Effects on Dental Treatment Key adverse event(s)
related to dental treatment: Stomatitis
In patients with hereditary antithrombin (AT) deficiency, Effects on Bleeding No information available to
spontaneous thrombosis may occur due to decreased require special precautions
AT concentrations; therapy with human or recombinant Adverse Reactions
AT restores functional AT activity. >10%:
Pharmacodynamics/Kinetics Central nervous system: Chills, headache
Half-life Elimination Dermatologic: Dermatological reaction (wheal/flare),
Plasma derived (Thrombate III): Biologic: 2.5 days pruritus, skin rash, urticaria
(immunologic assay); 3.8 days (functional AT assay). Hematologic & oncologic: Leukopenia, thrombocyto-
Half-life may be decreased following surgery, with penia
hemorrhage, acute thrombosis, and/or during hepa- Neuromuscular & skeletal: Arthralgia
rin administration. Miscellaneous: Fever
Recombinant derived (ATryn): 12-18 hours; surgery, 1% to 10%:
childbirth hemorrhage, and/or concomitant heparin Cardiovascular: Bradycardia, cardiac disease, cardiac
may shorten half-life failure, chest pain, edema, hypertension, hypoten-
Pregnancy Risk Factor B (Thrombate III); C (ATryn) sion, myocarditis, phlebitis, thrombophlebitis
Pregnancy Considerations Central nervous system: Agitation, brain disease
ATryn: Adverse events were observed in some animal (viral), burning sensation (burning of soles and burn-
reproduction studies. An increased risk of adverse ing of palms), dizziness, encephalitis, generalized
fetal or neonatal effects has not been observed in ache, lethargy, seizure
studies involving a limited number of pregnant women Dermatologic: Diaphoresis, night sweats
144
APIXABAN
Gastrointestinal: Diarrhea, nausea, stomatitis, vom- Adverse Reactions

iting >10%:
Genitourinary: Proteinuria Cardiovascular: Hypertension (25%), peripheral
Hematologic & oncologic: Lymphadenopathy edema (11%)
Hepatic: Abnormal hepatic function tests, hepatosple- Central nervous system: Fatigue (39%), falling (16%)
nomegaly Dermatologic: Skin rash (24%)
Hypersensitivity: Anaphylaxis, serum sickness Endocrine & metabolic: Hypercholesterolemia (76%),
Infection: Viral infection hyperglycemia (70%), hypertriglyceridemia (67%),
Local: Injection site reaction (pain, redness, swelling) hyperkalemia (32%), increased thyroid stimulating
Neuromuscular & skeletal: Back pain, joint stiffness, hormone level (25%), weight loss (16%), hot
myalgia flash (14%)
Ophthalmic: Periorbital edema Gastrointestinal: Diarrhea (20%), nausea (18%),
Renal: Renal function test abnormality decreased appetite (12%)
Respiratory: Dyspnea, pleural effusion, respiratory Hematologic & oncologic: Anemia (70%; grades 3/4:
distress <1%), leukopenia (47%; grades 3/4: <1%), lympho-
<1%, postmarketing, and/or case reports: Abdominal cytopenia (41%; grades 3/4: 2%)
pain, acute renal failure, anaphylactoid reaction, ane- Neuromuscular & skeletal: Arthralgia (16%), bone
mia, apnea, confusion, cough, deep vein thrombosis, fracture (12%)
disorientation, dizziness, eosinophilia, epigastric pain, 1% to 10%:
epistaxis, erythema, flank pain, gastrointestinal hem- Cardiovascular: Ischemic heart disease (4%), cardiac
orrhage, gastrointestinal perforation, granulocytope- failure (2%)
nia, hemolysis, hemolytic anemia, herpes simplex Dermatologic: Pruritus (6%)
infection (reactivation), hiccups, hyperglycemia, infec- Endocrine & metabolic: Hypothyroidism (8%)
tion, involuntary body movements, laryngospasm, <1%, postmarketing, and/or case reports: Seizure
malaise, muscle rigidity, neutropenia, pancytopenia, Mechanism of Action Apalutamide is a nonsteroidal
paresthesia, pulmonary edema, pure red cell aplasia, androgen receptor inhibitor; apalutamide binds directly
renal artery thrombosis, sore mouth, sore throat, to the androgen receptor ligand-binding domain to
tachycardia, thrombosis of vein (iliac), toxic epidermal prevent androgen-receptor translocation, DNA binding,
necrolysis, tremor, vasculitis, viral hepatitis, weak- and receptor-mediated transcription (Smith 2018).
ness, wound dehiscence Androgen receptor inhibition results in decreased pro-
Mechanism of Action Immunosuppressant involved in liferation of tumor cells and increased apoptosis, lead-
the elimination of antigen-reactive T lymphocytes (killer ing to a decrease in tumor volume.
cells) in peripheral blood or alteration in the function of Pharmacodynamics/Kinetics
T-lymphocytes, which are involved in humoral immunity Half-life Elimination ~3 days
and partly in cell-mediated immunity; induces complete Time to Peak 2 hours (range: 1 to 5 hours)
or partial hematologic response in aplastic anemia Pregnancy Considerations
Pharmacodynamics/Kinetics Use is contraindicated during pregnancy.
Half-life Elimination 5.7 ± 3 days
Pregnancy Considerations Animal reproduction studies have not been conducted.
Adverse events were observed in some animal repro- Based on the mechanism of action, apalutamide may
duction studies. cause fetal harm if administered during pregnancy.
Males with female partners of reproductive potential
The Transplant Pregnancy Registry International (TPR) should use effective contraception during therapy and
is a registry that follows pregnancies that occur in for 3 months after the last apalutamide dose. Apaluta-
maternal transplant recipients or those fathered by male mide may impair fertility in males of reproductive poten-
transplant recipients. The TPR encourages reporting of tial (based on findings in animal studies).
pregnancies following solid organ transplant by contact-
ing them at 1-877-955-6877 or https://www.-
transplantpregnancyregistry.org.
Apixaban (a PIX a ban)
Related Information
Apalutamide (a pa LOO ta mide) Antiplatelet and Anticoagulation Considerations in Den-
tistry on page 1454
Brand Names: US Erleada Brand Names: US Eliquis; Eliquis Starter Pack
Brand Names: Canada Erleada Brand Names: Canada Eliquis
Pharmacologic Category Antineoplastic Agent, Anti- Pharmacologic Category Anticoagulant; Anticoagu-
androgen lant, Factor Xa Inhibitor; Direct Oral Anticoagulant
Use Prostate cancer, non-metastatic, castration- (DOAC)
resistant: Treatment of non-metastatic, castration- Use
resistant prostate cancer (NM-CRPC). Deep vein thrombosis: Treatment of deep vein throm-
Local Anesthetic/Vasoconstrictor Precautions bosis (DVT); to reduce the risk of recurrent DVT
No information available to require special precautions following initial therapy
Effects on Dental Treatment No significant effects or Nonvalvular atrial fibrillation: To reduce the risk of
complications reported stroke and systemic embolism in patients with non-
Effects on Bleeding Chemotherapy with apalutamide valvular atrial fibrillation (AF)
may result in significant myelosuppression, including Postoperative venous thromboprophylaxis follow-
anemia (70%; grades 3/4: <1%), leukopenia (47%; ing hip or knee replacement surgery: Prophylaxis of
grades 3/4: <1%), and lymphocytopenia (41%; grades DVT, which may lead to pulmonary embolism (PE), in
3/4: 2%). In patients who are under active treatment patients who have undergone hip or knee replacement
with apalutamide, medical consult is suggested. surgery
145
APIXABAN
Pulmonary embolism: Treatment of PE; to reduce the insufficient to evaluate the safety of oral factor Xa
risk of recurrent PE following initial therapy inhibitors in pregnant females, use during pregnancy
Local Anesthetic/Vasoconstrictor Precautions should be avoided (Bates 2012).
No information available to require special precautions Dental Health Professional Considerations At this
Effects on Dental Treatment Key adverse event(s) time there are no coagulation parameters for apixaban
related to dental treatment: Surgical site bleeding may to predict the extent of bleeding. Increased bleeding
occur. See Effects on Bleeding. may occur during invasive dental procedures in patients
Effects on Bleeding Apixaban inhibits platelet activa- taking apixaban. Medical consult is suggested prior to
tion and fibrin clot formation via direct, selective, and dental invasive procedures. Routine coagulation testing
reversible inhibition of factor Xa. As with all anticoagu- (INR) is not required, or necessary, for Direct-Acting
lants, bleeding is the major adverse effect of apixaban. Oral Anticoagulants (DOAC).
Hemorrhage may occur at virtually any site; risk is
dependent on multiple variables including the intensity
of anticoagulation and patient susceptibility. Medical
Apomorphine (a poe MOR feen)
consult is suggested. Brand Names: US Apokyn

Adverse Reactions Brand Names: Canada Movapo
>10%: Hematologic & oncologic: Hemorrhage (1% to Pharmacologic Category Anti-Parkinson Agent, Dop-
12%; major: ≤3%; clinically relevant nonmajor bleed- amine Agonist
ing: 2% to 4%) Use Parkinson disease: Treatment of hypomobility "off"
1% to 10%: episodes with advanced Parkinson disease
Endocrine & metabolic: Increased gamma-glutamyl Local Anesthetic/Vasoconstrictor Precautions
transferase (≤1%)
Apomorphine is one of the drugs confirmed to prolong
Gastrointestinal: Nausea (3%), gingival hemor-
rhage (≤1%)
causing torsade de pointes. The risk of drug-induced
Genitourinary: Hematuria (≤2%), hypermenor-
torsade de pointes is extremely low when a single QT
rhea (1%)
interval prolonging drug is prescribed. In terms of epi-
Hematologic & oncologic: Anemia (3%), bruise (1% to
nephrine, it is not known what effect vasoconstrictors in
2%), hematoma (1% to 2%), postprocedural hemor-
the local anesthetic regimen will have in patients with a
rhage (≤1%), rectal hemorrhage (≤1%)
known history of congenital prolonged QT interval or in
Hepatic: Increased serum transaminases (≤1%)
patients taking any medication that prolongs the QT
Respiratory: Epistaxis (≤4%), hemoptysis (≤1%)
interval. Until more information is obtained, it is sug-
gested that the clinician consult with the physician prior
hepatic function tests, abnormal uterine bleeding,
to the use of a vasoconstrictor in suspected patients,
acute posthemorrhagic anemia, allergic edema, anal
and that the vasoconstrictor (epinephrine, mepivacaine
hemorrhage, anaphylaxis, conjunctival hemorrhage,
and levonordefrin [Carbocaine® 2% with Neo-Cobe-
gastrointestinal hemorrhage, genital bleeding, hema-
frin®]) be used with caution.
temesis, hematochezia, hematoma, hematoma at
injection site, hemophthalmos, hemorrhoidal bleeding, Effects on Dental Treatment Key adverse event(s)
hypersensitivity, hypotension, incision site hemor- related to dental treatment: Patients may experience
rhage, increased serum alkaline phosphatase, orthostatic hypotension as they stand up after treat-
increased serum AST, increased serum bilirubin, intra- ment; especially if lying in dental chair for extended
cranial hemorrhage, melena, muscle hemorrhage, periods of time. Use caution with sudden changes in
occult blood in urine, perioperative blood loss, peri- position during and after dental treatment.
orbital edema (Ahmad 2018), periorbital hematoma, Effects on Bleeding No information available to
petechia, postoperative hematoma (incision site), require special precautions
postprocedural hemorrhage, puncture site bleeding, Adverse Reactions Note: Frequency not always
retinal hemorrhage, skin rash, syncope, thrombocyto- defined.
penia, vaginal hemorrhage, wound hemorrhage, >10%:
wound secretion Cardiovascular: Angina pectoris (15%), chest pain
Mechanism of Action Inhibits platelet activation and (15%), chest pressure (15%)
fibrin clot formation via direct, selective and reversible Central nervous system: Drowsiness (35%), dizziness
inhibition of free and clot-bound factor Xa (FXa). FXa, (20%), orthostatic hypotension (20%)
as part of the prothrombinase complex consisting also Gastrointestinal: Nausea (30%), vomiting (30%)
of factor Va, calcium ions, and phospholipid, catalyzes Neuromuscular & skeletal: Dyskinesia (24% to 35%),
the conversion of prothrombin to thrombin. Thrombin falling (30%)
both activates platelets and catalyzes the conversion of Respiratory: Yawning (40%), rhinorrhea (20%)
fibrinogen to fibrin. 1% to 10%:
Pharmacodynamics/Kinetics Cardiovascular: Edema (10%), vasodilatation (3%),
Onset of Action 3 to 4 hours hypotension (2%), syncope (2%), cardiac failure
Half-life Elimination ~12 hours (8 to 15 hours) (AHA Central nervous system: Confusion (10%), hallucina-
[Raval 2017]) tions (10%), anxiety, depression, fatigue, headache,
Time to Peak 3 to 4 hours insomnia, pain
Pregnancy Risk Factor B Dermatologic: Bruise
Endocrine & metabolic: Dehydration
Gastrointestinal: Constipation, diarrhea
observed in animal reproduction studies.
Local: Injection site reaction
Based on placenta perfusion studies, apixaban is Neuromuscular & skeletal: Arthralgia, weakness
expected to cross the placenta (Bapat 2016). Informa- Miscellaneous: Diaphoresis
tion specific to the use of apixaban in pregnancy is <1%, postmarketing, and/or case reports: Aggressive
limited (Königsbrügge 2014). Because data are behavior, agitation, cardiac arrest, confusion,
146
APREMILAST
hemolytic anemia (combination therapy, Colosimo Respiratory: Asthma (<3%), dry nose (<3%), dyspnea
1994; Frankel 1990), impulse control disorder, impul- (<3%), pharyngitis (<3%), rhinitis (<3%)
sivity, increased libido, myocardial infarction, pannicu- <1%, postmarketing, and/or case reports: Blepharitis,
litis (focal), paranoia, priapism, psychosis (acute) blepharoconjunctivitis, bradycardia, conjunctival
Mechanism of Action Stimulates postsynaptic D2- edema, corneal erosion, corneal infiltrates, corneal
type receptors within the caudate putamen in the brain. staining, crusting of eyelid, epithelial keratopathy,
Pharmacodynamics/Kinetics erythema of eyelid, eyelid disease, eyelid retraction,
Onset of Action SubQ: Rapid eye irritation, eye pain, follicular conjunctivitis, hyper-
Half-life Elimination Terminal: ~40 minutes sensitivity reaction, keratitis, ocular edema, photopho-
Time to Peak Plasma: 10 to 60 minutes bia, scaling of eyelid, visual disturbance
Pregnancy Considerations Adverse events have Mechanism of Action Apraclonidine is a potent alpha-
been observed in animal reproduction studies. adrenergic agent similar to clonidine; relatively selective
Prescribing and Access Restrictions Apokyn is for alpha2-receptors but does retain some binding to
only available through specialty pharmacies and cannot alpha1-receptors; appears to result in reduction of aque-
be obtained through a retail pharmacy. For more infor- ous humor formation; its penetration through the blood-
mation, contact 1-877-7APOKYN (1-877-727-6596). brain barrier is more polar than clonidine which reduces
Dental Health Professional Considerations See its penetration through the blood-brain barrier and
Local Anesthetic/Vasoconstrictor Precautions suggests that its pharmacological profile is character-
ized by peripheral rather than central effects.
Apraclonidine (a pra KLOE ni deen)
Onset of Action 1 hour; Peak effect: Decreased
Brand Names: US Iopidine intraocular pressure: 3 to 5 hours
Brand Names: Canada Iopidine Half-life Elimination Systemic: 0.5% solution: 8
Pharmacologic Category Alpha2 Agonist, Ophthal- hours
mic Pregnancy Considerations Adverse events have
Use been observed in animal reproduction studies. If oph-
Elevated intraocular pressure: thalmic agents are needed during pregnancy, the mini-
0.5% solution: Short-term, adjunctive therapy in mum effective dose should be used in combination with
patients who require additional reduction of intra- punctual occlusion to decrease potential exposure to
ocular pressure (IOP) the fetus (Samples 1988).
1% solution: Prevention and treatment of postsurgi-
cal IOP elevation following argon laser trabeculo- Apremilast (a PRE mi last)
plasty, argon laser iridotomy or Nd:YAG posterior
capsulotomy (manufacturer's labeling) or as part of Brand Names: US Otezla
a 4-drug medical management regimen in acute Brand Names: Canada Otezla
angle-closure glaucoma when the patient cannot be Pharmacologic Category Phosphodiesterase-4
seen by an ophthalmologist for ≥1 hour (off-label Enzyme Inhibitor
use) (Krawitz 1990; Pokhrel 2007; Weizer 2019). Use
Local Anesthetic/Vasoconstrictor Precautions Psoriasis: Treatment of patients with moderate to
No information available to require special precautions severe plaque psoriasis who are candidates for photo-
Effects on Dental Treatment Key adverse event(s) therapy or systemic therapy
related to dental treatment: Xerostomia (normal salivary Psoriatic arthritis: Treatment of adult patients with
flow resumes upon discontinuation) active psoriatic arthritis (PsA)
Effects on Bleeding No information available to Local Anesthetic/Vasoconstrictor Precautions
Adverse Reactions Effects on Dental Treatment No significant effects or
Frequency not always defined.
5% to 15%:
Gastrointestinal: Xerostomia (10%)
Ophthalmic: Eye discomfort, eye pruritus, ocular
hyperemia Adverse Reactions Frequency not always defined.
1% to 5%: Central nervous system: Tension headache (7%), head-
Cardiovascular: Cardiac arrhythmia (<3%), chest pain ache (6%), fatigue (3%), depression (2%), insomnia
(<3%), facial edema (<3%), peripheral edema (<3%), (2%), migraine (2%), paresthesia (<2%)
localized blanching Dermatologic: Skin rash (<2%), folliculitis (1%)
Central nervous system: Altered sense of smell (<3%), Endocrine & metabolic: Weight loss (5% to 10% of body
ataxia (<3%), depression (<3%), dizziness (<3%), weight: 10% to 12%; ≥10% of body weight: 2%)
drowsiness (<3%), headache (<3%), insomnia Gastrointestinal: Diarrhea (18%), nausea (17%), vomit-
(<3%), malaise (<3%), nervousness (<3%), pares- ing (4%), decreased appetite (3%), dyspepsia (3%),
thesia (<3%) abdominal distress (2%), abdominal pain (2%), fre-
Dermatologic: Contact dermatitis (<3%), dermati- quent bowel movements (2%), upper abdominal pain
tis (<3%) (2%), abdominal distention (<2%), gastroesophageal
Gastrointestinal: Constipation (<3%), dysgeusia reflux disease (<2%)
(<3%), nausea (<3%) Hypersensitivity: Hypersensitivity reaction (<2%)
Neuromuscular & skeletal: Myalgia (<3%), weak- Infection: Influenza (<2%), tooth abscess (1%)
ness (<3%) Neuromuscular & skeletal: Back pain (2%), arthralgia
Ophthalmic: Blurred vision, conjunctivitis, dry eye (<2%), muscle spasm (<2%), myalgia (<2%)
syndrome, eyelid edema, eye discharge, foreign Respiratory: Upper respiratory tract infection (8%),
body sensation of eye, lacrimation nasopharyngitis (7%), sinusitis (2%), bronchitis
147
APREMILAST
(<2%), cough (<2%), pharyngitis (<2%), rhinitis (<2%), Adverse Reactions Adverse reactions may be
sinus headache (<2%) reported in combination with other antiemetic agents.
<1%: Atrial fibrillation, exacerbation of psoriasis As reported for highly emetogenic cancer chemother-
(rebound following discontinuation), severe diarrhea, apy or moderately emetogenic cancer chemotherapy,
suicidal ideation, tachyarrhythmia unless otherwise noted as reported for postoperative
Mechanism of Action Apremilast inhibits phospho- nausea and vomiting (PONV).
diesterase 4 (PDE4) specific for cyclic adenosine >10%:
monophosphate (cAMP) which results in increased Central nervous system: Fatigue (adults: 1% to 13%;
intracellular cAMP levels and regulation of numerous children & adolescents: 5%)
inflammatory mediators (eg, decreased expression of Hematologic & oncologic: Neutropenia (children &
nitric oxide synthase, TNF-α, and interleukin [IL]-23, as adolescents: 13%; adults: <3%)
well as increased IL-10) (Schafer, 2012). 1% to 10%:
Pharmacodynamics/Kinetics Cardiovascular: Hypotension (PONV: 6%), bradycar-
Half-life Elimination ~6 to 9 hours dia (PONV: <3%), flushing (<3%), palpitations (<3%),
Time to Peak ~2.5 hours peripheral edema (<3%), syncope (PONV: <3%)
Pregnancy Risk Factor C Central nervous system: Headache (children & ado-
Pregnancy Considerations Adverse events were lescents: 9%), dizziness (<3% to 5%), anxiety (<3%),
observed in some animal reproduction studies. A regis- hypoesthesia (PONV: <3%), hypothermia (PONV:
try is available for women exposed to apremilast during <3%), malaise (<3%), peripheral neuropathy (<3%),
pregnancy (877-311-8972). abnormal behavior (children & adolescents: 2%),
agitation (children & adolescents: 2%)
Dermatologic: Pruritus (3%), alopecia (<3%), hyper-
Aprepitant (ap RE pi tant) hidrosis (<3%), skin rash (<3%), urticaria (<3%)
Endocrine & metabolic: Dehydration (≤3%),
Brand Names: US Cinvanti; Emend; Emend Tri-Pack decreased serum albumin (PONV: <3%), decreased
Brand Names: Canada Emend serum potassium (PONV: <3%), decreased serum
Pharmacologic Category Antiemetic; Substance P/ sodium (<3%), hot flash (<3), hypokalemia (<3%),
Neurokinin 1 Receptor Antagonist hypovolemia (PONV: <3%), increased serum glu-
Use cose (PONV: <3%), weight loss (<3%)
IV (Cinvanti): Gastrointestinal: Constipation (PONV: ≤9%), diarrhea
Prevention of chemotherapy-induced nausea and (6% to 9%), dyspepsia (≤7%), abdominal pain (≤6%),
vomiting: hiccups (4% to 5%), decreased appetite (<3% to
Prevention of acute and delayed nausea and vomit- 5%), dysgeusia (<3%), eructation (<3%), flatulence
ing associated with highly emetogenic chemother- (<3%), gastritis (<3%), gastroesophageal reflux dis-
apy, including high-dose cisplatin (initial and repeat ease (<3%), nausea (<3%), vomiting (<3%), xero-
courses; in combination with other antiemetics) in stomia (<3%)
adults. Genitourinary: Proteinuria (<3%)
Prevention of nausea and vomiting associated with Hematologic & oncologic: Decreased hemoglobin
moderately emetogenic chemotherapy (initial and (children & adolescents: 5%), decreased white blood
repeat courses; in combination with other antiemet- cell count (≤4%), anemia (<3%), febrile neutropenia
ics) in adults. (<3%), hematoma (PONV: <3%), thrombocytope-
Oral (Emend oral): nia (<3%)
Prevention of chemotherapy-induced nausea and Hepatic: Increased serum ALT (3%), increased serum
vomiting: alkaline phosphatase (<3%), increased serum AST
Prevention of acute and delayed nausea and vomit- (<3%), increased serum bilirubin (PONV: <3%)
ing associated with highly emetogenic chemother- Infection: Candidiasis (<3%), postoperative infection
apy (initial and repeat courses; in combination with (PONV: <3%)
other antiemetics) in patients ≥12 years (capsules) Local: Induration at injection site (3%), inflammation at
and in patients ≥6 months (oral suspension). injection site (3%), infusion site reaction (3%)
Prevention of nausea and vomiting associated with Neuromuscular & skeletal: Weakness (≤7%), muscu-
moderately emetogenic chemotherapy (initial and loskeletal pain (<3%)
repeat courses; in combination with other antiemet- Renal: Increased blood urea nitrogen (<3%)
ics) in patients ≥12 years (capsules) and in patients Respiratory: Cough (<3% to 5%), dyspnea (<3%),
≥6 months (oral suspension). hypoxia (PONV: <3%), oropharyngeal pain (<3%),
Postoperative nausea and vomiting: Prevention of pharyngitis (<3%), respiratory depression
postoperative nausea and vomiting (PONV) in (PONV: <3%)
adults. Miscellaneous: Wound dehiscence (PONV: <3%)
<1%, postmarketing, and/or case reports: Abdominal
Limitations of use: Aprepitant has not been studied for distention, abnormal dreams, abnormal gait, acne
the management of existing nausea and vomiting. vulgaris, anaphylaxis, angioedema, anxiety, cardiac
Chronic, continuous administration is not recom- disease, chest discomfort, chills, cognitive dysfunc-
mended (has not been studied and chronic use may tion, conjunctivitis, decreased neutrophils, disorienta-
alter aprepitant’s drug interaction profile). tion, drowsiness, dysfunction, dysuria, edema,
Local Anesthetic/Vasoconstrictor Precautions epigastric distress, euphoria, hematuria, hyperglyce-
No information available to require special precautions mia, hypersensitivity reaction, hyponatremia,
Effects on Dental Treatment Key adverse event(s) increased thirst, lethargy, muscle cramps, myalgia,
related to dental treatment: Hiccups, stomatitis, and neutropenic enterocolitis, oily skin, perforated duode-
mucous membrane disorder. nal ulcer, pollakiuria, polyuria, polydipsia, post nasal
Effects on Bleeding No information available to drip, skin lesion, skin photosensitivity, sneezing,
require special precautions staphylococcal infection, Stevens-Johnson syndrome,
148
ARGATROBAN
stomatitis, throat irritation, tinnitus, toxic epidermal arthritis, skin discoloration, skin hypertrophy, supra-
necrolysis, weight gain ventricular tachycardia, tendinous contracture, tremor,
Mechanism of Action Aprepitant prevents acute and urinary tract abnormality, urine abnormality, viral infec-
delayed vomiting by inhibiting the substance P/neuro- tion, visual disturbance, voice disorder, xeroderma
kinin 1 (NK1) receptor; augments the antiemetic activity Mechanism of Action Arformoterol, the (R,R)-enan-
of 5-HT3 receptor antagonists and corticosteroids to tiomer of the racemic formoterol, is a long-acting beta2-
inhibit acute and delayed phases of chemotherapy- agonist that relaxes bronchial smooth muscle by selec-
induced emesis. tive action on beta2-receptors with little effect on car-
Pharmacodynamics/Kinetics diovascular system.
Half-life Elimination Terminal: IV, Oral: ~9 to 13 Pharmacodynamics/Kinetics
hours Onset of Action 7-20 minutes; Peak effect: 1-3 hours
Time to Peak Plasma: Pediatric: Capsule: ~4 hours; Half-life Elimination 26 hours
Suspension ~6 hours; Adults: 40 mg: ~3 hours; Time to Peak 0.5-3 hours
125 mg followed by 80 mg for 2 days: ~4 hours
Pregnancy Risk Factor C
Pregnancy Considerations Adverse events were
observed in animal reproduction studies. The injection
observed in some animal reproduction studies. Beta-
formulation contains ethanol; use should be avoided in
agonists may interfere with uterine contractility if admin-
females who are pregnant.
istered during labor.
Efficacy of hormonal contraceptive may be reduced
during and for 28 days following the last aprepitant
dose; alternative or additional effective methods of
Argatroban (ar GA troh ban)
contraception should be used both during treatment Related Information
with fosaprepitant or aprepitant and for at least 1 month Cardiovascular Diseases on page 1442
following the last fosaprepitant/aprepitant dose.
Pharmacologic Category Anticoagulant; Anticoagu-
lant, Direct Thrombin Inhibitor
Arformoterol (ar for MOE ter ol) Use
Heparin-induced thrombocytopenia: Prophylaxis or
Related Information treatment of thrombosis in adults with heparin-induced
Respiratory Diseases on page 1467 thrombocytopenia (HIT).
Brand Names: US Brovana Percutaneous coronary intervention: As an antico-
Pharmacologic Category Beta2-Adrenergic Agonist; agulant for percutaneous coronary intervention (PCI)
Beta2-Adrenergic Agonist, Long-Acting in adults who have or are at risk of developing HIT.
Use Chronic obstructive pulmonary disease: Long- Local Anesthetic/Vasoconstrictor Precautions
term maintenance treatment of bronchoconstriction in No information available to require special precautions
patients with chronic obstructive pulmonary disease Effects on Dental Treatment Key adverse event(s)
(COPD), including chronic bronchitis and emphysema related to dental treatment: Bleeding is a potential
Local Anesthetic/Vasoconstrictor Precautions adverse effect of argatroban during dental surgery; it
No information available to require special precautions is unlikely that ambulatory patients presenting for dental
Effects on Dental Treatment No significant effects or treatment will be taking intravenous anticoagulant ther-
complications reported apy. See Effects on Bleeding.
Effects on Bleeding No information available to Effects on Bleeding As with all anticoagulants, bleed-
require special precautions ing is a potential adverse effect of argatroban during
Adverse Reactions dental surgery; risk is dependent on multiple variables,
2% to 10%: including the intensity of anticoagulation and patient
Cardiovascular: Chest pain (7%), peripheral susceptibility. Medical consult is suggested. It is unlikely
edema (3%)
that ambulatory patients presenting for dental treatment
Central nervous system: Pain (8%)
will be taking intravenous anticoagulant therapy such as
argatroban.
Gastrointestinal: Diarrhea (6%)
Neuromuscular & skeletal: Back pain (6%), leg Adverse Reactions As with all anticoagulants, bleed-
cramps (4%) ing is the major adverse effect of argatroban. Hemor-
Respiratory: Dyspnea (4%), sinusitis (5%), flu-like rhage may occur at virtually any site. Risk is dependent
symptoms (3%), respiratory congestion (2%) on multiple variables, including the intensity of anti-
<2%: Abscess, agitation, arteriosclerosis, arthralgia, coagulation and patient susceptibility.
arthritis, atrial flutter, atrioventricular block, bone dis- >10%:
ease, calcium crystalluria, cardiac failure, cerebral Cardiovascular: Chest pain (PCI related: <1% to
infarction, constipation, cystitis, decreased glucose 15%), hypotension (7% to 11%)
tolerance, dehydration, digitalis intoxication, drowsi- Genitourinary: Genitourinary tract hemorrhage (includ-
ness, ECG changes, edema, fever, gastritis, glau- ing hematuria; major: <1%; minor: 2% to 12%)
coma, glycosuria, gout, heart block, hematuria, 1% to 10%:
hernia, hyperglycemia, hyperlipidemia, hypersensitiv- Cardiovascular: Vasodilation (1% to 10%), cardiac
ity reaction, hypoglycemia, hypokalemia, hypokinesia, arrest (6%), bradycardia (5%), ventricular tachycar-
inversion T wave on ECG, lung carcinoma, melena, dia (5%), myocardial infarction (PCI: 4%), angina
myocardial infarction, neck stiffness, neoplasm, neph- pectoris (2%), coronary occlusion (2%), ischemic
rolithiasis, nocturia, oral candidiasis, paradoxical bron- heart disease (2%), thrombosis (<1% to 2%)
chospasm, paralysis, paresthesia (circumoral), pelvic Central nervous system: Headache (5%), pain (5%),
pain, periodontal abscess, prolonged Q-T interval on intracranial hemorrhage (1% to 4%)
ECG, prostate specific antigen increase, pyuria, rectal Dermatologic: Dermatological reaction (bullous erup-
hemorrhage, retroperitoneal hemorrhage, rheumatoid tion, rash; 1% to <10%)
149
ARGATROBAN
Gastrointestinal: Nausea (5% to 7%), diarrhea (6%), Local Anesthetic/Vasoconstrictor Precautions

vomiting (4% to 6%), abdominal pain (3% to 4%), No information available to require special precautions
gastrointestinal hemorrhage (major: <1% to 3%; Effects on Dental Treatment Key adverse event(s)
minor: 3%) related to dental treatment: Extrapyramidal symptoms
Hematologic & oncologic: Decreased hematocrit (similar to placebo) (see Dental Health Professional
(minor: ≤10%; major: <1%), decreased hemoglobin Considerations); xerostomia and changes in salivation
(minor: ≤10%; major: <1%; ≥2 g/dL), groin bleeding (normal salivary flow resumes upon discontinuation).
(5%), brachial bleeding (2%), minor hemorrhage Effects on Bleeding No information available to
(CABG related: 2%) require special precautions
Neuromuscular & skeletal: Back pain (PCI
Adverse Reactions Unless otherwise noted, fre-
related: 8%)
quency of adverse reactions is shown as reported for
Respiratory: Dyspnea (10%), cough (3% to 10%),
adult patients receiving aripiprazole monotherapy.
hemoptysis (minor: ≤1% to 3%)
Spectrum and incidence of adverse effects similar in
Miscellaneous: Fever (<1% to 7%)
children; exceptions noted when incidence is much
<1% (Limited to important or life-threatening): Aortic
higher in children.
valve stenosis, bleeding at injection site (or access
site; minor), cerebrovascular disease, gastroesopha- IV:
geal reflux disease, hypersensitivity reaction, local >10%:
hemorrhage (limb and below-the-knee stump), pulmo- Central nervous system: Headache (12%), akathisia
nary edema, retroperitoneal bleeding (dose-related; 2% to 12%)
Mechanism of Action A direct, highly-selective throm- Endocrine & metabolic: Weight gain (17% to 22%),
bin inhibitor. Reversibly binds to the active thrombin site increased serum cholesterol (4% to 22%),
of free and clot-associated thrombin. Inhibits fibrin for- increased serum triglycerides (7% to 20%),
mation; activation of coagulation factors V, VIII, and XIII; increased LDL cholesterol (10% to 14%),
activation of protein C; and platelet aggregation. decreased HDL cholesterol (14%)
Pharmacodynamics/Kinetics 1% to 10%:
Onset of Action Immediate Cardiovascular: Tachycardia (≤2%), anxiety (≥1%)
Half-life Elimination 39 to 51 minutes; Hepatic Central nervous system: Extrapyramidal reaction
impairment: 181 minutes (10%), drowsiness (9%), sedation (5%), dizziness
Time to Peak Steady-state: 1 to 3 hours (4%), dystonia (2%), fatigue (dose-related; 1% to
Pregnancy Considerations Information related to 2%), restlessness (≥1%), insomnia
argatroban in pregnancy is limited. Use of parenteral Endocrine & metabolic: Increased serum glucose
direct thrombin inhibitors in pregnancy should be limited (8%), weight loss (4%)
to those women who have severe allergic reactions to Gastrointestinal: Constipation (10%), xerostomia
heparin, including heparin-induced thrombocytopenia, (4%), diarrhea (3%), vomiting (3%)
and who cannot receive danaparoid (Guyatt 2012). Hematologic & oncologic: Neutropenia (6%)
Local: Pain at injection site (5%), injection site reac-
tion (≤1%; including erythema, induration, inflam-
ARIPiprazole (ay ri PIP ray zole) mation, hemorrhage, pruritus, rash, swelling)
Neuromuscular & skeletal: Arthralgia (4%), back pain
Brand Names: US Abilify; Abilify Discmelt [DSC];
(4%), myalgia (4%), musculoskeletal pain (3%),
Abilify Maintena; Abilify MyCite
tremor (dose-related; 3%)
Brand Names: Canada Abilify; Abilify Maintena
Pharmacologic Category Second Generation (Atyp-
nasal congestion (2%)
ical) Antipsychotic
Oral:
Use
>10%:
Oral:
Central nervous system: Headache (adults: 27%;
Bipolar I disorder: As monotherapy or as adjunctive
children and adolescents: 10% to 12%), extrapyr-
therapy to lithium or valproate for acute treatment of
amidal reaction (dose-related; children and adoles-
manic or mixed episodes and maintenance (tablet
cents: 6% to 27%; adults: 5% to 13%), drowsiness
with sensor only) associated with bipolar I disorder
Irritability associated with autistic disorder: Treat- (children and adolescents: 10% to 26%; adults: 5%
ment of irritability associated with autistic disorder to 13%), akathisia (dose-related; adults: 2% to
(tablet, orally disintegrating tablet and oral solu- 25%; children and adolescents: 6% to 11%), fatigue
tion only) (dose-related; children and adolescents: 4% to
Major depressive disorder: Adjunctive treatment of 22%; adults: 6%), sedation (dose-related; children
major depressive disorder and adolescents: 9% to 21%; adults: 3% to 11%),
Schizophrenia: Treatment of schizophrenia agitation (19%), insomnia (18%), anxiety (17%)
Tourette disorder: Treatment of Tourette disorder Endocrine & metabolic: Weight gain (children and
(tablet, orally disintegrating tablet and oral solu- adolescents: 3% to 26%; adults 2% to 8%),
tion only) increased serum glucose (adults: 18%; children
Injection: and adolescents: 3% to 5%), decreased HDL cho-
Agitation associated with schizophrenia or bipolar lesterol (children and adolescents: 4%)
mania (immediate-release injection only): Treat- Gastrointestinal: Nausea (8% to 15%), vomiting (8%
ment of agitation associated with schizophrenia or to 14%), constipation (adults: 11%; children and
bipolar mania adolescents: 2%)
Bipolar I disorder (extended -release injection Local: Application site rash (Mycite patch: 12%)
only): Maintenance monotherapy treatment of bipo- Neuromuscular & skeletal: Tremor (dose-related; 5%
lar I disorder to 12%)
Schizophrenia (extended-release injection only): 1% to 10%:
Treatment of schizophrenia Cardiovascular: Orthostatic hypotension (≤1%)
150
ARIPIPRAZOLE
Central nervous system: Dizziness (3% to 10%), mastalgia, memory impairment, menstrual disease,
drooling (children and adolescents: 3% to 9%), mobility disorder, muscle rigidity (injection), muscle
restlessness (5% to 6%), lethargy (older adults: spasm (injection), muscle twitching, myasthenia,
5%; children: 3% to 5%), pain (3%), dystonia myocardial infarction, myoclonus, nasal congestion
(2%), irritability (children and adolescents: 2%) (oral), nasopharyngitis (injection), nausea (injection),
Dermatologic: Skin rash (2%) neuroleptic malignant syndrome, nocturia, obesity,
Endocrine & metabolic: Increased serum triglycer- oculogyric crisis, oropharyngeal spasm, pain (oral),
ides (5% to 10%), weight loss (≥1%), increased palpitations, pancreatitis, panic attack, Parkinson
serum cholesterol (1%) disease, peripheral edema, pharyngolaryngeal pain
Gastrointestinal: Dyspepsia (9%), decreased appe- (injection), photophobia, photopsia, pollakiuria, poly-
tite (children and adolescents: 5% to 7%), dipsia, polyuria, presyncope, priapism, prolonged Q-
increased appetite (children and adolescents: T interval on ECG, pruritus, psychosis, rhabdomyol-
7%), xerostomia (5%), diarrhea (children and ado- ysis, seizure (including injection), seizure (tonic
lescents: 4%), toothache (4%), stomach discomfort clonic), sinus tachycardia, skin photosensitivity, skin
(3%), upper abdominal pain (children and adoles- rash (injection), sleep apnea (obstructive) (Health
cents: 3%), abdominal distress (2% to 3%), ano- Canada, August 16, 2016; Shirani 2011), sleep talk-
rexia ing, somnambulism, speech disturbance, stomach
G en i to uri na r y : U r in ar y i nc o nt in en c e ( ol de r discomfort (injection), suicidal ideation, suicidal ten-
adults: 5%) dencies, supraventricular tachycardia, swollen
Neuromuscular & skeletal: Arthralgia (4%), limb pain tongue, syncope, tardive dyskinesia, thrombocytope-
(4%), stiffness (2% to 4%), asthenia (children and nia, tics, tongue spasm, toothache (injection), tor-
adolescents: 2%), muscle rigidity (children and sades de pointes, transient ischemic attacks,
adolescents: 2%), muscle spasm (2%), myal- trismus, uncontrolled diabetes mellitus, upper
gia (2%) abdominal pain (injection), urinary incontinence
Ophthalmic: Blurred vision (3% to 8%) (injection), urinary retention, urticaria, venous throm-
Respiratory: Nasopharyngitis (children and adoles- boembolism, ventricular tachycardia
cents: 6% to 9%), cough (3%), pharyngolaryngeal Mechanism of Action Aripiprazole is a quinolinone
pain (3%), epistaxis (children and adolescents: 2%) antipsychotic which exhibits high affinity for D2, D3,
Miscellaneous: Fever (children and adolescents: 4% 5-HT1A, and 5-HT2A receptors; moderate affinity for
to 9%) D4, 5-HT2C, 5-HT7, alpha1 adrenergic, and H1 recep-
<1%, postmarketing, and/or case reports: Abdominal tors. It also possesses moderate affinity for the seroto-
distress (injection), abnormal bilirubin levels, abnor- nin reuptake transporter; has no affinity for muscarinic
mal gait, abnormal hepatic function tests, abnormal T (cholinergic) receptors. Aripiprazole functions as a par-
waves on ECG, aggressive behavior, agitation (injec- tial agonist at the D2 and 5-HT1A receptors, and as an
tion), agranulocytosis, akinesia, alopecia, altered antagonist at the 5-HT2A receptor (de Bartolomeis
serum glucose, amenorrhea, anaphylaxis, angina 2015).
pectoris, angioedema, anorexia (injection), anorgas- Pharmacodynamics/Kinetics
mia, aspiration pneumonia, asthenia (injection), Onset of Action Initial: 1 to 3 weeks
ataxia, atrial fibrillation, atrial flutter, atrioventricular Half-life Elimination
block, blurred vision (injection), bradycardia, brady- Aripiprazole: 75 hours; dehydro-aripiprazole: 94
kinesia, bruxism, cardiac arrhythmia, catatonia, cer- hours; IM, extended release (terminal): ~30 to 47
ebrovascular accident, change in libido, chest days (dose-dependent)
discomfort, chest pain, choreoathetosis, cogwheel CYP2D6 poor metabolizers: Aripiprazole: 146 hours
rigidity, decreased appetite (injection), decreased Time to Peak Plasma:
serum cholesterol, decreased serum triglycerides, IM:
delayed ejaculation, delirium, depression, diabetes Immediate release: 1 to 3 hours
mellitus, diabetic ketoacidosis, diplopia, disruption of Extended release (after multiple doses): 4 days
body temperature regulation, dysgeusia, dyspepsia (deltoid administration); 5 to 7 days (gluteal admin-
(injection), dysphagia, dyspnea, dystonia (oroman- istration)
dibular), edema, elevated glycosylated hemoglobin, Tablet: 3 to 5 hours
erectile dysfunction, esophagitis, extrasystoles, eye- With high-fat meal: Aripiprazole: Delayed by 3 hours;
lid edema, facial edema, falling, fever (injection), dehydro-aripiprazole: Delayed by 12 hours
gastroesophageal reflux disease, glycosuria, gyne- Pregnancy Considerations Adverse events have
comastia, heatstroke, hepatic failure, hepatitis, hep- been observed in animal reproduction studies. Aripipra-
atotoxicity, hirsutism, homicidal ideation, hostility,
zole crosses the placenta; aripiprazole and dehydro-
hyperglycemia, hyperhidrosis, hyperinsulinism, aripiprazole can be detected in the cord blood at deliv-
hyperlipidemia, hypersensitivity reaction, hypersom-
ery (Nguyen 2011; Watanabe 2011). Antipsychotic use
nia, hypertension, hypertonia, hypoglycemia, hypo-
during the third trimester of pregnancy has a risk for
kalemia, hypokinesia, hyponatremia, hypotension
abnormal muscle movements (extrapyramidal symp-
(oral), hypothermia, hypotonia, impulse control dis-
toms [EPS]) and/or withdrawal symptoms in newborns
order (including pathologic gambling and hypersex-
following delivery. Symptoms in the newborn may
uality), increased blood urea nitrogen, increased
include agitation, feeding disorder, hypertonia, hypoto-
creatinine clearance, increased creatine phosphoki-
nia, respiratory distress, somnolence, and tremor; these
nase, increased gamma-glutamyl transferase,
effects may be self-limiting or require hospitalization.
increased lactate dehydrogenase, increased liver
enzymes, increased serum bilirubin, increased Treatment algorithms have been developed by the
serum prolactin, inhibition of prolactin secretion, ACOG and the APA for the management of depression
intentional injury, irritability (injection), ischemic heart in women prior to conception and during pregnancy
disease, jaundice, joint stiffness, laryngospasm, leth- (Yonkers 2009). The ACOG recommends that therapy
argy (injection), leukopenia, limb pain (injection), during pregnancy be individualized; treatment with
151
ARIPIPRAZOLE
psychiatric medications during pregnancy should incor- Frequency not defined:

porate the clinical expertise of the mental health clini- Cardiovascular: Angina pectoris, palpitations, tachy-
cian, obstetrician, primary health care provider, and cardia
pediatrician. Safety data related to atypical antipsy- Central nervous system: Anxiety, dizziness, myas-
chotics during pregnancy is limited, as such, routine thenia
use is not recommended. However, if a woman is Gastrointestinal: Constipation, xerostomia
inadvertently exposed to an atypical antipsychotic while Neuromuscular & skeletal: Asthenia
pregnant, continuing therapy may be preferable to <1%, postmarketing, and/or case reports: Erythema at
switching to an agent that the fetus has not yet been injection site, impulse control disorder (including com-
exposed to; consider risk:benefit (ACOG 2008). If treat- pulsive shopping, intense gambling urges, binge eat-
ment is needed in a woman planning a pregnancy or if ing, and hypersexuality), induration at injection site,
treatment is initiated during pregnancy, use of an agent orthostatic hypotension (patient taking 882 mg aripi-
other than aripiprazole is preferred (Larsen 2015). prazole lauroxil), swelling at injection site
Mechanism of Action Aripiprazole lauroxil is a pro-
Health care providers are encouraged to enroll women
drug of aripiprazole. Following intramuscular injection,
exposed to aripiprazole during pregnancy in the
aripiprazole lauroxil is likely converted by enzyme-medi-
National Pregnancy Registry for Atypical Antipsychotics
ated hydrolysis to N-hydroxymethyl aripiprazole, which
(866-961-2388 or http://www.womensmentalhealth.org/
is then hydrolyzed to aripiprazole. Aripiprazole is a
clinical-and-research-programs/pregnancyregistry/).
quinolinone antipsychotic that exhibits high affinity for
Product Availability D2, D3, 5-HT1A, and 5-HT2A receptors; moderate affinity
Abilify immediate-release injection (9.75 mg/1.3 mL) for D4, 5-HT2C, 5-HT7, alpha1 adrenergic, and H1 recep-
has been discontinued in the US for more than 1 year. tors. It also possesses moderate affinity for the seroto-
Dental Health Professional Considerations Aripi- nin reuptake transporter; has no affinity for muscarinic
prazole works differently from the classic antipsy- (cholinergic) receptors. Aripiprazole functions as a par-
chotics, such as chlorpromazine, in that it does not tial agonist at the D2 and 5-HT1A receptors, and as an
appear to block central dopaminergic receptors, but antagonist at the 5-HT2A receptor (de Bartolomeis
rather seems to be a stabilizer of dopamine-serotonin 2015).
central systems. The risk of extrapyramidal reactions Pharmacodynamics/Kinetics
such as pseudoparkinsonism, acute dystonic reactions, Onset of Action
akathisia, and tardive dyskinesia are low and the fre- Aristada: 5 to 6 days following injection; within 4 days
quencies reported are similar to placebo. Aripiprazole following injection when administered concomitantly
may be associated with neuroleptic malignant syn- with oral aripiprazole.
drome (NMS). Aristada Initio (675 mg strength): Reaches systemic
circulation on day of injection; reaches clinically
ARIPiprazole Lauroxil (ay ri PIP ray zole lawr OX il) relevant serum concentrations 4 days following injec-
tion when administered concomitantly with oral aripi-
Brand Names: US Aristada; Aristada Initio prazole 30 mg.
Pharmacologic Category Second Generation (Atyp- Duration of Action Aristada: 36 days following
ical) Antipsychotic appearance in the systemic circulation.
Use Half-life Elimination
Schizophrenia: Treatment of schizophrenia in adults Aristada: 53.9 to 57.2 days
Limitations of use: The 675 mg strength aripiprazole Aristada Initio (675 mg strength): 15 to 18 days
lauroxil (Aristada Initio) is only to be used as a single Time to Peak Serum: Aristada Initio (675 mg
dose in combination with oral aripiprazole for initiation strength): 16 to 35 days (median 27 days)
of long-term treatment with aripiprazole lauroxil (Aris- Pregnancy Considerations
tada) or as a single dose to reinitiate treatment after a Aripiprazole crosses the placenta; aripiprazole and
missed dose of aripiprazole lauroxil (Aristada). It is not dehydro-aripiprazole can be detected in the cord blood
intended for repeat dosing. at delivery (Nguyen 2011; Watanabe 2011).
Antipsychotic use during the third trimester of preg-
Adverse effects of palpitations, tachycardia have been
nancy has a risk for abnormal muscle movements
observed; monitor, and if present, use caution with the
(extrapyramidal symptoms [EPS]) and/or withdrawal
use of vasoconstrictor
symptoms in newborns following delivery. Symptoms
Effects on Dental Treatment Key adverse event(s) in the newborn may include agitation, feeding disorder,
related to dental treatment: Xerostomia; Parkinson-like
hypertonia, hypotonia, respiratory distress, somno-
syndrome and restlessness in 3% to 4% of patients has
lence, and tremor; these effects may be self-limiting or
been reported. require hospitalization.
require special precautions Data collection to monitor pregnancy and infant out-
Adverse Reactions comes following exposure to aripiprazole lauroxil is
>10%: Central nervous system: Akathisia (11%) ongoing. Healthcare providers are encouraged to enroll
1% to 10%: women exposed to aripiprazole lauroxil during preg-
Central nervous system: Headache (5%), parkinso- nancy in the National Pregnancy Registry for Atypical
nian-like syndrome (4%), insomnia (3% to 4%), rest- Antipsychotics at 1-866-961-2388 or visit http://
lessness (3%), dystonia (2%) womensmentalhealth.org/clinical-and-research-pro-
Endocrine & metabolic: Weight gain (2%; ≥7% grams/pregnancyregistry.
increase: 9% to 10%)
Local: Pain at injection site (3% to 4%) Armodafinil (ar moe DAF i nil)
phokinase (1% to 2%) Brand Names: US Nuvigil
152
ARTEMETHER AND LUMEFANTRINE
Pharmacologic Category Central Nervous System transporter and inhibits dopamine reuptake, which
Stimulant may result in increased extracellular dopamine levels
Use in the brain. However, it does not appear to be a
Narcolepsy: To improve wakefulness in patients with dopamine receptor agonist and also does not appear
excessive sleepiness associated with narcolepsy. to bind to or inhibit the most common receptors or
Obstructive sleep apnea: To improve wakefulness in enzymes that are relevant for sleep/wake regulation.
patients with excessive sleepiness associated with Pharmacodynamics/Kinetics
obstructive sleep apnea (OSA). Half-life Elimination ~15 hours
Limitations of use: In OSA, armodafinil is indicated to Time to Peak 2 hours (fasted)
treat excessive sleepiness and not as treatment for Pregnancy Considerations Intrauterine growth
the underlying obstruction. If continuous positive air- restriction and spontaneous abortion have been
way pressure (CPAP) is the treatment of choice for a reported in association with armodafinil. Efficacy of
patient, a maximal effort to treat with CPAP for an steroidal contraceptives may be decreased; alternate
adequate period of time should be made prior to means of contraception should be considered during
initiating armodafinil for excessive sleepiness. therapy and for 1 month after armodafinil is discontin-
Shift-work disorder: To improve wakefulness in ued.
patients with excessive sleepiness associated with
shift-work disorder. A pregnancy registry has been established for patients
Local Anesthetic/Vasoconstrictor Precautions exposed to armodafinil; healthcare providers are
Use vasoconstrictor with caution. Patients may experi- encouraged to register pregnant patients or pregnant
ence heart palpitations and increased heart rate when women may register themselves by calling
taking armodafinil. 1-866-404-4106.
Effects on Dental Treatment Key adverse event(s) Controlled Substance C-IV
related to dental treatment: Armodafinil causes tachy-
cardia, increases in blood pressure, and palpitations. Artemether and Lumefantrine
Consider monitoring blood pressure prior to using local (ar TEM e ther & loo me FAN treen)
anesthetic with a vasoconstrictor. Symptoms associ-
ated with bruxism have been observed in some Related Information
patients. Clinical Risk Related to Drugs Prolonging QT Interval
Effects on Bleeding No information available to on page 1462
require special precautions Brand Names: US Coartem
Adverse Reactions Pharmacologic Category Antimalarial Agent
>10%: Central nervous system: Headache (14% to Use Treatment of acute, uncomplicated malaria infec-
23%; dose related) tions due to Plasmodium falciparum, including geo-
1% to 10%: graphical regions where chloroquine resistance has
Cardiovascular: Palpitations (2%), increased heart been reported
rate (1%) Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Insomnia (4% to 6%; dose Artemether and lumefantrine is one of the drugs con-
related), dizziness (5%), anxiety (4%), depression firmed to prolong the QT interval and is accepted as
(1% to 3%; dose related), fatigue (2%), agitation having a risk of causing torsade de pointes. The risk of
(1%), depressed mood (1%), lack of concentration drug-induced torsade de pointes is extremely low when
(1%), migraine (1%), nervousness (1%), pain (1%), a single QT interval prolonging drug is prescribed. In
paresthesia (1%) terms of epinephrine, it is not known what effect vaso-
Dermatologic: Skin rash (1% to 4%; dose related), constrictors in the local anesthetic regimen will have in
contact dermatitis (1%), diaphoresis (1%) patients with a known history of congenital prolonged
QT interval or in patients taking any medication that
transferase (1%), increased thirst (1%)
prolongs the QT interval. Until more information is
Gastrointestinal: Nausea (6% to 9%; dose related),
obtained, it is suggested that the clinician consult with
xerostomia (2% to 7%; dose related), diarrhea (4%),
the physician prior to the use of a vasoconstrictor in
dyspepsia (2%), upper abdominal pain (2%), ano-
suspected patients, and that the vasoconstrictor (epi-
rexia (1%), constipation (1%), decreased appetite
nephrine, mepivacaine and levonordefrin [Carbocaine®
(1%), loose stools (1%), vomiting (1%)
2% with Neo-Cobefrin®]) be used with caution.
Hypersensitivity: Seasonal allergy (1%)
Neuromuscular & skeletal: Tremor (1%) Effects on Dental Treatment No significant effects or
Renal: Polyuria (1%) complications reported
Respiratory: Dyspnea (1%), flu-like symptoms (1%) Effects on Bleeding No information available to
Miscellaneous: Fever (1%) require special precautions
<1%, postmarketing, and/or case reports: Anaphylaxis, Adverse Reactions
angioedema, DRESS syndrome, hypersensitivity >10%:
reaction (including bronchospasm, dysphagia), hypo- Cardiovascular: Palpitation (adults: 18%)
uricemia, increased liver enzymes, increased serum Central nervous system: Headache (adults 56%; chil-
alkaline phosphatase, irritability, multi-organ hyper- dren 13%), dizziness (adults 39%; children 4%),
sensitivity, oral mucosa changes (including blistering, fever (25% to 29%), chills (adults 23%; children
sores, ulceration), pancytopenia, skin changes 5%), sleep disorder (adults: 22%), fatigue (adults
(including blistering, sores, ulceration), Stevens-John- 17%; children 3%)
son syndrome, suicidal ideation, systolic hypertension, Gastrointestinal: Anorexia (adults 40%; children 13%),
toxic epidermal necrolysis nausea (adults 26%; children 5%), vomiting (17% to
Mechanism of Action The exact mechanism of action 18%), abdominal pain (8% to 17%)
of armodafinil is unknown. It is the R-enantiomer of Infection: Plasmodium falciparum (exacerbation: chil-
modafinil. Armodafinil binds to the dopamine dren: 17%)
153
ARTEMETHER AND LUMEFANTRINE
Neuromuscular & skeletal: Weakness (adults 38%; Artemether may reduce the effectiveness of hormonal
children 5%), arthralgia (adults 34%; children 3%), contraceptives. An additional nonhormonal method of
myalgia (adults 32%; children 3%) birth control should be used during therapy.
Respiratory: Cough (adults 6%; children 23%) Dental Health Professional Considerations See
Miscellaneous: Fever (25% to 29%) Local Anesthetic/Vasoconstrictor Precautions
3% to 10%:
Central nervous system: Insomnia (adults: 5%),
malaise (adults: 3%), vertigo (adults: 3%) Artesunate (ar TES oo nate)
Dermatologic: Pruritus (adults: 4%), skin rash (3%) Pharmacologic Category Antimalarial Agent; Artemi-
Gastrointestinal: Diarrhea (7% to 8%) sinin Derivative
Hematologic & oncologic: Anemia (4% to 9%) Local Anesthetic/Vasoconstrictor Precautions
Hepatic: Hepatomegaly (6% to 9%), increased serum No information available to require special precautions
AST (≤4%)
Infection: Malaria (≤3%)
related to dental treatment: Metallic taste has been
Respiratory: Rhinitis (4%), nasopharyngitis (≤3%)
reported
gait, abnormal lymphocytes, abscess, agitation, ana-
pylaxis, angioedema, asthma, ataxia, back pain, bron- require special precautions
chitis, bullous dermatitis, change in platelet count Adverse Reactions Frequency not defined.
(increased), clonus, conjunctivitis, constipation, Cardiovascular: Hypotension
decreased hematocirt, decreased platelet count, Central nervous system: Anxiety, ataxia, dizziness,
decreased white blood cell count, dermatitis (hands headache, hyperreflexia, metallic taste, restlessness,
and feet), dyspepsia, dysphagia, emotional lability, slurred speech
eosinophilia, fine motor control disorder, gastroenter- Dermatologic: Erythema, pruritus, skin rash, urticaria
itis, helminthiasis, hematuria, hemolytic anemia Endocrine & metabolic: Hypoglycemia
(delayed), hookworm infection, hyper-reflexia, hypo- Gastrointestinal: Anorexia, diarrhea, nausea, vomiting
esthesia, hypokalemia, impetigo, increased serum Hematologic & oncologic: Anemia, hemolysis, neutro-
ALT, influenza, leukocytosis, leukopenia, lower respi- penia, reticulocytopenia
ratory tract infection, nystagmus, oral herpes, otic Hepatic: Increased serum ALT
infection, peptic ulcer, pharyngolaryngeal pain, pneu- Hypersensitivity: Angioedema, hypersensitivity reaction
monia, proteinuria, respiratory tract infection, subcuta- Neuromuscular & skeletal: Tremor
neous abscess, tinnitus, tremor, upper respiratory tract Renal: Increased blood urea nitrogen
infection, urinary tract infection, urticaria Respiratory: Dyspnea
Mechanism of Action A coformulation of artemether Mechanism of Action Artesunate, a semisynthetic
and lumefantrine with activity against Plasmodium falci- derivative of artemisinin, is a prodrug which is con-
parum. Artemether and major metabolite dihydroarte- verted to dihydroartemisinin (DHA). DHA is an antima-
misinin (DHA) are rapid schizontocides with activity larial agent active against all of the erythrocytic stages
attributed to the endoperoxide moiety common to each of the parasite including gametocytes; inhibits parasite
substance. Artemether inhibits an essential calcium metabolism and enhances the clearance of infected
adenosine triphosphatase. The exact mechanism of erythrocytes.
lumefantrine is unknown, but it may inhibit the formation Antiparasitic activity is hypothesized to involve cleavage
of β-hematin by complexing with hemin. Both arte- of the Fe2+of endoperoxide bridge, thereby producing
mether and lumefantrine inhibit nucleic acid and protein free radicals and damaging parasite proteins. DHA may
synthesis. Artemether rapidly reduces parasite biomass also inhibit calcium adenosine triphosphatase (cATP) of
and lumefantrine eliminates residual parasites. the sarcoplasmic endoplasmic reticulum and impair
Pharmacodynamics/Kinetics parasite protein folding.
Half-life Elimination Artemether: 1-2 hours; DHA: 2 Pharmacodynamics/Kinetics
hours; Lumefantrine: 72-144 hours Half-life Elimination Artesunate: Adults infected with
Time to Peak Plasma: Artemether: ~2 hours; Lume- severe malaria: 0.22 hours (range: 0.08 to 0.61
fantrine: ~6-8 hours hours); Dihydroartemisinin (DHA): 0.34 hours (range:
Pregnancy Risk Factor C 0.14 to 0.87 hours) (Newton 2006)
Pregnancy Considerations Time to Peak Dihydroartemisinin (DHA): Adults
Safety data from an observational pregnancy study infected with severe malaria: Within 15 minutes (New-
included 500 pregnant women exposed to artemether/ ton 2006)
lumefantrine and did not show an increase in adverse Pregnancy Considerations Adverse events have
outcomes or teratogenic effects over background rate. been observed in some animal reproduction studies.
Approximately one-third of these patients were in the Studies in pregnant women have not revealed an
third trimester. increased risk of congenital abnormalities in newborns
Malaria infection in pregnant women may be more (Kovacs 2015, McGready 1998, McGready 2008).
severe than in nonpregnant women. Infection may Malaria infection in pregnant women may be more
increase the risk of adverse pregnancy outcomes, severe than in nonpregnant women. Because P. falci-
including miscarriage, premature delivery, low birth parum malaria can cause maternal death, congenital
weight, congenital infection, or perinatal death (CDC malaria, and fetal loss, pregnant women traveling to
July 2013). Artemether/lumefantrine may be used to malaria-endemic areas must use personal protection
treat uncomplicated malaria during the second and third against mosquito bites. Artesunate is recommended
trimesters. Artemether/lumefantrine also may be used for the treatment of severe malaria in pregnant women
as an alternative treatment during the first trimester (Kovacs 2015).
when preferred agents are not available. Dosing is the Prescribing and Access Restrictions
same as nonpregnant patients (Ballard [CDC] 2018). Investigational agent – not approved for use in the US
154
ARTICAINE AND EPINEPHRINE
Artesunate is available in the U.S. for IV use in patients Adverse reactions are characteristic of those associ-
with malaria through an Investigational New Drug (IND) ated with other amide-type local anesthetics; adverse
protocol. To obtain artesunate via the IND protocol, reactions to this group of drugs may also result from
clinicians must contact the Centers for Disease Control excessive plasma levels which may be due to over-
(CDC) Malaria Hotline at 770-488-7788 (business dosage, unintentional intravascular injection, or slow
hours) or 770-488-7100 (nonbusiness hours) and metabolic degradation.
request to speak with a CDC Malaria Branch clinician. Cardiovascular: Facial edema (1%), cardiac arrhythmia,
Additional information from the CDC is available at cardiac insufficiency
https://www.cdc.gov/laboratory/drugservice/formulary.- Central nervous system: Pain (13%), headache (4%),
html. paresthesia (1%), seizure
Gastrointestinal: Gingivitis (1%)
Eligibility criteria under the IND protocol include (Call-
Hypersensitivity: Hypersensitivity reaction
ender 2011; Hess 2010):
Local: Injection site reaction
- Patients must have malaria: Confirmation by
Respiratory: Asthma
microscopy or undetermined but strong clinical sus-
Miscellaneous: Tissue necrosis
picion of Plasmodium falciparum or other Plasmo-
dium spp. infection
pain, accidental injury, arthralgia, back pain, constipa-
- Patients must require parenteral therapy: Unable
tion, dermatological disease, diarrhea, dizziness,
to take oral medications, high-density parasitemia
drowsiness, dysgeusia, dysmenorrhea, dyspepsia,
(eg, >5%), or diagnosis of severe malaria (eg, seiz-
ecchymoses, edema, facial paralysis, gingival hemor-
ures, shock, hemoglobin <7 g/dL, disseminated
rhage, glossitis, hemorrhage, hyperesthesia,
intravascular coagulation, or acute respiratory dis-
increased thirst, lymphadenopathy, malaise, methe-
tress syndrome [ARDS]).
moglobinemia, migraine, myalgia, nausea, neck pain,
- IV artesunate must be the preferred treatment: IV
nervousness, neuropathy, oral mucosa ulcer, osteo-
artesunate is at least as readily available as IV
myelitis, otalgia, pharyngitis, pruritus, rhinitis, sialor-
quinidine or the patient has experienced quinidine
rhea, stomatitis, syncope, tachycardia, tongue edema,
failure (eg, parasitemia >10% baseline after 48 hours
vomiting, weakness, xerostomia
of quinidine therapy), quinidine intolerance (eg, per-
sistent hypotension, QRS prolongation >50% of Dental Usual Dosage Adults:
baseline or QTc interval prolongation >25% of base- Infiltration: Injection volume of 4% solution: 0.5-2.5 mL;
line), or contraindications to quinidine (eg, allergy, left total dose: 20-100 mg
bundle branch block, myasthenia gravis, digoxin Nerve block: Injection volume of 4% solution: 0.5-3.4
toxicity). mL; total dose: 20-136 mg
Oral surgery: Injection volume of 4% solution: 1-5.1 mL;
For medical access to IV artesunate in Canada, please total dose: 40-204 mg
refer to special access information on the Public Health Note: These dosages are guides only; other dosages
Agency of Canada website, http://www.phac-aspc.gc. may be used; however, do not exceed maximum
ca/tmp-pmv/quinine/. recommended dose
Special populations: The clinician is reminded that
Articaine and Epinephrine these doses serve only as a guide to the amount of
(AR ti kane & ep i NEF rin) anesthetic required for most routine procedures. The
Related Information actual volumes to be used depend upon a number of
EPINEPHrine (Systemic) on page 495 factors, such as type and extent of surgical procedure,
depth of anesthesia, degree of muscular relaxation, and
Oral Pain on page 1520
condition of the patient. In all cases, the smallest dose
Brand Names: US Articadent; Orabloc; Septocaine that will produce the desired result should be given.
with Epinephrine 1:100,000; Septocaine with Epinephr-
Dosages should be reduced for pediatric patients, eld-
ine 1:200,000; Zorcaine
erly patients, and patients with cardiac and/or liver
Brand Names: Canada Astracaine with Epinephrine disease.
1:200,000; Astracaine with Epinephrine forte 1:100,000; Dosing
Karticaine; Karticaine Forte; Orabloc 1:100,000; Ora- Adult
bloc 1:200,000; Posicaine N; Posicaine SP; Septanest Dental anesthesia: Submucosal infiltration and/or
N; Septanest SP; Ultracaine DS; Ultracaine DS Forte; nerve block: Articaine 4%/epinephrine: Note: These
Zorcaine
dosages are guides only; other dosages may be
Generic Availability (US) No used; however, do not exceed maximum recom-
Pharmacologic Category Local Anesthetic mended dose. The actual volumes to be used
Dental Use Local, infiltrative, or conductive anesthesia depend upon a number of factors, such as type
in both simple and complex dental and periodontal and extent of surgical procedure, depth of anesthe-
procedures sia, degree of muscular relaxation, and condition of
Use Dental anesthesia: Local, infiltrative, or conductive the patient. In all cases, the smallest dose that will
anesthesia in both simple and complex dental proce- produce the desired result should be given. For most
dures routine dental procedures, epinephrine 1:200,000 is
Local Anesthetic/Vasoconstrictor Precautions preferred; when more pronounced hemostasis or
No information available to require special precautions improved visualization of the surgical field are
(see Dental Health Professional Considerations) required, epinephrine 1:100,000 may be used. Dos-
Effects on Dental Treatment No significant effects or ages should be reduced for patients with cardiac
complications reported disease and acutely ill and/or debilitated patients:
Effects on Bleeding No information available to Infiltration: 0.5 to 2.5 mL; total dose of articaine: 20 to
require special precautions 100 mg; maximum dose of articaine: 7 mg/kg
Adverse Reactions Frequency not always defined. (0.175 mL/kg).
155
Nerve block: 0.5 to 3.4 mL; total dose of articaine: 20 Adolescents ≥17 years: Submucosal infiltration and/
to 136 mg; maximum dose of articaine: 7 mg/kg or nerve block: Articaine 4%/epinephrine: Injection:
(0.175 mL/kg). Infiltration: 0.5 to 2.5 mL (total articaine dose: 20 to
Oral surgery: 1 to 5.1 mL; total dose of articaine: 40 100 mg); not to exceed 7 mg/kg (0.175 mL/kg of
to 204 mg; maximum dose of articaine: 7 mg/kg 4% solution) of articaine
(0.175 mL/kg). Nerve block: 0.5 to 3.4 mL (total articaine dose: 20
Geriatric to 136 mg); not to exceed 7 mg/kg (0.175 mL/kg
Dental anesthesia: Submucosal infiltration and/or of 4% solution) of articaine
nerve block: Articaine 4%/epinephrine: Note: These Oral surgery: 1 to 5.1 mL (total articaine dose: 40 to
dosages are guides only; other dosages may be 204 mg); not to exceed 7 mg/kg (0.175 mL/kg of
used; however, do not exceed maximum recom- 4% solution) of articaine
mended dose. The actual volumes to be used Renal Impairment: Pediatric There are no dosage
depend upon a number of factors, such as type adjustments provided in the manufacturer’s labeling
and extent of surgical procedure, depth of anesthe- (has not been studied).
sia, degree of muscular relaxation, and condition of Hepatic Impairment: Pediatric There are no dos-
the patient. In all cases, the smallest dose that will age adjustments provided in the manufacturer’s label-
produce the desired result should be given. For most ing (has not been studied). Use with caution in
routine dental procedures, epinephrine 1:200,000 is patients with severe hepatic disease.
preferred; when more pronounced hemostasis or Mechanism of Action
improved visualization of the surgical field are Articaine: Blocks both the initiation and conduction of
required, epinephrine 1:100,000 may be used. Dos- nerve impulses by increasing the threshold for elec-
ages should be reduced for patients with cardiac trical excitation in the nerve, slowing the propagation
disease and acutely ill and/or debilitated patients: of the nerve impulse, and reducing the rate of rise of
65 to 75 years: the action potential.
Simple procedures: 0.43 to 4.76 mg/kg of articaine. Epinephrine: Increases the duration of action of arti-
Complex procedures: 1.05 to 4.27 mg/kg of articaine by causing vasoconstriction (via alpha effects)
caine. which slows the vascular absorption of articaine.
≥75 years: Contraindications
Simple procedures: 0.78 to 4.76 mg/kg of articaine. Sulfite hypersensitivity.
Complex procedures: 1.12 to 2.17 mg/kg of arti- Documentation of allergenic cross-reactivity for local
caine. anesthetics is limited. However, because of similarities
Renal Impairment: Adult There are no dosage in chemical structure and/or pharmacologic actions,
adjustments provided in the manufacturer’s labeling the possibility of cross-sensitivity cannot be ruled out
(has not been studied). with certainty.
Hepatic Impairment: Adult There are no dosage Canadian labeling: Additional contraindications (not in
adjustments provided in the manufacturer’s labeling US labeling): Hypersensitivity to articaine, epinephr-
(has not been studied). Use with caution in patients ine, or any component of the formulation; allergies to
with severe hepatic disease. dental anesthetics; patients with inflammation and/or
Pediatric sepsis near the proposed injection site, severe shock,
Dental anesthesia: Note: The provided dosages are paroxysmal tachycardia, frequent arrhythmia, neuro-
guides only; other dosages may be necessary; how- logical disease, severe hypertension; children <4
ever, do not exceed maximum recommended dose. years of age; anesthesia of fingers, toes, tip of nose,
The actual volumes to be used depend upon a ears, and penis; narrow-angle glaucoma; severe heart
number of factors, such as type and extent of surgi- disease, heart block, or known arrhythmias; recent (3
cal procedure, depth of anesthesia, degree of mus- to 6 months) myocardial infarction; recent (3 months)
cular relaxation, and condition of the patient. In all coronary artery bypass surgery; concurrent use of
cases, the smallest dose that will produce the non-cardioselective beta-blockers, tricyclic antide-
desired result should be used. Two concentrations pressants, MAO inhibitors, ergot derivatives, and hal-
of epinephrine (1:100,000 or 1:200,00) with 4% othane (or other similar inhalation type drugs);
articaine are available; when more pronounced pheochromocytoma; thyrotoxicosis; severe hepatic/
hemostasis or improved visualization of the surgical renal insufficiency; bronchial asthma; intravascu-
field are required, epinephrine 1:100,000 may be lar use.
used; in clinical trials of pediatric patients 4 to 16 Warnings/Precautions Systemic toxicity may occur.
years of age, the 1:100,000 was also used; in adults, Systemic absorption of local anesthetics may produce
the manufacturer recommends epinephrine cardiovascular and/or CNS effects. Toxic blood concen-
1:200,000 for most routine dental procedures. Dos- trations of local anesthetics depress cardiac conduction
ages should be reduced for patients with cardiac and excitability, which may lead to AV block, ventricular
disease and acutely ill and/or debilitated patients. arrhythmias, and cardiac arrest (sometimes resulting in
Dosing presented in variable unit (mg/kg, mg, mL/ death). In addition, myocardial contractility is depressed
kg, and mL); use extra precaution to verify dosing and peripheral vasodilation occurs, leading to
units. decreased cardiac output and arterial blood pressure.
Children ≥4 years and Adolescents ≤16 years: Sub- Restlessness, anxiety, tinnitus, dizziness, blurred
mucosal infiltration and/or nerve block: Articaine vision, tremors, depression, or drowsiness may be early
4%/epinephrine: Injection: warning signs of CNS toxicity. Small doses of local
Simple procedures: Reported range: 0.76 to anesthetics injected into dental blocks may produce
5.65 mg/kg of articaine; maximum articaine dose: adverse reactions similar to systemic toxicity, including
7 mg/kg (0.175 mL/kg of 4% solution) confusion, convulsions, respiratory depression and/or
Complex procedures: 0.37 to 7 mg/kg of articaine; respiratory arrest, and cardiovascular stimulation or
maximum articaine dose: 7 mg/kg (0.175 mL/kg of depression; these reactions may be due to intra-arterial
4% solution) injection of the local anesthetic with retrograde flow to
156
the cerebral circulation. Constantly monitor cardiovas- Lurasidone; Neuromuscular-Blocking Agents; Sol-
cular and respiratory vital signs and patient's state of riamfetol; Sympathomimetics
consciousness carefully following each injection. Epi-
The levels/effects of Articaine and Epinephrine may
nephrine may cause local toxicity, including ischemic
be increased by: AtoMOXetine; Beta-Blockers (Non-
injury or necrosis. Methemoglobinemia has been
selective); Cannabinoid-Containing Products; Chloro-
reported with local anesthetics; clinically significant
procaine; Cocaine (Topical); COMT Inhibitors; Ergot
methemoglobinemia requires immediate treatment
Derivatives; Guanethidine; Hyaluronidase; Inhala-
along with discontinuation of the anesthetic and other
tional Anesthetics; Linezolid; Methemoglobinemia
oxidizing agents. Onset may be immediate or delayed
Associated Agents; Monoamine Oxidase Inhibitors;
(hours) after anesthetic exposure. Patients with glu-
Serotonin/Norepinephrine Reuptake Inhibitors; Tedi-
cose-6-phosphate dehydrogenase deficiency, congen-
zolid; Tricyclic Antidepressants
ital or idiopathic methemoglobinemia, cardiac or
pulmonary compromise, exposure to oxidizing agents Decreased Effect
or their metabolites, or infants <6 months of age are Articaine and Epinephrine may decrease the levels/
more susceptible and should be closely monitored for effects of: Antidiabetic Agents; Benzylpenicilloyl Poly-
signs and symptoms of methemoglobinemia (eg, cya- lysine; Technetium Tc 99m Tilmanocept
nosis, headache, rapid pulse, shortness of breath, light- The levels/effects of Articaine and Epinephrine may
headedness, fatigue). Use with caution in patients with be decreased by: Alpha1-Blockers; Benperidol; Beta-
impaired cardiovascular function, including patients with Blockers (Beta1 Selective); Beta-Blockers (with Alpha-
heart block. Use local anesthetics containing a vaso- Blocking Properties); Blonanserin; Bromperidol; Clo-
constrictor with caution in patients with vascular dis- ZAPine; Promethazine; Spironolactone
ease; patients with peripheral vascular disease or Pharmacodynamics/Kinetics
hypertensive vascular disease may exhibit exaggerated Onset of Action 1 to 9 minutes
vasoconstrictor response, possibly resulting in ischemic Duration of Action Complete anesthesia: ~1 hour
injury or necrosis. Dosages should be reduced for (infiltration); ~2 hours (nerve block)
patients with cardiac disease. Use with caution in Half-life Elimination Articaine/epinephrine: 43.8 to
patients with severe hepatic disease (has not been 44.4 minutes
studied). Time to Peak Articaine: ~25 minutes (single dose); 48
Administer reduced dosages, commensurate with age minutes (3 doses)
and physical condition to pediatric, elderly, debilitated Pregnancy Risk Factor C
and/or acutely-ill patients. Avoid intravascular injection; Pregnancy Considerations Adverse events have
accidental intravascular injection may be associated been observed in some animal reproduction studies
with convulsions, followed by CNS or cardiorespiratory using this combination. Articaine crosses the placenta
depression and coma, progressing ultimately to respi- (Strasser 1977).
ratory arrest. Aspiration should be performed prior to Breastfeeding Considerations It is not known if
administration; the needle must be repositioned until no articaine or epinephrine are excreted in breast milk.
return of blood can be elicited by aspiration; however, The manufacturer recommends that caution be exer-
absence of blood in the syringe does not guarantee that cised when administering articaine/epinephrine to
intravascular injection has been avoided. To avoid breastfeeding women; consideration may be given to
serious adverse effects and high plasma levels, use pumping and discarding milk for 4 hours after the last
the lowest dosage resulting in effective anesthesia. dose. In general, women administered single dose local
Repeated doses may cause significant increases in anesthesia for dental procedures may resume breast-
blood levels due to the possibility of accumulation of feeding once they are awake and stable (Montgomery
the drug or its metabolites. Dosage recommendations 2012).
should not be exceeded. Health care providers should Dosage Forms: US
be well trained in diagnosis and management of emer- Injection, solution [for dental use]:
gencies that may arise from the use of these agents. Articadent: Articaine hydrochloride 4% [40 mg/mL]
Resuscitative equipment, oxygen, and other resuscita- and epinephrine 1:100,000 (1.7 mL)
tive drugs should be available for immediate use. May Articadent: Articaine hydrochloride 4% [40 mg/mL]
contain sodium metabisulfite, which may cause allergic- and epinephrine 1:200,000 (1.7 mL)
type reactions (including anaphylactic symptoms, and Orabloc: Articaine hydrochloride 4% [40 mg/mL] and
life-threatening or less severe asthmatic episodes) in epinephrine 1:100,000 (1.8 mL)
certain susceptible patients. The overall prevalence of Orabloc: Articaine hydrochloride 4% [40 mg/mL] and
the sulfite sensitivity in the general population is epinephrine 1:200,000 (1.8 mL)
unknown, and is seen more frequently in asthmatic than Septocaine with epinephrine 1:100,000: Articaine 4%
in nonasthmatic persons. Potentially significant interac- [40 mg/mL] and epinephrine 1:100,000 (1.7 mL)
tions may exist, requiring dose or frequency adjust- Septocaine with epinephrine 1:200,000: Articaine 4%
ment, additional monitoring, and/or selection of [40 mg/mL] and epinephrine 1:200,000 (1.7 mL)
alternative therapy. Zorcaine: Articaine 4% [40 mg/mL] and epinephrine
Drug Interactions 1:100,000 (1.7 mL)
Metabolism/Transport Effects Refer to individual Dosage Forms: Canada
components. Injection, solution [for dental use]:
Avoid Concomitant Use Astracaine with epinephrine 1:200,000: Articaine 4%
Avoid concomitant use of Articaine and Epinephrine and epinephrine 1:200,000 (1.8 mL)
with any of the following: Blonanserin; Bromperidol; Astracaine Forte with epinephrine forte 1:100,000:
Bupivacaine (Liposomal); Ergot Derivatives; Lurasi- Articaine 4% and epinephrine 1:100,000 (1.8 mL)
done Septanest N: Articaine 4% and epinephrine 1:200,000
Increased Effect/Toxicity (1.7 mL)
Articaine and Epinephrine may increase the levels/ Septanest SP: Articaine 4% and epinephrine
effects of: Bupivacaine (Liposomal); Doxofylline; 1:100,000 (1.7 mL)
157
Ultracaine DS: Articaine 4% and epinephrine injection. A single case involved infiltration around tooth
1:200,000 (1.7 mL) number 35 (European numbering system; tooth number
Ultracaine DS Forte: Articaine 4% and epinephrine 20 for Universal numbering system) and the final case
1:100,000 (1.7 mL) involved infiltration and intraligamentary injection in the
Dental Health Professional Considerations Sep- maxillary anterior region.
tocaine (articaine hydrochloride 4% and epinephrine
A 2010 report, reviewed adverse events submitted
1:100,000) is the first FDA approval in 30 years of a
voluntarily over a 10-year period involving the dental
new local dental anesthetic providing complete pulpal
local anesthetics articaine, bupivacaine, lidocaine,
anesthesia for approximately 1 hour. Chemically, arti-
caine contains both an amide linkage and an ester mepivacaine, and prilocaine in the United States. Arti-
linkage, making it chemically unique in the class of local caine reported incidence: One case per 4,159,848
anesthetics. Since it contains the ester linkage, arti- cartridges sold. The reported incidence of paresthesia
caine HCl is rapidly metabolized by plasma carboxyes- was one case for 13,800,970 cartridges of all local
terase to its primary metabolite, articainic acid, which is anesthetics sold in the U.S. (Garisto, 2010).
an inactive product of this metabolism. According to the
manufacturer, in vitro studies show that the human liver Asenapine (a SEN a peen)
microsomal P450 isoenzyme system metabolizes
approximately 5% to 10% of available articaine with Related Information
nearly quantitative conversion to articainic acid. The Clinical Risk Related to Drugs Prolonging QT Interval
elimination half-life of articaine is about 1.8 hours, and on page 1462
that of articainic acid is about 1.5 hours. Articaine is Brand Names: US Saphris
excreted primarily through urine with 53% to 57% of the Brand Names: Canada Saphris
administered dose eliminated in the first 24 hours Pharmacologic Category Antimanic Agent; Second
following submucosal administration. Articainic acid is Generation (Atypical) Antipsychotic
the primary metabolite in urine. A minor metabolite, Use
articainic acid glucuronide, is also excreted in the urine. Bipolar disorder: Treatment of acute manic or mixed
Articaine constitutes only 2% of the total dose excreted episodes associated with bipolar I disorder (as mono-
in urine. therapy in adult and pediatric patients 10 years and
The anesthetic efficacy of the articaine 4% with older or adjunctive treatment with lithium or valproate
1:200,000 epinephrine (A/200) was compared to that in adults) and maintenance treatment in adults (as
of articaine 4% with 1:100,000 (A/100) using electric monotherapy)
pulp tester to assess anesthesia using 63 subjects after Schizophrenia: Treatment of adults with schizophrenia
either maxillary infiltration (Moore, 2006) or inferior Local Anesthetic/Vasoconstrictor Precautions
alveolar block (Hersh, 2006). Asenapine is one of the drugs confirmed to prolong
After maxillary infiltration of 1 mL of each formula, the
causing torsade de pointes. The risk of drug-induced
onset times to anesthesia were 3.1 ± 2.3 minutes for
torsade de pointes is extremely low when a single QT
articaine 4% and 1:200,000 epinephrine (A/200), 3 ±
2.1 minutes for articaine 4% and 1:100,000 epinephrine
(A/100), 3 ± 2 minutes for articaine 4% with no epi-
nephrine (A/no). These three mean times of onset were
not statistically different. Durations of anesthesia were
41.6 ± 21.1 minutes A/200, 45 ± 23.6 minutes A/100,
interval. Until more information is obtained, it is sug-
13.3 ± 6.8 minutes for A/no. There was no statistically
significant difference between the durations elicited by gested that the clinician consult with the physician prior
the A/200 and A/100 formulations (Moore, 2006). In the to the use of a vasoconstrictor in suspected patients,
second trial of the study, also using 63 subjects, the and that the vasoconstrictor (epinephrine, mepivacaine
investigators administered an inferior alveolar nerve and levonordefrin [Carbocaine® 2% with Neo-Cobe-
block injection of one cartridge (1.7 mL) using a stand- frin®]) be used with caution.
ard intra-oral injection technique for inferior alveolar Effects on Dental Treatment Key adverse event(s)
block anesthesia. Pulpal anesthesia was measured related to dental treatment: Xerostomia and increase in
again using the pulp tester. salivation (normal salivary flow resumes upon discon-
tinuation). Abnormal taste, toothache, and edema of the
The onset times to anesthesia were 4.7 ± 2.6 minutes tongue have been reported. Patients may experience
A/200, 4.2 ± 2.8 minutes A/100, and 4.3 ± 2.5 minutes orthostatic hypotension as they stand up after treat-
for A/no. There were no statistically significant differ- ment; especially if lying in dental chair for extended
ences in these times to onset. Durations of anesthesia periods of time. Use caution with sudden changes in
were 51.2 ± 55.9 minutes A/200, 61.8 ± 59 minutes A/ position during and after dental treatment. Asenapine
100, and 49.7 ± 44.6 minutes for A/no. There were no may cause extrapyramidal symptoms including tardive
statistically significant differences in the duration dyskinesia; risk may be greater with increased doses.
between A/200, A/100, and A/no formulations Effects on Bleeding No information available to
(Hersh, 2006). require special precautions
Oral paresthesia: The occurrence of oral paresthesia Adverse Reactions Actual frequency may be depend-
associated with 4% solutions of prilocaine or articaine, ent upon dose and/or indication.
although rare, continue to be slightly more frequent than >10%:
other local anesthetics. From 1999-2008, there were Central nervous system: Drowsiness (children and
182 cases of nonsurgical paresthesia (Gaffen, 2009). adolescents: 46% to 53%; adults: 13% to 26%;),
Of the cases, 172 involved mandibular block injection insomnia (adults: 10% to 16%; children and adoles-
only. Another eight cases involved mandibular block cents: 4%), akathisia (adults: 4% to 15%; children
combined with at least one other type of anesthetic and adolescents: 1% to 2%; dose-related), fatigue
158
ASPARAGINASE (E. COLI)
(4% to 14%), extrapyramidal reaction (4% to 12%), Mechanism of Action Asenapine is a dibenzo-oxe-
headache (children and adolescents: 8% to 11%) pino pyrrole atypical antipsychotic with mixed serotonin-
Endocrine & metabolic: Weight gain (adults: 1% to dopamine antagonist activity. It exhibits high affinity for
22%; children and adolescents: 2% to 12%), 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5-7, D1-4,
increased serum glucose (adults: 5% to 16%; chil- H1 and, alpha1- and alpha2-adrenergic receptors; mod-
dren and adolescents: 2%), decreased HDL choles- erate affinity for H2 receptors. Asenapine has no sig-
terol (6% to 15%), increased serum triglycerides nificant affinity for muscarinic receptors. The binding
(adults: 6% to 13%; children and adolescents: 2% affinity to the D2 receptor is 19 times lower than the
to 4%) 5-HT2A affinity (Weber 2009). The addition of serotonin
Gastrointestinal: Oral hypoesthesia (5% to 30%) antagonism to dopamine antagonism (classic neuro-
Neuromuscular and skeletal: Increased creatine phos- leptic mechanism) is thought to improve negative symp-
phokinase (adults: 11%) toms of psychoses and reduce the incidence of
1% to 10%: extrapyramidal side effects as compared to typical
Cardiovascular: Hypertension (adults: 3%), peripheral antipsychotics (Huttunen 1995).
edema (adults: 3%), tachycardia (children and ado- Pharmacodynamics/Kinetics
lescents: 1% to 3%; adults: <1%), syncope (≤1%) Half-life Elimination Terminal: ~24 hours
Central nervous system: Dizziness (4% to 10%), Time to Peak 0.5 to 1.5 hours
bipolar mood disorder (exacerbation; adults: ≤8%), Pregnancy Considerations Antipsychotic use during
mania (adults: ≤8%), agitation (adults: 3% to 4%), the third trimester of pregnancy has a risk for abnormal
suicidal ideation (children and adolescents: 3% to muscle movements (extrapyramidal symptoms [EPS])
4%), anxiety (adults: 3%), hyperinsulinism (children and/or withdrawal symptoms in newborns following
and adolescents: 1% to 3%), outbursts of anger delivery. Symptoms in the newborn may include agita-
(children and adolescents: 2%), drug-induced Par- tion, feeding disorder, hypertonia, hypotonia, respiratory
kinson disease (children and adolescents: 1% to distress, somnolence, and tremor; these effects may be
2%), irritability (1% to 2%) self-limiting or require hospitalization; monitoring of the
Dermatologic: Skin rash (children and adoles- neonate is recommended. Asenapine may cause
cents: 2%) hyperprolactinemia, which may decrease reproductive
Endocrine & metabolic: Increased serum cholesterol function in both males and females.
(adults: 2% to 8%), increased serum prolactin (2% to The ACOG recommends that therapy during pregnancy
3%), dehydration (children and adolescents: 2%) be individualized; treatment with psychiatric medica-
Gastrointestinal: Increased appetite (2% to 10%), tions during pregnancy should incorporate the clinical
abdominal pain (children and adolescents: 9%; expertise of the mental health clinician, obstetrician,
adults: 2% to 3%), dysgeusia (3% to 9%), constipa- primary healthcare provider, and pediatrician. Safety
tion (adults: 3% to 7%), vomiting (3% to 7%), nausea data related to atypical antipsychotics during pregnancy
(4% to 6%), sialorrhea (adults: ≤4%), dyspepsia is limited and routine use is not recommended. How-
(adults: 3%), abdominal distress (adults: 2% to ever, if a woman is inadvertently exposed to an atypical
3%), toothache (adults: 2% to 3%), xerostomia antipsychotic while pregnant, continuing therapy may
(adults: 2% to 3%), glossalgia (children and adoles- be preferable to switching to a typical antipsychotic that
cents: 2%) the fetus has not yet been exposed to; consider risk:
Genitourinary: Dysmenorrhea (children and adoles- benefit (ACOG 2008).
cents: 2%)
Hepatic: Increased serum transaminases (adults: 2% Healthcare providers are encouraged to enroll women
to 3%), increased serum ALT (1% to 3%), increased 18-45 years of age exposed to asenapine during preg-
serum AST (children and adolescents: 2%) nancy in the Atypical Antipsychotics Pregnancy Regis-
Neuromuscular & skeletal: Arthralgia (adults: 2%), try (866-961-2388 or http://www.womensmentalhealth.
strain (children and adolescents: 2%), myalgia (chil- org/pregnancyregistry).
dren and adolescents: 1% to 2%) Dental Health Professional Considerations See
Respiratory: Nasopharyngitis (adults: 3% to 5%), oro- Local Anesthetic/Vasoconstrictor Precautions
pharyngeal pain (children and adolescents: 3%),
dyspnea (2%), nasal congestion (children and ado- Asparaginase (E. coli) (a SPEAR a ji nase e ko lye)
lescents: 2%)
Miscellaneous: Fever (≤1%) Brand Names: Canada Kidrolase
Frequency not defined: Pharmacologic Category Antineoplastic Agent,
Cardiovascular: Prolonged Q-T interval on ECG Enzyme; Antineoplastic Agent, Miscellaneous
Central nervous system: Dystonia Use Acute lymphoblastic leukemia: Treatment of
Gastrointestinal: Oral paresthesia acute lymphoblastic leukemia (ALL) (in combination
<1%, postmarketing, and/or case reports: Accommoda- with other chemotherapy)
tion disturbance, anaphylaxis, anemia, angioedema, Local Anesthetic/Vasoconstrictor Precautions
application site reaction (including blisters, inflamma- No information available to require special precautions
tion, peeling, oral ulcers, sloughing), blurred vision, Effects on Dental Treatment Key adverse event(s)
bundle branch block (temporary), choking sensation, related to dental treatment: Stomatitis
diabetes mellitus, diplopia, dysarthria, dyslipidemia, Effects on Bleeding Thrombotic and hemorrhagic
dysphagia, falling, gastroesophageal reflux disease, events have been reported with asparaginase (E. coli).
hyperglycemia, hypersensitivity reaction, hyponatre- A medical consult is recommended.
mia, hypotension, leukopenia, neuroleptic malignant Adverse Reactions Frequency not defined.
syndrome, neutropenia, seizure, skin photosensitivity, Cardiovascular: Cerebrovascular accident (hemorrha-
tardive dyskinesia, thrombocytopenia, tongue edema, gic stroke and thrombotic stroke [Morgan 2011]),
urinary incontinence, wheezing thrombosis (including cerebral thrombosis)
159
ASPARAGINASE (E. COLI)
Central nervous system: Central nervous system dis- lymphoblastic leukemia (ALL) in patients with hyper-
ease (adults; includes delusion, disorientation, mild sensitivity to E. coli-derived asparaginase
depression, Parkinsonian-like syndrome, personality Local Anesthetic/Vasoconstrictor Precautions
disorder, seizure), cerebral hemorrhage, cerebrovas- No information available to require special precautions
cular hemorrhage (Morgan 2011) Effects on Dental Treatment No significant effects or
Endocrine & metabolic: Amenorrhea, decreased glu- complications reported
cose tolerance, hyperammonemia (with clinical signs Effects on Bleeding Thrombotic and hemorrhagic
of metabolic encephalopathy [eg, impaired conscious- events have been reported with asparaginase (Erwinia).
ness with coma, confusion, and stupor]), hypercholes- A medical consult is recommended.
terolemia, hyperglycemia, hypertriglyceridemia, Adverse Reactions
hypoalbuminemia, hypocholesterolemia, increased Frequency of adverse reactions is for both IM and IV
uric acid, weight loss routes unless specified.
Gastrointestinal: Abdominal pain (infrequent), acute >10%: Hypersensitivity: Hypersensitivity reaction (14%
pancreatitis (may be fatal), cholestatic injury, diarrhea [IV: ≤37%]; grades 3/4: 4%; includes anaphylaxis,
(infrequent), intestinal perforation (rare), nausea (fre- urticaria)
quent, but rarely severe; may be secondary to 1% to 10%:
increased blood urea nitrogen and increased uric Cardiovascular: Thrombosis (2% [IV: ≤7%]; grades
acid), vomiting (frequent, but rarely severe; may be 3/4: ≤1%; includes pulmonary embolism and cere-
secondary to increased blood urea nitrogen and brovascular accident)
increased uric acid) Endocrine & metabolic: Hyperglycemia (4% [IV:
Genitourinary: Azoospermia ≤17%]; grades 3/4: 4%), abnormal transaminase
Hematologic: Antithrombin III deficiency, blood coagu- (4%), decreased glucose tolerance (4%)
lation disorder (change in hemostatic function), bone Gastrointestinal: Nausea (3% [IV: ≤20%]), vomiting
marrow depression, decreased clotting factors (factors (3% [IV: ≤17%]), pancreatitis (4%; grades 3/4:
VII, VIII, IX, and X), decreased plasminogen, hypofi- <1%), abdominal pain (1%), diarrhea (1%), mucositis
brinogenemia, prolonged partial thromboplastin time, (1%)
prolonged prothrombin time Local: Injection site reaction (3%)
Hepatic: Hepatic injury, hepatotoxicity (usually mild and Miscellaneous: Fever (4%)
regressive, but may be fatal rarely), hyperbilirubine- <1%, postmarketing, and/or case reports: Acute renal
mia, increased serum alkaline phosphatase, failure, anorexia, azotemia, bone marrow depression
increased serum ALT, increased serum AST (mild), (rare), changes in serum lipids, chills, decreased
jaundice, liver steatosis serum albumin, decreased serum cholesterol, disse-
Hypersensitivity: Allergic reactions (includes anaphylac- minated intravascular coagulation, headache, hemor-
tic shock, anaphylaxis, bronchospasm, edema, hypo- r h a g e , h e p a t o m e g a l y, h y p e r a m m o n e m i a ,
tension, laryngeal edema, skin rash, urticaria; onset hyperbilirubinemia, irritability, malabsorption syn-
usually within 1 hour of administration and risk drome, proteinuria, seizure, transient ischemic
increasing with increasing number of exposures) attacks, weight loss
Immunologic: Increased serum globulins (beta and Mechanism of Action Asparaginase catalyzes the
gamma) deamidation of asparagine to aspartic acid and ammo-
Infection: Septicemia (during bone marrow depression) nia, reducing circulating levels of asparagine. Leukemia
Renal: Increased blood urea nitrogen, renal failure cells lack asparagine synthetase and are unable to
Respiratory: Respiratory distress (with retrosternal synthesize asparagine. Asparaginase reduces the
pressure) exogenous asparagine source for the leukemic cells,
Miscellaneous: Fever resulting in cytotoxicity specific to leukemic cells.
Mechanism of Action In leukemic cells, asparaginase Pharmacodynamics/Kinetics
hydrolyzes L-asparagine to ammonia and L-aspartic Half-life Elimination IM: ~16 hours (Asselin 1993;
acid, leading to depletion of asparagine. Leukemia Avramis 2005); IV: ~7.5 hours
cells, especially lymphoblasts, require exogenous Pregnancy Risk Factor C
asparagine; normal cells can synthesize asparagine. Pregnancy Considerations Adverse events were
Asparagine depletion in leukemic cells leads to inhib- observed in animal reproduction studies.
ition of protein synthesis and apoptosis. Asparaginase Prescribing and Access Restrictions For order
is cycle-specific for the G1 phase. information contact 877-625-2566 or visit http://
Pharmacodynamics/Kinetics erwinaze.com/healthcare-professionals/order-erwi-
Half-life Elimination IM: 34 to 49 hours; IV: 8 to 30 naze/
hours
Time to Peak IM: 14 to 24 hours Aspirin (AS pir in)
Pregnancy Considerations Use is contraindicated.
Product Availability US product, Elspar, was discon- Related Information
tinued more than 1 year ago. Antiplatelet and Anticoagulation Considerations in Den-
tistry on page 1454
Asparaginase (Erwinia) Cardiovascular Diseases on page 1442
(a SPEAR a ji nase er WIN i ah) Oral Pain on page 1520
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
Brand Names: US Erwinaze on page 1484
Brand Names: Canada Erwinase Brand Names: US Ascriptin Maximum Strength [OTC];
Pharmacologic Category Antineoplastic Agent, Ascriptin Regular Strength [OTC]; Aspercin [OTC];
Enzyme; Antineoplastic Agent, Miscellaneous Aspir-low [OTC]; Aspirin Adult Low Dose [OTC]; Aspirin
Use Acute lymphoblastic leukemia: Treatment (in Adult Low Strength [OTC]; Aspirin EC Low Strength
combination with other chemotherapy) of acute [OTC]; Aspirtab [OTC]; Bayer Aspirin EC Low Dose
160
ASPIRIN
[OTC]; Bayer Aspirin Extra Strength [OTC]; Bayer and patient susceptibility. Many adverse effects of
Aspirin Regimen Adult Low Strength [OTC]; Bayer aspirin are dose related, and are rare at low dosages.
Aspirin Regimen Children's [OTC]; Bayer Aspirin Regi- Other serious reactions are idiosyncratic, related to
men Regular Strength [OTC]; Bayer Genuine Aspirin allergy or individual sensitivity (see Dental Health Pro-
[OTC]; Bayer Plus Extra Strength [OTC]; Bayer Wom- fessional Considerations).
en's Low Dose Aspirin [OTC]; Buffasal [OTC]; Bufferin
Extra Strength [OTC]; Bufferin [OTC]; Buffinol [OTC]; Aspirin as sole antiplatelet agent: Patients taking
Durlaza; Ecotrin Arthritis Strength [OTC]; Ecotrin Low aspirin for ischemic stroke prevention are safe to con-
Strength [OTC]; Ecotrin [OTC]; Halfprin [OTC] [DSC]; St tinue it during dental procedures (Armstrong, 2013).
Joseph Adult Aspirin [OTC]; Tri-Buffered Aspirin [OTC] Concurrent aspirin use with other antiplatelet
Brand Names: Canada Asaphen; Asaphen E.C.; agents: Aspirin in combination with clopidogrel (Plavix),
Entrophen; Novasen; Praxis ASA EC 81 Mg Daily prasugrel (Effient), or ticagrelor (Brilinta) is the primary
Dose; Pro-AAS EC-80 prevention strategy against stent thrombosis after
Generic Availability (US) May be product dependent placement of drug-eluting metal stents in coronary
Pharmacologic Category Analgesic, Nonopioid; Anti- patients. Premature discontinuation of combination anti-
platelet Agent; Nonsteroidal Anti-inflammatory Drug platelet therapy (ie, dual antiplatelet therapy) strongly
(NSAID), Oral; Salicylate increases the risk of a catastrophic event of stent
Dental Use Treatment of postoperative pain thrombosis leading to myocardial infarction and/or
Use death, so says a science advisory issued in January
Immediate release: 2007 from the American Heart Association in collabo-
Analgesic/Antipyretic: For the temporary relief of ration with the American Dental Association and other
headache, pain, and fever caused by colds, muscle professional healthcare organizations. The advisory
aches and pains, menstrual pain, toothache pain, stresses a 12-month therapy of dual antiplatelet therapy
and minor aches and pains of arthritis. after placement of a drug-eluting stent in order to
Revascularization procedures: In patients who have prevent thrombosis at the stent site. Any elective sur-
undergone revascularization procedures (ie, coro- gery should be postponed for 1 year after stent implan-
nary artery bypass graft [CABG], percutaneous tation, and if surgery must be performed, consideration
transluminal coronary angioplasty, or carotid endar- should be given to continuing the antiplatelet therapy
terectomy). during the perioperative period in high-risk patients with
Rheumatoid disease: For the relief of the signs and drug-eluting stents.
symptoms of rheumatoid arthritis (RA), juvenile idio- This advisory was issued from a science panel made up
pathic arthritis (formerly called juvenile RA), osteo- of representatives from the American Heart Associa-
arthritis, spondyloarthropathies, and arthritis and tion (AHA), the American College of Cardiology, the
pleurisy associated with systemic lupus erythema- Society for Cardiovascular Angiography and Interven-
tosus. tions, the American College of Surgeons, the Ameri-
Vascular indications (ischemic stroke, transient can Dental Association (ADA), and the American
ischemic attack, acute myocardial infarction, pre- College of Physicians (Grines, 2007).
vention of recurrent myocardial infarction, unsta-
Effects on Bleeding Aspirin irreversibly inhibits plate-
ble angina, and chronic stable angina): To reduce
let aggregation which can prolong bleeding. Upon dis-
the combined risk of death and nonfatal stroke in
continuation, normal platelet function returns only when
patients who have had ischemic stroke or transient
new platelets are released (~7 to 10 days). However, in
ischemia of the brain due to fibrin platelet emboli; to
the case of dental surgery, there is no scientific evi-
reduce the risk of vascular mortality in patients with a
dence to support discontinuation of aspirin. This was
suspected acute myocardial infarction (MI); to reduce
the combined risk of death and nonfatal MI in recently supported by the American Academy of Neu-
patients with a previous MI or unstable angina; to rology in patients with ischemic cerebrovascular dis-
reduce the combined risk of MI and sudden death in ease (Armstrong, 2013). A recent study compared
patients with chronic stable angina. blood loss after a single tooth extraction in coronary
Extended-release capsules: artery disease patients who were either on aspirin
Chronic coronary artery disease: To reduce the risk (100 mg daily) or off aspirin for the extraction. The
of death and MI in patients with chronic coronary mean volume of bleeding was not statistically different
artery disease (eg, history of MI, unstable angina, or between the groups. Local hemostatic measures were
chronic stable angina). sufficient to control bleeding and there were no reported
History of ischemic stroke or transient ischemic episodes of hemorrhaging intra- or postoperatively
attack: To reduce the risk of death and recurrent (Medeiros, 2011).
stroke in patients who have had an ischemic stroke Adverse Reactions As with all drugs which may affect
or transient ischemic attack (TIA). hemostasis, bleeding is associated with aspirin. Hem-
Limitations of use: Do not use extended-release cap- orrhage may occur at virtually any site. Risk is depend-
sules in situations for which a rapid onset of action is ent on multiple variables including dosage, concurrent
required (such as acute treatment of MI or before use of multiple agents which alter hemostasis, and
percutaneous coronary intervention); use immediate- patient susceptibility. Many adverse effects of aspirin
release formulations instead. are dose related, and are rare at low dosages. Other
Local Anesthetic/Vasoconstrictor Precautions serious reactions are idiosyncratic, related to allergy or
No information available to require special precautions individual sensitivity. Accurate estimation of frequencies
Effects on Dental Treatment Key adverse event(s) is not possible. The reactions listed below have been
related to dental treatment: As with all drugs which may reported for aspirin.
affect hemostasis, bleeding is associated with aspirin. Cardiovascular: Cardiac arrhythmia, edema, hypoten-
Hemorrhage may occur at virtually any site; risk is sion, tachycardia
dependent on multiple variables including dosage, con- Central nervous system: Agitation, cerebral edema,
current use of multiple agents which alter hemostasis, coma, confusion, dizziness, fatigue, headache,
161
ASPIRIN
hyperthermia, insomnia, lethargy, nervousness, used with ticagrelor, the recommended mainte-
Reye's syndrome nance dose of aspirin is 81 mg/day (ACC/AHA
Dermatologic: Skin rash, urticaria [Amsterdam 2014]; ACCF/AHA [O’Gara 2013])
Endocrine & metabolic: Acidosis, dehydration, hyper- According to the STEMI guidelines, 81 mg once
glycemia, hyperkalemia, hypernatremia (buffered daily is preferred (ACCF/AHA [O’Gara 2013]).
forms), hypoglycemia (children) Concomitant antiplatelet therapy:
Gastrointestinal: Gastrointestinal ulcer (6% to 31%), STEMI: Aspirin is recommended in combination
duodenal ulcer, dyspepsia, epigastric distress, gastri- with either clopidogrel, prasugrel, or ticagrelor
tis, gastrointestinal erosion, heartburn, nausea, stom- given as early as possible or at time of PCI. In
ach pain, vomiting addition to dual antiplatelet therapy, parenteral
Genitourinary: Postpartum hemorrhage, prolonged ges- anticoagulant therapy is indicated. Post-PCI stent-
tation, prolonged labor, proteinuria, stillborn infant ing, consult clinical practice guidelines for recom-
Hematologic & oncologic: Anemia, blood coagulation mended duration of maintenance antiplatelet
disorder, disseminated intravascular coagulation, therapy depending on type of stenting (ACCF/
hemolytic anemia, hemorrhage, iron deficiency ane- AHA [O'Gara 2013]).
mia, prolonged prothrombin time, thrombocytopenia NSTE-ACS:
Hepatic: Hepatitis (reversible), hepatotoxicity, increased If early-invasive strategy chosen: Aspirin is rec-
serum transaminases ommended in combination with either clopidog-
Hypersensitivity: Anaphylaxis, angioedema rel or ticagrelor. In addition to dual antiplatelet
Neuromuscular & skeletal: Acetabular bone destruction, therapy, parenteral anticoagulant therapy is indi-
rhabdomyolysis, weakness cated. In select high-risk patients (ie, troponin
Otic: Hearing loss, tinnitus positive), an IV GP IIb/IIIa inhibitor may be
Renal: Increased blood urea nitrogen, increased serum considered as part of initial antiplatelet therapy
creatinine, interstitial nephritis, renal failure (including (if given before PCI, eptifibatide and tirofiban are
cases caused by rhabdomyolysis), renal insufficiency, preferred agents). In patients post-PCI with
renal papillary necrosis stenting (bare metal or drug-eluting stent),
Respiratory: Asthma, bronchospasm, dyspnea, hyper- aspirin should be given with either clopidogrel,
ventilation, laryngeal edema, noncardiogenic pulmo- ticagrelor, or prasugrel for at least 12 months
nary edema, respiratory alkalosis, tachypnea (ACC/AHA [Amsterdam 2014]).
Miscellaneous: Low birth weight If ischemia-guided strategy (ie, noninvasive strat-
Postmarketing and/or case reports: Anorectal stenosis egy) chosen: Aspirin is recommended in combi-
(suppository), atrial fibrillation (toxicity), cardiac con- nation with clopidogrel or ticagrelor for up to 12
duction disturbance (toxicity), cerebral infarction months. In addition to dual antiplatelet therapy,
(ischemic), cholestatic jaundice, colitis, colonic ulcer- parenteral anticoagulant therapy is indicated
ation, coronary artery vasospasm, delirium, esopha- (ACC/AHA [Amsterdam 2014]).
geal obstruction, esophagitis (with esophageal ulcer), Analgesic and antipyretic:
hematoma (esophageal), macular degeneration (age- Oral: Immediate release: 325 to 650 mg as needed
related) (Li 2014), periorbital edema, rhinosinusitis every 4 hours or 975 mg as needed every 6 hours
Dental Usual Dosage Postoperative pain: or 500 to 1,000 mg as needed every 4 to 6 hours
Analgesic and antipyretic: Oral, rectal: for no more than 10 days or as directed by health
Children: 10 to 15 mg/kg/dose every 4 to 6 hours, up care provider; maximum daily dose: 4 g/day.
to a total of 4 g/day Rectal: 300 to 600 mg every 4 hours for no more
Adults: 325 to 650 mg every 4 to 6 hours up to 4 g/day than 10 days or as directed by health care provider
Anti-inflammatory: Oral: Initial: Anti-inflammatory (off-label dosing): Note: The use
Children: 60 to 90 mg/kg/day in divided doses; usual of non-aspirin NSAIDs has largely supplanted the
maintenance: 80 to 100 mg/kg/day divided every 6 to use of aspirin for osteoarthritis, rheumatoid arthritis,
8 hours; monitor serum concentrations and other inflammatory arthritides.
Adults: 2.4 to 3.6 g/day in divided doses; usual main- Immediate release: Oral: Usual maintenance dose:
tenance: 3.6 to 5.4 g/day; monitor serum concentra- 2.1 to 7.3 g/day in divided doses (individualize
tions dose); monitor serum salicylate concentrations
Dosing especially when symptoms of salicylism (eg, tinni-
Adult & Geriatric Note: For most cardiovascular tus) appear; adjust dose accordingly (Csuka 1989).
uses, typical maintenance dosing of aspirin is 81 mg Aortic valve repair (off-label use): Immediate
once daily. Manufacturer recommended dosing for release: Oral: 50 to 100 mg once daily (ACCP
some indications have been superseded by more [Guyatt 2012])
recent guideline recommended doses and therefore Atrial fibrillation (to prevent thromboembolism)
manufacturer recommended dosing may not be rep- (off-label use): Immediate release: Oral: Primary
resented; terminologies may also differ from manufac- prevention: Patients at low risk of ischemic stroke
turer's prescribing information. (CHA2DS2-VASc score of 1): 75 to 325 mg once
Acute coronary syndrome (ST-elevation myocar- daily may be considered (AHA/ACC/HRS [Janu-
dial infarction [STEMI], non-ST-elevation acute ary 2014]).
coronary syndromes [NSTE-ACS]): Oral: Carotid artery stenosis (asymptomatic) (off-label
Initial: 162 to 325 mg given on presentation (patient use): Immediate release: Oral: 75 to 100 mg once
should chew nonenteric-coated aspirin especially if daily (ACCP [Alonso-Coello 2012]). Note: The addi-
not taking before presentation) (ACC/AHA [Amster- tion of statin therapy has also been recommended
dam 2014]; ACCF/AHA [O'Gara 2013]); for patients for asymptomatic carotid stenosis (AHA/ASA
unable to take oral, may use a rectal suppository [Meschia 2014]). When symptomatic, the use of
dose of 600 mg (Maalouf 2009). clopidogrel or aspirin/extended-release dipyridamole
Maintenance (secondary prevention): 81 to 325 mg has been suggested over aspirin alone (ACCP
once daily continued indefinitely; when aspirin is [Alonso-Coello 2012]).
162
ASPIRIN
Carotid endarterectomy (off-label dosing): Immedi- revascularization (AHA/ACC [Gerhard-Herman

ate release: Oral: 75 to 100 mg once daily (ACCP 2016]). Note: These recommendations also pertain
[Alonso-Coello 2012]; AHA [Biller 1998]). The use of to patients with intermittent claudication or critical
clopidogrel or aspirin/extended-release dipyridamole limb ischemia, prior lower extremity revasculariza-
has been suggested over aspirin alone (ACCP tion, or prior amputation for lower extremity ischemia
[Alonso-Coello 2012]). (Rooke 2011).
Colorectal cancer risk reduction (off-label use): Peripheral artery percutaneous transluminal
Note: The optimal dose and duration of therapy for angioplasty (with or without stenting) or periph-
colorectal cancer risk reduction are unknown. Con- eral artery bypass graft surgery, postprocedure
sider risk versus benefit ratio when initiating aspirin (off-label use): Immediate release: Oral: 75 to
for this indication. 100 mg once daily (ACCP [Guyatt 2012]). Note:
Primary/Secondary prevention: Immediate release: For below-knee bypass graft surgery with prosthetic
Oral: 75 to 325 mg once daily (Rothwell 2010; grafts, combine with clopidogrel (ACCP
Sandler 2003; Ye 2013) [Guyatt 2012]).
Hereditary nonpolyposis colon cancer (HNPCC; Polycythemia vera (off-label use): Immediate
Lynch Syndrome) carriers: Immediate release: release: Oral: 75 or 100 mg once daily (Barbui
Oral: 600 mg once daily for at least 2 years (ASCO 2006; McMullin 2005).
[Stoffel 2014]; Burn 2011) Pregnant women: 75 mg once daily (Barbui 2011;
Coronary artery disease (CAD), established or McMullin 2005).
chronic: Preeclampsia prevention (women at risk) (off-label
Immediate release (off-label dosing): Oral: 75 to use): Immediate release: Oral: One low-dose aspirin
100 mg once daily (ACCP [Guyatt 2012]) daily. The definition of low-dose varies by guideline
Extended release capsule: Oral: 162.5 mg once daily and study; recommended ranges are 75 mg (ACCP
Percutaneous coronary intervention (PCI) (off- [Guyatt 2012]) to 150 mg once daily (Roberge 2017;
label dosing): Immediate release: Oral: Rolnik 2017). A dose of 100 to 150 mg once daily
Non-emergent PCI: Preprocedure: 81 to 325 mg may be more effective than lower doses (Roberge
(325 mg [nonenteric coated] in aspirin-naive 2017). Treatment is generally started ~12 weeks
patients) starting at least 2 hours (preferably 24 gestation; however, therapy initiated after 16 weeks
hours) before procedure. Postprocedure: 81 mg gestation but prior to the development of symptoms
once daily continued indefinitely (in combination is effective (Meher 2017; Roberge 2016; Roberge
with a P2Y12 inhibitor [eg, clopidogrel, prasugrel, 2017). Most studies discontinue therapy at ~36 to 37
ticagrelor] up to 12 months) (ACCF/AHA/SCAI weeks gestation (Roberge 2016).
[Levine 2011]) Prevention (primary) of cardiovascular disease
Primary PCI: Preprocedure: 162 to 325 mg as early (off-label use): Immediate release: Oral:
as possible prior to procedure; 325 mg preferred. American College of Chest Physicians: Select indi-
Postprocedure: 81 mg once daily continued indef- viduals ≥50 years of age (without symptomatic
initely (in combination with a P2Y12 inhibitor [eg, cardiovascular disease): 75 to 100 mg once daily
clopidogrel] for at least 14 days and up to 12 (ACCP [Vandvik 2012])
months) (ACCF/AHA [O'Gara 2013]). American Diabetes Association: Individuals ≥50
Alternatively, in patients who have undergone elec- years of age with diabetes (type 1 or 2) and at least
tive PCI with either bare metal or drug-eluting stent one additional risk factor: 75 to 162 mg once daily
placement: The American College of Chest Physi- (ADA 2019)
cians recommends the use of 75 to 325 mg once Prevention (secondary) of cardiovascular disease
daily (in combination with clopidogrel) for 1 month (patients with diabetes) (off-label use): Immediate
in patients receiving a bare metal stent or 3 to 6 release: Oral: 75 to 162 mg once daily (ADA 2019)
months (dependent upon drug eluting stent type) Prevention (secondary) after coronary artery
followed by 75 to 100 mg once daily (in combina- bypass graft (CABG) surgery (off-label dosing):
tion with clopidogrel) for up to 12 months. For Immediate release: Oral: 81 to 325 mg once daily
patients who underwent PCI but did not have stent administered preoperatively and within 6 hours post-
placement, 75 to 325 mg once daily (in combination operatively; continue indefinitely. Following off-pump
with clopidogrel) for 1 month is recommended. In CABG, administer aspirin 81 to 162 mg in combina-
either case, single antiplatelet therapy (either tion with clopidogrel for 12 months (AHA
aspirin or clopidogrel) is recommended indefinitely [Kulik 2015]).
(ACCP [Guyatt 2012]). Prosthetic heart valve replacement (thrombopro-
Pericarditis (off-label use): Immediate release: Oral: phylaxis) (off-label use): Immediate release: Oral:
Initial: 2.4 to 3.6 g daily in 3 to 4 divided doses; usual Bioprosthetic aortic or mitral valve: 75 to 100 mg
maintenance: 3.6 to 5.4 g daily in divided doses; daily (AHA/ACC [Nishimura 2014]) is reasonable
gradually taper over 2- to 3-week period as appro- in all patients; patients may also receive anticoagu-
priate (Imazio 2004; Imazio 2009). lation with warfarin for the first 3 to 6 months after
Pericarditis in association with myocardial infarc- surgery. Note: Patients with a history of ischemic
tion (off-label use): Immediate release: Oral: Initial: stroke or TIA before valve insertion and who are at
650 mg 4 times daily; may increase after 24 hours to a low risk of bleeding and no other indication for
975 mg 4 times daily if necessary (ACCF/AHA anticoagulation therapy beyond 3 to 6 months from
[O'Gara 2013]; Berman 1981). the valve placement are recommended to continue
Peripheral arterial disease (off-label use): Immedi- aspirin in preference to long-term anticoagulation
ate release: Oral: 75 to 100 mg once daily (ACCP (AHA/ASA [Kernan 2014]).
[Guyatt 2012]) or 75 to 325 mg once daily (AHA/ Mechanical aortic or mitral valve: 75 to 100 mg once
ACC [Gerhard-Herman 2016]). The use in combina- daily (in combination with warfarin) (AHA/ACC
tion with clopidogrel may be considered in patients [Nishimura 2014]). Note: For patients with an
with symptomatic PAD after lower extremity ischemic stroke or systemic embolism despite
163
ASPIRIN
adequate antithrombotic therapy, it may be reason- ambulate within 24 hours after surgery, and who do
able to increase to 325 mg once daily (AHA/ASA not have additional risk factors for VTE, indications
[Kernan 2014]). for long-term anticoagulation, lower limb or hip frac-
Pregnant women, mechanical or bioprosthetic: 75 to ture in the previous 3 months, or expected major
100 mg once daily during the second and third surgery in the upcoming 3 months (Pai 2018).
trimesters (when used for mechanical prosthetic Oral: After a 5-day course of postoperative rivarox-
valve, combine with warfarin) (AHA/ACC [Nishi- aban prophylaxis, initiate aspirin at 81 mg once
mura 2014]). daily starting on postoperative day 6 and continue
Transcatheter aortic valve replacement (TAVR): 75 to for 9 days for TKA (total duration: 14 days) or 30
100 mg once daily (in combination with clopidogrel) days for THA (total duration: 35 days) (Ander-
(AHA/ACC [Nishimura 2014]). Note: For patients son 2018).
who require anticoagulation for another indication Renal Impairment: Adult
post-TAVR, practice varies and local protocols Analgesia or anti-inflammatory uses: The manufac-
should be established. It may be reasonable to turer recommends avoiding in patients with CrCl
use anticoagulation (warfarin or a non-warfarin oral <10 mL/minute. However, may use with caution
anticoagulant) plus aspirin or clopidogrel (eg, not and monitor renal function or consider the use of
dual antiplatelet therapy) after the procedure an alternative analgesic/anti-inflammatory agent
(Kalich 2018). (NKF [Henrich 1996], Whelton 2000).
Stroke/TIA: Oral: Antiplatelet uses: The manufacturer recommends
Acute ischemic stroke/TIA: avoiding in patients with CrCl <10 mL/minute. How-
Immediate release (off-label dosing): Initial: 160 to ever, in general, the benefit of low-dose aspirin out-
325 mg within 48 hours of stroke/TIA onset, fol- weighs any risk associated with nephropathy or other
lowed by 75 to 100 mg once daily (ACCP [Guyatt adverse effects even in the setting of severe renal
2012]). The AHA/ASA recommends an initial dose impairment; the recommended aspirin dose should
of 325 mg within 24 to 48 hours after stroke; do not be reduced in any patient with suspected or
not administer aspirin within 24 hours after admin- documented ACS, other cardiovascular disease, or
istration of alteplase (Jauch 2013). The combina- other antithrombotic indication (Fernandez 2001,
tion of aspirin and clopidogrel might be considered Harter 1979, Summaria 2015). In patients with dia-
within 24 hours of a minor ischemic stroke or TIA betes and chronic kidney disease or in dialysis
and continued for 21 days (AHA/ASA [Ker- patients, the National Kidney Foundation recom-
nan 2014]). mends the use of antithrombotic doses of aspirin
Extended-release capsule: Maintenance (secon-
(ie, 75 to 162 mg daily) for prevention and manage-
dary prevention): 162.5 mg once daily. Note: Not
ment of ischemic heart disease or primary prevention
for initial dosing during acute ischemic stroke or
of atherosclerotic disease (KDOQI 2005,
TIA (use immediate release)
KDOQI 2007).
Cardioembolic, secondary prevention (oral anticoa-
Hemodialysis: Dialyzable (concentration dependent;
gulation unsuitable) (off-label): Immediate release:
higher salicylate concentrations are more readily
75 to 100 mg once daily (AHA/ASA [Kernan 2014])
dialyzable: 50% to 60%) (Juurlink 2015; Rosenberg
Cryptogenic with patent foramen ovale (PFO) or
1981); consider administration after hemodialysis on
atrial septal aneurysm (off-label use): Immediate
dialysis days (Aronoff 2007).
releas e: 50 to 100 mg once daily (ACCP
[Guyatt 2012]) Hepatic Impairment: Adult Avoid use in severe liver
Intracranial atherosclerosis (50% to 99% stenosis of disease.
a major intracranial artery), secondary prevention Pediatric
(off-label): 325 mg once daily (consider the addition Note: Doses are typically rounded to a convenient
of clopidogrel for 90 days in patients with recent amount (eg, 1/4 of 81 mg tablet):
stroke/TIA due to severe stenosis [70% to 99%]) Analgesic: Oral, rectal: Note: Do not use aspirin in
(AHA/ASA [Kernan 2014]). pediatric patients <18 years who have or who are
Noncardioembolic, secondary prevention (off-label recovering from chickenpox or flu symptoms (eg,
use): Immediate release: 75 to 325 mg once daily viral illness) due to the association with Reye
(Smith, 2011) or 75 to 100 mg once daily (ACCP syndrome (APS 2016):
[Guyatt 2012]). Note: Combination aspirin/ Infants, Children, and Adolescents weighing <50
extended release dipyridamole or clopidogrel is kg: Limited data available: 10 to 15 mg/kg/dose
preferred over aspirin alone (ACCP [Guyatt 2012]). every 4 to 6 hours; maximum daily dose:
Women at high risk for first stroke, primary preven- 90 mg/kg/day or 4,000 mg/day whichever is less
tion: Immediate release: 81 mg once daily or (APS 2016)
100 mg every other day (AHA/ASA Children ≥12 years and Adolescents weighing ≥50
[Meschia 2014]). kg: 325 to 650 mg every 4 to 6 hours; maximum
Venous thromboembolism (VTE), extended ther- daily dose: 4,000 mg/day
apy to prevent recurrence (in patients who have Anti-inflammatory: Limited data available: Infants,
completed anticoagulation treatment and Children, and Adolescents: Oral: Initial: 60 to
decided to stop oral anticoagulation) (off-label 90 mg/kg/day in divided doses; usual maintenance:
use): Oral: 100 mg once daily (Becattini 2012; Brigh- 80 to 100 mg/kg/day divided every 6 to 8 hours;
ton 2012; Simes 2014) monitor serum concentrations (Levy 1978)
Venous thromboembolism (VTE) prophylaxis for Antiplatelet effects: Limited data available: Infants,
total hip (THA) or knee (TKA) arthroplasty (off- Children, and Adolescents: Oral: Adequate pedia-
label use): Note: This is a hybrid strategy using tric studies have not been performed; pediatric
rivaroxaban followed by aspirin. Limit this strategy dosage is derived from adult studies. Usual adult
(rivaroxaban followed by aspirin) to low-risk patients maximum daily dose for antiplatelet effects is
who undergo elective unilateral THA or TKA, 325 mg/day.
164
ASPIRIN
Acute ischemic stroke (AIS): dosing range: 1 to 5 mg/kg/day; initiate after

Noncardioembolic: 1 to 5 mg/kg/dose once daily fever resolves for at least 48 to 72 hours (or after
for ≥2 years; patients with recurrent AIS or TIAs 14 days). In patients without coronary artery
should be transitioned to clopidogrel, LMWH, or abnormalities, administer the lower dose for 6
warfarin (ACCP [Monagle 2012]) to 8 weeks. In patients with coronary artery
Secondary to Moyamoya and non-Moyamoya abnormalities, low-dose aspirin should be con-
vasculopathy: 1 to 5 mg/kg/dose once daily; tinued indefinitely (in addition to therapy with
Note: In non-Moyamoya vasculopathy, continue warfarin) (AAP [Red Book 2015]; ACCP [Mona-
aspirin for 3 months, with subsequent use gle 2012]; AHA [Giglia 2013]; AHA [McCrin-
guided by repeat cerebrovascular imaging dle 2017]).
(ACCP [Monagle 2012]). Rheumatic fever: Limited data available: Infants,
Prosthetic heart valve: Children, and Adolescents: Oral: Initial:
Bioprosthetic aortic valve (with normal sinus 100 mg/kg/day divided into 4 to 5 doses; if
rhythm): 1 to 5 mg/kg/dose once daily for 3 response inadequate, may increase dose to
months (AHA [Giglia 2013]; ACCP [Guyatt 125 mg/kg/day; continue for 2 weeks; then
2012]; ACCP [Monagle 2012]) decrease dose to 60 to 70 mg/kg/day in divided
Mechanical aortic and/or mitral valve: 1 to doses for an additional 3 to 6 weeks (WHO Guide-
5 mg/kg/dose once daily combined with vitamin lines 2004)
K antagonist (eg, warfarin) is recommended as Migratory polyarthritis, with carditis without cardio-
first-line antithrombotic therapy (ACCP [Guyatt megaly or congestive heart failure: Initial:
2012]; ACCP [Monagle 2012]). Alternative regi- 100 mg/kg/day in 4 divided doses for 3 to 5 days,
mens: 6 to 20 mg/kg/dose once daily in combi- followed by 75 mg/kg/day in 4 divided doses for 4
nation with dipyridamole (Bradley 1985; el weeks
Makhlouf 1987; LeBlanc 1993; Serra 1987; Sol- Carditis and cardiomegaly or congestive heart fail-
ymar 1991) ure: At the beginning of the tapering of the pre-
Shunts: Blalock-Taussig; Glenn; postoperative; pri- dnisone dose, aspirin should be started at
mary prophylaxis: 1 to 5 mg/kg/dose once daily 75 mg/kg/day in 4 divided doses for 6 weeks
(ACCP [Monagle 2012]; AHA [Giglia 2013]) Renal Impairment: Pediatric
Norwood, Fontan surgery, postoperative; primary Infants, Children, and Adolescents: There are no
prophylaxis: 1 to 5 mg/kg/dose once daily (ACCP recommendations in the manufacturer’s labeling;
[Monagle 2012]; AHA [Giglia 2013]) however, the following adjustments have been rec-
Transcatheter Atrial Septal Defect (ASD) or Ven- ommended (Aronoff 2007):
tricular Septal Defect (VSD) devices, postproce- GFR ≥10 mL/minute/1.73 m2: No dosage adjustment
dure prophylaxis: 1 to 5 mg/kg/dose once daily necessary.
starting one to several days prior to implantation GFR <10 mL/minute/1.73 m2: Avoid use.
and continued for at least 6 months. For older Intermittent hemodialysis: Dialyzable: 50% to 100%
children and adolescents, after device closure of (concentration dependent; higher salicylate con-
ASD, an additional anticoagulant may be given centrations are more readily dialyzable) (Juurlink
with aspirin for 3 to 6 months, but the aspirin 2015; Rosenberg 1981); administer daily dose after
should continue for at least 6 months (AHA [Giglia dialysis session on dialysis days (Aronoff 2007).
2013]). Peritoneal dialysis: Avoid use.
Ventricular assist device (VAD) placement: 1 to CRRT: No dosage adjustment necessary; monitor
5 mg/kg/dose once daily initiated within 72 hours serum concentrations.
of VAD placement; should be used with heparin Hepatic Impairment: Pediatric All ages: Avoid use
(initiated between 8 to 48 hours following implan- in severe liver disease.
tation) and with or without dipyridamole (ACCP Mechanism of Action Irreversibly inhibits cyclooxyge-
[Monagle 2012]) nase-1 and 2 (COX-1 and 2) enzymes, via acetylation,
Kawasaki disease: Limited data available; optimal which results in decreased formation of prostaglandin
dose not established: Note: Patients with Kawasaki precursors; irreversibly inhibits formation of prostaglan-
disease and presenting with influenza or viral ill- din derivative, thromboxane A2, via acetylation of pla-
ness should not receive aspirin; acetaminophen is telet cyclooxygenase, thus inhibiting platelet
suggested as an antipyretic in these patients and aggregation; has antipyretic, analgesic, and anti-inflam-
an alternate antiplatelet agent suggested for a matory properties
minimum of 2 weeks (AHA [McCrindle 2017]). Contraindications
Infants, Children, and Adolescents: Oral: Hypersensitivity to NSAIDs; patients with asthma, rhini-
Initial therapy (acute phase): Recommended dos- tis, and nasal polyps; use in children or teenagers for
ing regimens vary. Use in combination with IV viral infections, with or without fever.
immune globulin (within first 10 days of symptom Documentation of allergenic cross-reactivity for salicy-
onset) and corticosteroids in some cases. lates is limited. However, because of similarities in
High dose: 80 to 100 mg/kg/day divided every 6 chemical structure and/or pharmacologic actions, the
hours for up to 14 days until fever resolves for possibility of cross-sensitivity cannot be ruled out with
at least 48 to 72 hours (AAP [Red Book 2015]; certainty.
ACCP [Monagle 2012]; AHA [Giglia 2013]; AHA Warnings/Precautions Use with caution in patients
[McCrindle 2017]) with platelet and bleeding disorders, renal dysfunction,
Moderate dose: 30 to 50 mg/kg/day divided dehydration, or erosive gastritis. Avoid use in patients
every 6 hours for up to 14 days until fever with active peptic ulcer disease. Heavy ethanol use (>3
resolves for at least 48 to 72 hours (AHA drinks/day) can increase bleeding risks. When using
[McCrindle 2017]) high dosages (eg, analgesic or anti-inflammatory uses),
Subsequent therapy (low-dose; antiplatelet use with caution and monitor renal function or consider
effects): 3 to 5 mg/kg/day once daily; reported the use of an alternative analgesic/anti-inflammatory
165
ASPIRIN
agent (NKF [Henrich 1996]; Whelton 2000). Low-dose behavior (along with nausea and vomiting) may be an
aspirin (eg, 75 to 162 mg daily) may be safely used in early sign of Reye syndrome; instruct patients and
patients with any degree of renal impairment (KDOQI caregivers to contact their health care provider if these
2005; KDOQI 2007). Avoid use in severe hepatic fail- symptoms occur; patients should be kept current on
ure. Low-dose aspirin for cardioprotective effects is their influenza and varicella immunizations. Although
associated with a two- to fourfold increase in UGI Reye syndrome has been observed in patients receiv-
events (eg, symptomatic or complicated ulcers); risks ing prolonged, high-dose aspirin therapy after Kawasaki
of these events increase with increasing aspirin dose; disease presentation; it has not been observed in
during the chronic phase of aspirin dosing, doses pediatric patients receiving low (antiplatelet) dosing
>81 mg are not recommended unless indicated (Bhatt regimens. Patients with Kawasaki disease and present-
2008). ing with influenza or viral illness should not receive
aspirin; acetaminophen is suggested as an antipyretic
Discontinue use if tinnitus or impaired hearing occurs. in these patients, and an alternate antiplatelet agent is
Caution in mild-to-moderate renal failure (only at high suggested for a minimum of 2 weeks (AHA [McCrindle
dosages). Patients with sensitivity to tartrazine dyes, 2017]).
nasal polyps, and asthma may have an increased risk Drug Interactions
of salicylate sensitivity. In the treatment of acute ische- Metabolism/Transport Effects Substrate of
mic stroke, avoid aspirin for 24 hours following admin- CYP2C9 (minor); Note: Assignment of Major/Minor
istration of alteplase; administration within 24 hours substrate status based on clinically relevant drug
increases the risk of hemorrhagic transformation (Jauch interaction potential
2013). Concurrent use of aspirin and clopidogrel is not Avoid Concomitant Use
recommended for secondary prevention of ischemic Avoid concomitant use of Aspirin with any of the
stroke or TIA in patients unable to take oral anticoagu- following: Dexibuprofen; Dexketoprofen; Floctafenine;
lants due to hemorrhagic risk (Furie 2011). Aspirin Influenza Virus Vaccine (Live/Attenuated); Ketorolac
should be avoided (if possible) in surgical patients for (Nasal); Ketorolac (Systemic); Macimorelin; Omace-
1 to 2 weeks prior to elective surgery, to reduce the risk taxine; Sulfinpyrazone; Urokinase
of excessive bleeding. In patients with cardiac stents or Increased Effect/Toxicity
who have recently (within the previous 14 days) under- Aspirin may increase the levels/effects of: Agents with
gone balloon angioplasty that have not completed their Antiplatelet Properties; Ajmaline; Alendronate; Angio-
full course of antiplatelet therapy (eg, dual antiplatelet tensin-Converting Enzyme Inhibitors; Anticoagulants;
therapy), antiplatelet therapy should be continued and Apixaban; Blood Glucose Lowering Agents; Carbonic
elective surgery should be delayed until course of Anhydrase Inhibitors; Carisoprodol; Cephalothin; Col-
antiplatelet therapy is complete; patient specific situa- lagenase (Systemic); Corticosteroids (Systemic);
tions should be discussed with cardiologist (ACC/AHA Dabigatran Etexilate; Deoxycholic Acid; Dexibuprofen;
[Fleisher 2014]; ACC/AHA [Levine 2016]; AHA/ACC/ Dexketoprofen; Edoxaban; Heparin; Ibritumomab
SCAI/ACS/ADA [Grines 2007]). Tiuxetan; Methotrexate; Nicorandil; Nonsteroidal
When used for self-medication (OTC labeling): Children Anti-Inflammatory Agents (COX-2 Selective); Obinu-
and teenagers who have or are recovering from chick- tuzumab; Omacetaxine; PRALAtrexate; Rivaroxaban;
enpox or flu-like symptoms should not use this product. Salicylates; Talniflumate; Thiopental; Thrombolytic
Changes in behavior (along with nausea and vomiting) Agents; Ticagrelor; Urokinase; Valproate Products;
may be an early sign of Reye's syndrome; patients Varicella Virus-Containing Vaccines; Vitamin K Antag-
should be instructed to contact their healthcare provider onists
if these occur. The levels/effects of Aspirin may be increased by:
Some dosage forms may contain polysorbate 80 (also Agents with Antiplatelet Properties; Alcohol (Ethyl);
known as Tweens). Hypersensitivity reactions, usually a Ammonium Chloride; Calcium Channel Blockers
delayed reaction, have been reported following expo- (Nondihydropyridine); Dasatinib; Fat Emulsion (Fish
sure to pharmaceutical products containing polysorbate Oil Based); Felbinac; Floctafenine; Ginkgo Biloba;
80 in certain individuals (Isaksson 2002; Lucente 2000; Glucosamine; Herbs (Anticoagulant/Antiplatelet Prop-
Shelley 1995). Thrombocytopenia, ascites, pulmonary erties); Ibrutinib; Influenza Virus Vaccine (Live/Attenu-
deterioration, and renal and hepatic failure have been ated); Inotersen; Ketorolac (Nasal); Ketorolac
reported in premature neonates after receiving paren- (Systemic); Limaprost; Loop Diuretics; Multivitamins/
teral products containing polysorbate 80 (Alade 1986; Fluoride (with ADE); Multivitamins/Minerals (with
CDC 1984). See manufacturer's labeling. ADEK, Folate, Iron); Multivitamins/Minerals (with AE,
No Iron); Nonsteroidal Anti-Inflammatory Agents (Non-
Aspirin resistance is defined as measurable, persistent selective); Omega-3 Fatty Acids; Pentosan Polysul-
platelet activation that occurs in patients prescribed a fate Sodium; Pentoxifylline; Potassium Phosphate;
therapeutic dose of aspirin. Clinical aspirin resistance, Prostacyclin Analogues; Selective Serotonin Reup-
the recurrence of some vascular event despite a regular take Inhibitors; Serotonin/Norepinephrine Reuptake
therapeutic dose of aspirin, is considered aspirin treat- Inhibitors; Tipranavir; Tricyclic Antidepressants (Terti-
ment failure. Estimates of biochemical aspirin resist- ary Amine); Vitamin E (Systemic)
ance range from 5.5% to 60% depending on the Decreased Effect
population studied and the assays used (Gasparyan Aspirin may decrease the levels/effects of: Angioten-
2008). Patients with aspirin resistance may have a sin-Converting Enzyme Inhibitors; Benzbromarone;
higher risk of cardiovascular events compared to those Carisoprodol; Dexketoprofen; Hyaluronidase; Lesi-
who are aspirin sensitive (Gum 2003). nurad; Loop Diuretics; Macimorelin; Multivitamins/Flu-
Warnings: Additional Pediatric Considerations oride (with ADE); Multivitamins/Minerals (with ADEK,
Do not use aspirin in pediatric patients <18 years of Folate, Iron); Multivitamins/Minerals (with AE, No
age (APS 2016) who have or who are recovering from Iron); Nonsteroidal Anti-Inflammatory Agents (Nonse-
chickenpox or flu symptoms (due to the association with lective); Probenecid; Sincalide; Spironolactone; Sulfin-
Reye syndrome); when using aspirin, changes in pyrazone; Ticagrelor; Tiludronate
166
ASPIRIN
The levels/effects of Aspirin may be decreased by: warfarin is recommended, along with low-dose aspirin,
Alcohol (Ethyl); Corticosteroids (Systemic); Dexibu- in those with mechanical prosthetic valves (AHA/ACC
profen; Dexketoprofen; Floctafenine; Ketorolac [Nishimura 2014]). Low-dose aspirin may also be used
(Nasal); Ketorolac (Systemic); Nonsteroidal Anti- after the first trimester in women with low-risk conditions
Inflammatory Agents (Nonselective); Sucroferric Oxy- requiring antiplatelet therapy (AHA/ASA [Kernan
hydroxide 2014]). When needed in doses required for the man-
Food Interactions Food may decrease the rate but not agement of pain, agents other than aspirin are preferred
the extent of oral absorption. Benedictine liqueur, in pregnant women and use in the third trimester is not
prunes, raisins, tea, and gherkins have a potential to recommended (Källén 2016; Shah 2015).
cause salicylate accumulation. Fresh fruits containing Breastfeeding Considerations
vitamin C may displace drug from binding sites, result- Salicylic acid is present in breast milk following mater-
ing in increased urinary excretion of aspirin. Curry nal use of aspirin (Bailey 1982; Findlay 1981; Jamali
powder, paprika, licorice; may cause salicylate accu- 1981).
mulation. These foods contain 6 mg salicylate/100 g. The relative infant dose (RID) of aspirin is 8% when
An ordinary American diet contains 10-200 mg/day of calculated using the highest breast milk concentration
salicylate. Management: Administer with food or large located and compared to an infant therapeutic dose of
volume of water or milk to minimize GI upset. Limit curry 90 mg/kg/day.
powder, paprika, licorice. In general, breastfeeding is considered acceptable
Pharmacodynamics/Kinetics when the RID is <10% (Anderson 2016; Ito 2000).
Onset of Action Immediate release: Platelet inhib- The RID of aspirin was calculated using a milk concen-
ition: Within 1 hour (nonenteric-coated). Onset of tration of 48.1 mcg/mL, providing an estimated daily
enteric-coated aspirin expected to be delayed (Eikel- infant dose via breast milk of 7.2 mg/kg/day. This milk
boom 2012). Note: Chewing nonenteric-coated or concentration was obtained following maternal admin-
enteric-coated tablets results in inhibition of platelet istration of aspirin 1,500 mg as a single dose (Jamali
aggregation within 20 minutes; therefore, nonenteric- 1981). The reported time to peak milk concentration is
coated tablets should be chewed in settings where a variable (2 to 9 hours), milk concentrations decline
more rapid onset is required (eg, acute MI) and slowly, and do not correlate strongly to maternal serum
enteric-coated tablets may be chewed when a rapid concentration (Bailey 1982; Bar-Oz 2003; Findlay
effect is required and immediate release nonenteric- 1981; Jamali 1981). Salicylate is measurable in the
coated tablets are not available (Eikelboom 2012; serum (Unsworth 1987) and urine (Clark 1981) of
Feldman 1999; Sai 2011). breastfed infants following maternal use of oral
Duration of Action Immediate release: 4 to 6 hours; aspirin. Higher salicylate concentrations may be
however, platelet inhibitory effects last the lifetime of present in breast milk following multiple maternal
the platelet (~10 days) due to its irreversible inhibition doses. In addition, salicylate concentrations may be
of platelet COX-1 (Eikelboom, 2012). higher than reported as metabolite concentrations of
Half-life Elimination Parent drug: Plasma concen- salicylic acid were not evaluated in most studies; the
tration: 15 to 20 minutes; Salicylates (dose depend- longer elimination half-life in infants compared to
ent): 3 hours at lower doses (300 to 600 mg), 5 to 6 adults should also be considered (Bar-Oz 2003; Spig-
hours (after 1 g), 10 hours with higher doses set 2000).
Time to Peak Serum: Immediate release: ~1 to 2 Metabolic acidosis was reported in a 16-day old
hours (nonenteric-coated), 3 to 4 hours (enteric- breastfed full-term infant following maternal doses of
coated) (Eikelboom, 2012); Extended-release cap- aspirin 3.9 g/day (Clark 1981). Thrombocytopenic pur-
sule: ~2 hours. Note: Chewing nonenteric-coated pura was also reported in one infant following salicy-
tablets results in a time to peak concentration of 20 late exposure via breast milk (Spigset 2000). There
minutes (Feldman, 1999). Chewing enteric-coated were no cases of diarrhea, drowsiness, or irritability
tablets results in a time to peak concentration of 2 noted in breastfed infants in the study which included
hours (Sai, 2011). 15 mother-infant pairs following aspirin exposure
(dose, duration, and relationship to breastfeeding not
Pregnancy Considerations Salicylates have been
provided) (Ito 1993).
noted to cross the placenta and enter fetal circulation.
Breastfeeding is not recommended by the manufac-
Adverse effects reported in the fetus include mortality,
turer. When a nonopioid analgesic is needed in post-
intrauterine growth retardation, salicylate intoxication,
partum women who wish to breastfeed, agents other
bleeding abnormalities, and neonatal acidosis. Use of
than aspirin are preferred (Montgomery 2012). The
aspirin close to delivery may cause premature closure
WHO considers occasional doses of aspirin to be
of the ductus arteriosus. Adverse effects reported in the
compatible with breastfeeding, but recommends to
mother include anemia, hemorrhage, prolonged gesta-
avoid long-term therapy and consider monitoring the
tion, and prolonged labor (Østensen 1998).
infant for adverse effects (hemolysis, prolonged bleed-
Low-dose aspirin may be used to prevent preeclampsia ing, metabolic acidosis) (WHO 2002). Other sources
in women with a history of early-onset preeclampsia suggest avoiding aspirin while breastfeeding due to
and preterm delivery (<34 0/7 weeks), or preeclampsia the theoretical risk of Reye syndrome (Bar-Oz 2003;
in ≥1 prior to pregnancy (ACOG 2013). Treatment is Spigset 2000). When used for vascular indications,
started after 12 weeks' gestation in women at risk for breastfeeding may be continued during low-dose
preeclampsia (ACCP [Bates 2012]; LeFevre 2014). aspirin therapy (ACCP [Bates 2012]; AHA/ASA [Ker-
Low-dose aspirin is used to treat complications result- nan 2014]; WHO 2002).
ing from antiphospholipid syndrome in pregnancy Dosage Forms: US
(either primary or secondary to SLE) (ACCP [Bates Caplet, oral: 500 mg
2012]; Carp 2004; Tincani 2003). Low-dose aspirin to Ascriptin Maximum Strength [OTC]: 500 mg
prevent thrombosis may also be used during the sec- Bayer Aspirin Extra Strength [OTC]: 500 mg
ond and third trimesters in women with prosthetic Bayer Genuine Aspirin [OTC]: 325 mg
valves (mechanical or bioprosthetic). The use of Bayer Plus Extra Strength [OTC]: 500 mg
167
ASPIRIN
Bayer Women's Low Dose Aspirin [OTC]: 81 mg Additional information is available at: http://www.fda.
Caplet, enteric coated, oral: gov/Drugs/DrugSafety/PostmarketDrugSafetyInforma-
Bayer Aspirin Regimen Regular Strength [OTC]: tionforPatientsandProviders/ucm125222.htm
325 mg
Capsule Extended Release, oral: Aspirin and Dipyridamole
Durlaza: 162.5 mg (AS pir in & dye peer ID a mole)
Suppository, rectal: 300 mg (12s); 600 mg (12s)
Tablet, oral: 325 mg Related Information
Ascriptin Regular Strength [OTC]: 325 mg Aspirin on page 160
Aspercin [OTC]: 325 mg Dipyridamole on page 440
Aspirtab [OTC]: 325 mg Brand Names: US Aggrenox
Bayer Genuine Aspirin [OTC]: 325 mg Brand Names: Canada Aggrenox
Buffasal [OTC]: 325 mg Pharmacologic Category Antiplatelet Agent
Bufferin [OTC]: 325 mg Use Stroke prevention: Reduction in the risk of stroke
Bufferin Extra Strength [OTC]: 500 mg in patients who have had transient ischemia of the brain
Buffinol [OTC]: 324 mg or complete ischemic stroke due to thrombosis.
Tri-Buffered Aspirin [OTC]: 325 mg Local Anesthetic/Vasoconstrictor Precautions
Tablet, chewable, oral: 81 mg No information available to require special precautions
Bayer Aspirin Regimen Children's [OTC]: 81 mg Effects on Dental Treatment Key adverse event(s)
St Joseph Adult Aspirin [OTC]: 81 mg related to dental treatment: As with all drugs which may
Tablet, delayed release, oral: 81 mg affect hemostasis, bleeding is associated with aspirin.
Aspirin Adult Low Dose: 81 mg Hemorrhage may occur at virtually any site; risk is
Aspirin Adult Low Strength: 81 mg dependent on multiple variables including dosage, con-
Aspirin EC Low Strength: 81 mg current use of multiple agents which alter hemostasis,
Tablet, enteric coated, oral: 81 mg, 325 mg, 650 mg and patient susceptibility. Many adverse effects of
Aspir-low [OTC]: 81 mg aspirin are dose related, and are rare at low dosages.
Bay er Aspi rin Regi men Ad ult L ow Stre ngth Other serious reactions are idiosyncratic, related to
[OTC]: 81 mg allergy or individual sensitivity (see Dental Health Pro-
Ecotrin [OTC]: 325 mg fessional Considerations).
Ecotrin Arthritis Strength [OTC]: 500 mg Aspirin as sole antiplatelet agent: Patients taking
Ecotrin Low Strength [OTC]: 81 mg aspirin for ischemic stroke prevention are safe to con-
St Joseph Adult Aspirin [OTC]: 81 mg tinue it during dental procedures (Armstrong 2013).
Dental Health Professional Considerations The
Food and Drug Administration (FDA), has issued a Concurrent aspirin use with other antiplatelet
agents: Aspirin in combination with clopidogrel (Plavix),
letter updating information and considerations regard-
prasugrel (Effient), or ticagrelor (Brilinta™) is the pri-
ing the use of ibuprofen (400 mg doses) in patients who
mary prevention strategy against stent thrombosis after
are taking low dose aspirin (81 mg, immediate release;
placement of drug-eluting metal stents in coronary
not enteric coated) for cardioprotection and stroke pre-
patients. Premature discontinuation of combination anti-
vention. Ibuprofen, at these doses, may interfere with platelet therapy (ie, dual antiplatelet therapy) strongly
aspirin’s antiplatelet effect depending upon when it is increases the risk of a catastrophic event of stent
administered. Patients initiated on aspirin first (for ~1 thrombosis leading to myocardial infarction and/or
week) then ibuprofen (400 mg 3 times/day for 10 days) death, so says a science advisory issued in January
seem to maintain aspirin’s platelet effect (Cryer, 2005). 2007 from the American Heart Association in collabo-
Ibuprofen has the greatest impact on aspirin if admin- ration with the American Dental Association and other
istered less than 8 hours before aspirin (Catella-Law- professional healthcare organizations. The advisory
son, 2001). stresses a 12-month therapy of dual antiplatelet therapy
Patients may require counseling about the appropriate after placement of a drug-eluting stent in order to
timing of ibuprofen dosing in relationship to aspirin prevent thrombosis at the stent site. Any elective sur-
therapy. With occasional use of ibuprofen, a clinically- gery should be postponed for 1 year after stent implan-
tation, and if surgery must be performed, consideration
significant interaction with aspirin in unlikely. To avoid
should be given to continuing the antiplatelet therapy
interference during chronic dosing, a single dose of
during the perioperative period in high-risk patients with
ibuprofen should be taken 30 to 120 minutes after
drug-eluting stents.
aspirin ingestion or at least 8 hours should elapse after
This advisory was issued from a science panel made up
ibuprofen dosing before giving aspirin (Catella-Lawson, of representatives from the American Heart Associa-
2001; FDA, 2006). tion (AHA), the American College of Cardiology, the
The clinical implications of the interaction are unclear. Society for Cardiovascular Angiography and Interven-
There have not been any clinical endpoint studies tions, the American College of Surgeons, the Ameri-
conducted at this time. Avoidance of this interaction is can Dental Association (ADA), and the American
potentially important because aspirin’s vascular protec- College of Physicians (Grines 2007).
tion could be decreased or negated. Effects on Bleeding Aspirin irreversibly inhibits plate-
let aggregation which can prolong bleeding. Upon dis-
Other nonselective NSAIDs may have potential for a continuation, normal platelet function returns only when
similar interaction with aspirin. Such has been new platelets are released (~7-10 days). However, in
described with naproxen (Capone, 2005). Acetamino- the case of dental surgery, there is no scientific evi-
phen does not appear to interfere with the antiplatelet dence to support discontinuation of aspirin. This was
effect of aspirin. Other clinical scenarios (use of smaller recently supported by the American Academy of Neu-
ibuprofen doses, other aspirin products, other doses of rology in patients with ischemic cerebrovascular dis-
aspirin) have not been evaluated. ease (Armstrong 2013). A recent study compared
168
ATAZANAVIR
blood loss after a single tooth extraction in coronary not enteric coated) for cardioprotection and stroke pre-
artery disease patients who were either on aspirin vention. Ibuprofen, at these doses, may interfere with
(100 mg daily) or off aspirin for the extraction. The aspirin’s antiplatelet effect depending upon when it is
mean volume of bleeding was not statistically different administered. Patients initiated on aspirin first (for ~1
between the groups. Local hemostatic measures were week) then ibuprofen (400 mg 3 times/day for 10 days)
sufficient to control bleeding and there were no reported seem to maintain aspirin’s platelet effect (Cryer 2005).
episodes of hemorrhaging intra- or postoperatively Ibuprofen has the greatest impact on aspirin if admin-
(Medeiros 2011). istered less than 8 hours before aspirin (Catella-Lawson
Adverse Reactions 2001).
>10%:
Central nervous system: Headache (39%; tolerance Patients may require counseling about the appropriate
usually develops) timing of ibuprofen dosing in relationship to aspirin
Gastrointestinal: Abdominal pain (18%), dyspepsia therapy. With occasional use of ibuprofen, a clinically-
(18%), nausea (16%), diarrhea (13%) significant interaction with aspirin in unlikely. To avoid
1% to 10%: interference during chronic dosing, a single dose of
Cardiovascular: Cardiac failure (2%), syncope (1%) ibuprofen should be taken 30-120 minutes after aspirin
Central nervous system: Fatigue (6%), pain (6%), ingestion or at least 8 hours should elapse after ibupro-
amnesia (2%), malaise (2%), seizure (2%), confu- fen dosing before giving aspirin (Catella-Lawson 2001;
sion (1%), drowsiness (1%) FDA 2006).
Gastrointestinal: Vomiting (8%), gastrointestinal hem- The clinical implications of the interaction are unclear.
orrhage (1% to 4%), melena (2%), anorexia (1%), There have not been any clinical endpoint studies
hemorrhoids (1%) conducted at this time. Avoidance of this interaction is
Hematologic & oncologic: Hemorrhage (3%), anemia potentially important because aspirin’s vascular protec-
(2%), rectal hemorrhage (2%), purpura (1%) tion could be decreased or negated.
Neuromuscular & skeletal: Arthralgia (6%), back pain
(5%), arthritis (2%), weakness (2%), arthropathy Other nonselective NSAIDs may have potential for a
(1%), myalgia (1%) similar interaction with aspirin. Such has been
Respiratory: Cough (2%), epistaxis (2%), upper respi- described with naproxen (Capone 2005). Acetamino-
ratory tract infection (1%) phen does not appear to interfere with the antiplatelet
<1% (Limited to important or life-threatening): Ageusia, effect of aspirin. Other clinical scenarios (use of smaller
agitation, alopecia, anaphylaxis, angina pectoris, ibuprofen doses, other aspirin products, other doses of
angioedema, antepartum hemorrhage, aplastic ane- aspirin) have not been evaluated.
mia, asthma, auditory impairment, blood coagulation
disorder, bronchospasm, bruise, cardiac arrhythmia, Additional information is available at: http://www.fda.
cerebral edema, cerebral hemorrhage, changes in gov/Drugs/DrugSafety/PostmarketDrugSafetyInforma-
liver function, chest pain, cholelithiasis, coma, deaf- tionforPatientsandProviders/ucm125222.htm
ness, dehydration, disseminated intravascular coagu-
lation, dizziness, dyspnea, ecchymoses, fever, Atazanavir (at a za NA veer)
flushing, gastritis, gastrointestinal perforation, gastro-
intestinal ulcer, gingival hemorrhage, hematemesis, Related Information
hematoma, hematuria, hemoptysis, hepatic failure, HIV Infection and AIDS on page 1477
hepatitis, hyperglycemia, hyperkalemia, hypersensitiv- Brand Names: US Reyataz
ity angiitis, hypersensitivity reaction, hyperventilation, Brand Names: Canada Reyataz
hypoglycemia, hypokalemia, hypotension, hypother- Pharmacologic Category Antiretroviral, Protease
mia, increased thirst, interstitial nephritis, intracranial Inhibitor (Anti-HIV)
hemorrhage, jaundice, laryngeal edema, metabolic
Use HIV-1 Infection:
acidosis, migraine, palpitations, pancreatitis, pancyto-
Treatment of HIV-1 infection in combination with other
penia, paresthesia, postpartum hemorrhage, pro-
antiretroviral agents in patients ≥3 months weighing
longed prothrombin time, proteinuria, pruritus,
≥5 kg
pulmonary edema, renal failure, renal insufficiency,
Limitations of use:
renal papillary necrosis, respiratory alkalosis, Reye's
syndrome, rhabdomyolysis, skin rash, Stevens-John- Not recommended for use in pediatric patients <3
son syndrome, subarachnoid hemorrhage, supraven- months due to the risk of kernicterus
tricular tachycardia, tachycardia, tachypnea, Use in treatment-experienced patients should be
thrombocythemia, thrombocytopenia, tinnitus, urtica- guided by the number of baseline primary protease
ria, uterine hemorrhage inhibitor resistance substitutions
Mechanism of Action The antithrombotic action Local Anesthetic/Vasoconstrictor Precautions
results from additive antiplatelet effects. Dipyridamole No information available to require special precautions
inhibits the uptake of adenosine into platelets, endothe- Effects on Dental Treatment No significant effects or
lial cells, and erythrocytes. Aspirin inhibits platelet complications reported
aggregation by irreversible inhibition of platelet cyclo- Effects on Bleeding Increased bleeding has been
oxygenase and thus inhibits the generation of throm- noted with protease inhibitors, such as atazanavir, in
boxane A2. patients with hemophilia A or B. Thrombocytopenia has
Pregnancy Considerations Refer to individual mono- been reported. No other information is available to
graphs require special precautions in other patients.
Dental Health Professional Considerations The Adverse Reactions Includes data from both treat-
Food and Drug Administration (FDA), has issued a ment-naive and treatment-experienced patients. Unless
letter updating information and considerations regard- otherwise noted, frequency of adverse events is as
ing the use of ibuprofen (400 mg doses) in patients who reported in adults receiving combination antiretroviral
are taking low dose aspirin (81 mg, immediate release; therapy.
169
ATAZANAVIR
>10%: 13% to 21% of maternal serum concentrations at deliv-

Dermatologic: Skin rash (adults 3% to 21%; median ery.
onset: 7 weeks; children 14%)
An increased risk of teratogenic effects has not been
Endocrine & metabolic: Increased serum cholesterol
observed based on information collected by the anti-
(≥240 mg/dL: 6% to 25%), increased amylase
retroviral pregnancy registry. Maternal antiretroviral
(adults: >2 x ULN: ≤14%)
therapy (ART) may increase the risk of preterm delivery,
Gastrointestinal: Nausea (3% to 14%)
although available information is conflicting possibly
Hepatic: Increased serum bilirubin (≥2.6 x ULN: adults due to variability of maternal factors (disease severity;
35% to 49%; children 16%), jaundice (children 13% gestational age at initiation of therapy). An increased
to 15%; adults 5% to 9%) risk of stillbirth, low birth weight, and small for gesta-
Neuromuscular & skeletal: Increased creatine phos- tional age infants has been observed in some but not all
phokinase (>5 times ULN: 6% to 11%) studies. Because there is clear benefit to appropriate
Respiratory: Cough (children 21%) treatment, maternal ART should not be withheld due to
Miscellaneous: Fever (children 18% to 19%; concerns for adverse neonatal outcomes. Long-term
adults 2%) follow-up is recommended for all infants exposed to
1% to 10%: antiretroviral medications; children who develop signifi-
Cardiovascular: Peripheral edema (children 7%), first cant organ system abnormalities of unknown etiology
degree atrioventricular block (6%), second degree (particularly of the CNS or heart) should be evaluated
atrioventricular block (children ≤2%; adults [rare]) for potential mitochondrial dysfunction. Hyperglycemia,
Central nervous system: Headache (adults 1% to 6%; new onset of diabetes mellitus, or diabetic ketoacidosis
children 7% to 8%), peripheral neuropathy (<1% to have been reported with protease inhibitors; it is not
4%), insomnia (<1% to 3%), depression (2%), dizzi- clear if pregnancy increases this risk. Hyperbilirubine-
ness (<1% to 2%) mia or hypoglycemia may occur in neonates following in
Endocrine & metabolic: Increased serum triglycerides utero exposure to atazanavir, although data are con-
(≥751 mg/dL: <1% to 8%), hyperglycemia flicting (monitor).
(≥251 mg/dL: 5%), hypoglycemia (children: grades
3/4: 4%) The Health and Human Services (HHS) Perinatal HIV
Gastrointestinal: Vomiting (children 8% to 12%; adults Guidelines consider atazanavir (when combined with
3% to 4%), diarrhea (children 8% to 9%; adults 1% to low-dose ritonavir boosting) a preferred protease inhib-
3%), increased serum lipase (adults: >2 x ULN: itor for HIV-infected pregnant females who are antire-
≤5%), abdominal pain (4%) troviral-naive (initial therapy), who have had ART
Hematologic & oncologic: Decreased neutrophils therapy in the past but are restarting, who require a
(<750 cells/mm3: 3% to 7%), decreased hemoglobin new ART regimen (due to poor tolerance or poor
(<8.0 g/dL: <1% to 5%), decreased platelet count virologic response of current regimen), and who are
(<50,000 cells/mm3: 2%) not yet pregnant but are trying to conceive. In addition,
Hepatic: Increased serum ALT (adults and children: >5 females who become pregnant while taking atazanavir
may continue if viral suppression is effective and the
x ULN: 3% to 9%; 10% to 25% in adult patients co-
regimen is well tolerated. Atazanavir is not recom-
infected with hepatitis B and/or C), increased serum
mended in treatment-experienced pregnant females
AST (>5 times ULN: 2% to 7%; 9% to 10% in patients
taking both H2-receptor blockers and tenofovir diso-
co-infected with hepatitis B and/or C)
proxil fumarate. Pharmacokinetic studies suggest that
Neuromuscular & skeletal: Myalgia (4%), limb pain
standard dosing during pregnancy may provide
(children 6%)
decreased plasma concentrations and some experts
Respiratory: Nasal congestion (children 6%), orophar-
recommend increased doses during the second and
yngeal pain (children 6%), rhinorrhea (children 6%),
third trimesters. However, the manufacturer notes that
wheezing (children 6%)
dose adjustment is not required unless using concom-
Postmarketing and/or case reports: Alopecia, angioe-
itant H2-receptor blockers or tenofovir disoproxil fuma-
dema, arthralgia, cholecystitis, cholelithiasis, choles- rate in antiretroviral-experienced pregnant females.
tasis, chronic renal failure, complete atrioventricular Therapeutic drug monitoring may be useful.
block (rare), diabetes mellitus, DRESS syndrome,
edema, erythema multiforme, granulomatous intersti- In general, ART is recommended for all pregnant
tial nephritis, hepatic abnormality, immune reconstitu- females with HIV to keep the viral load below the limit
tion syndrome, interstitial nephritis, left bundle branch of detection and reduce the risk of perinatal trans-
block, maculopapular rash, nephrolithiasis, pancreati- mission. Monitoring during pregnancy is more frequent
tis, prolongation P-R interval on ECG, prolonged Q-T than in nonpregnant adults. ART should be continued
interval on ECG, pruritus, Stevens-Johnson syn- postpartum for all females living with HIV and can be
drome, torsades de pointes modified after delivery.
Mechanism of Action Binds to the site of HIV-1 Health care providers are encouraged to enroll preg-
protease activity and inhibits cleavage of viral Gag-Pol nant females exposed to antiretroviral medications as
polyprotein precursors into individual functional proteins early in pregnancy as possible in the Antiretroviral
required for infectious HIV. This results in the formation Pregnancy Registry (1-800-258-4263 or http://www.-
of immature, noninfectious viral particles. APRegistry.com). Health care providers caring for
Pharmacodynamics/Kinetics HIV-infected females and their infants may contact the
Half-life Elimination Unboosted therapy: 7 to 8 National Perinatal HIV Hotline (888-448-8765) for clin-
hours; Boosted therapy (with ritonavir): 9 to 18 hours; ical consultation (HHS [perinatal] 2018).
12 hours in patients with hepatic impairment
Time to Peak Plasma: 2 to 3 hours
Pregnancy Considerations Atazanavir and Cobicistat
(at a za NA veer & koe BIK i stat)
Atazanavir has a low level of transfer across the human
placenta with cord blood concentrations reported as Brand Names: US Evotaz
170
ATENOLOL
Brand Names: Canada Evotaz who become pregnant while taking this combination,
Pharmacologic Category Antiretroviral, Protease consider altering the regimen, or continue with frequent
Inhibitor (Anti-HIV); Cytochrome P-450 Inhibitor monitoring if viral suppression is effective and the
Use regimen is well tolerated (HHS [perinatal] 2018).
HIV-1 infection: Treatment of human immunodefi- Refer to individual monographs for additional infor-
ciency virus (HIV-1) infection in adults in combination mation.
with other antiretroviral agents.
Limitations of use: Use in treatment-experienced
patients should be guided by the number of baseline Atenolol (a TEN oh lole)
primary protease inhibitor resistance substitutions
Local Anesthetic/Vasoconstrictor Precautions Related Information
No information available to require special precautions Cardiovascular Diseases on page 1442
Effects on Dental Treatment No significant effects or Brand Names: US Tenormin
complications reported Brand Names: Canada Tenormin
Effects on Bleeding Increased bleeding has been Pharmacologic Category Antianginal Agent; Antihy-
noted with protease inhibitors, such as atazanavir, in pertensive; Beta-Blocker, Beta-1 Selective
patients with hemophilia A or B. Thrombocytopenia has Use
been reported. No other information is available to Acute MI: Management of hemodynamically stable
require special precautions in other patients. patients with definite or suspected acute MI to reduce
Adverse Reactions All adverse reactions are from cardiovascular mortality.
trials using cobicistat coadministered with atazanavir, Guideline recommendations: According to the
emtricitabine + tenofovir. Also see individual agents. American College of Cardiology Foundation/Ameri-
>10%: Hepatic: Increased serum bilirubin (grades can Heart Association (ACC/AHA) guidelines for the
3/4: 73%) management of ST-elevation myocardial infarction
1% to 10%: (STEMI) and the ACC/AHA guidelines for the man-
Central nervous system: Headache (2%), abnormal agement of non-ST-elevation ACS (NSTE-ACS), oral
dreams (<2%), depression (<2%), fatigue (<2%), beta-blockers should be initiated within the first 24
insomnia (<2%) hours unless the patient has signs of heart failure,
Dermatologic: Skin rash (5%) evidence of a low-output state, an increased risk for
Endocrine & metabolic: Increased gamma-glutamyl cardiogenic shock, or other contraindications. How-
transferase (grades 3/4: 4%), glycosuria (grades ever, recommendations do not specify any particular
3/4: 3%), increased serum glucose (grades 3/4: beta-blocking agent for optimal treatment of NSTE-
2%), Fanconi syndrome (<2%) ACS. Thus, clinicians must use practical experience
Gastrointestinal: Increased serum amylase (grades to determine proper therapy in managing patients
3/4: 4%), diarrhea (2%), nausea (2%), upper (ACC/AHA [Amsterdam 2014]; ACC/AHA
abdominal pain (<2%), vomiting (<2%) [O'Gara 2013]).
Genitourinary: Hematuria (grades 3/4: 6%) Angina pectoris caused by coronary atherosclero-
Hematologic & oncologic: Decreased neutrophils sis: Long-term management of patients with angina
(grades 3/4: 3%) pectoris.
Hepatic: Increased serum ALT (grades 3/4: 6%), Hypertension: Management of hypertension. Note:
jaundice (6%), increased serum AST (grades Beta-blockers are not recommended as first-line ther-
3/4: 4%) apy (ACC/AHA [Whelton 2017]).
Neuromuscular & skeletal: Increased creatine phos- Local Anesthetic/Vasoconstrictor Precautions
phokinase (grades 3/4: 8%), rhabdomyolysis (<2%) No information available to require special precautions
Ophthalmic: Scleral icterus (4%) Effects on Dental Treatment Atenolol is a cardiose-
Renal: Nephrolithiasis (<2%), renal disease (<2%) lective beta-blocker. Local anesthetic with vasoconstric-
Frequency not defined: Endocrine & metabolic: tor can be safely used in patients medicated with
Increased HDL cholesterol, increased LDL choles- atenolol. Nonselective beta-blockers (ie, propranolol,
terol, increased serum glucose, increased serum tri- nadolol) enhance the pressor response to epinephrine,
glycerides resulting in hypertension and bradycardia; this has not
Mechanism of Action been reported for atenolol. Many nonsteroidal anti-
Atazanavir binds to the site of HIV-1 protease activity inflammatory drugs, such as ibuprofen and indometha-
and inhibits cleavage of viral Gag-Pol polyprotein cin, can reduce the hypotensive effect of beta-blockers
precursors into individual functional proteins required after 3 or more weeks of therapy with the NSAID. Short-
for infectious HIV. This results in the formation of term NSAID use (ie, 3 days) requires no special pre-
immature, noninfectious viral particles. cautions in patients taking beta-blockers.
Cobicistat is a mechanism-based inhibitor of cyto- Effects on Bleeding No information available to
chrome P450 3A (CYP3A). Inhibition of CYP3A-medi- require special precautions
ated metabolism by cobicistat and increases the Adverse Reactions Incidence rates are from studies in
systemic exposure of CYP3A substrates (eg, ataza- hypertensive patients unless otherwise noted.
navir). >10%:
Pregnancy Considerations Cardiovascular: Hypotension (acute myocardial infarc-
The Health and Human Services (HHS) Perinatal HIV tion: 25%), cardiac failure (acute myocardial infarc-
Guidelines do not recommend this fixed-dose combination: 19%), bradycardia (acute myocardial infarction:
tion for HIV-infected pregnant females who are antire- 18%; 3%), ventricular tachycardia (acute myocardial
troviral-naive, who have had antiretroviral therapy infarction: 16%), cold extremities (12%), supraven-
(ART) in the past but are restarting, who require a tricular tachycardia (acute myocardial infarc-
new ART regimen (due to poor tolerance or poor tion: 12%)
virologic response of current regimen), and who are Central nervous system: Fatigue (≤26%), dizziness
not yet pregnant but are trying to conceive. For females (1% to 13%), depression (≤12%)
171
ATENOLOL
1% to 10%:
Cardiovascular: Bundle branch block (acute myocar- Atenolol and Chlorthalidone
dial infarction: 7%), atrial fibrillation (acute myocar- (a TEN oh lole & klor THAL i done)
dial infarction: 5%), heart block (acute myocardial Related Information
infarction: 5%), atrial flutter (acute myocardial infarc- Atenolol on page 171
tion: 2%), orthostatic hypotension (2%), pulmonary Chlorthalidone on page 305
embolism (acute myocardial infarction: 1%) Brand Names: US Tenoretic
Central nervous system: Abnormal dreams (3%), leth- Brand Names: Canada Tenoretic
argy (1% to 3%), vertigo (2%), drowsiness (≤2%) Pharmacologic Category Antihypertensive; Beta-
Gastrointestinal: Nausea (3% to 4%), diarrhea (2% Blocker, Beta-1 Selective; Diuretic, Thiazide
to 3%) Use Hypertension: Management of hypertension
Neuromuscular & skeletal: Limb pain (3%) Local Anesthetic/Vasoconstrictor Precautions
Respiratory: Bronchospasm (acute myocardial infarc- No information available to require special precautions
tion: 1%) Effects on Dental Treatment Atenolol is a cardiose-
<1%, postmarketing, and/or case reports: Antibody lective beta-blocker. Local anesthetic with vasoconstric-
development, cardiogenic shock, exacerbation of tor can be safely used in patients medicated with
psoriasis, hallucination, headache, impotence, atenolol. Nonselective beta-blockers (ie, propranolol,
increased liver enzymes, increased serum bilirubin, nadolol) enhance the pressor response to epinephrine,
lupus-like syndrome, nonthrombocytopenic purpura, resulting in hypertension and bradycardia; this has not
Peyronie disease, psoriasiform eruption, psychosis, been reported for atenolol. Many nonsteroidal anti-
Raynaud disease, renal failure syndrome, sick sinus inflammatory drugs, such as ibuprofen and indometha-
syndrome, thrombocytopenia, transient alopecia, vis- cin, can reduce the hypotensive effect of beta-blockers
ual disturbance, xerostomia after 3 or more weeks of therapy with the NSAID. Short-
Mechanism of Action Competitively blocks response term NSAID use (ie, 3 days) requires no special pre-
cautions in patients taking beta-blockers.
to beta-adrenergic stimulation, selectively blocks beta1-
receptors with little or no effect on beta2-receptors
except at high doses
Pharmacodynamics/Kinetics Adverse Reactions See individual agents.
Onset of Action Oral: ≤1 hour; Peak effect: Oral: 2 to Pregnancy Risk Factor D
4 hours Pregnancy Considerations Atenolol and chlorthali-
done cross the placenta. See individual agents.
Duration of Action Normal renal function: Beta-
blocking effect: 12 to 24 hours; Antihypertensive
effect: Oral: 24 hours AtoMOXetine (AT oh mox e teen)
Half-life Elimination Beta:
Related Information
Newborns (<24 hours of age) born to mothers receiv-
ing atenolol: Mean: 16 hours; up to 35 hours
(Rubin 1983) mia on page 1548
Children and Adolescents 5 to 16 years of age: Mean: Brand Names: US Strattera
4.6 hours; range: 3.5 to 7 hours; Patients >10 years Brand Names: Canada Apo-Atomoxetine; DOM-
of age may have longer half-life (>5 hours) compared Atomoxetine; Mylan-Atomoxetine; PMS-Atomoxetine;
to children 5 to 10 years of age (<5 hours) RIVA-Atomoxetine; Sandoz-Atomoxetine; Strattera;
(Buck 1989) Teva-Atomoxetine
Adults: Normal renal function: 6 to 7 hours, prolonged Pharmacologic Category Norepinephrine Reuptake
with renal impairment; End-stage renal disease Inhibitor, Selective
(ESRD): 15 to 35 hours Use Attention-deficit/hyperactivity disorder: Treat-
Time to Peak Plasma: Oral: 2 to 4 hours ment of attention-deficit/hyperactivity disorder (ADHD)
Pregnancy Risk Factor D Local Anesthetic/Vasoconstrictor Precautions
Pregnancy Considerations Use vasoconstrictor with caution. Atomoxetine may
Atenolol crosses the placenta and is found in cord increase heart rate or blood pressure in the presence
blood. Maternal use of atenolol may cause harm to of pressor agents. Pressor agents include the vaso-
the fetus. Adverse events, such as bradycardia, hypo- constrictors epinephrine or mepivacaine and levonorde-
glycemia and reduced birth weight, have been frin (Carbocaine® 2% with Neo-Cobefrin®)
observed following in utero exposure to atenolol. Effects on Dental Treatment Key adverse event(s)
related to dental treatment: Xerostomia (normal salivary
Adequate facilities for monitoring infants at birth is
flow resumes upon discontinuation)
generally recommended. The maternal pharmacoki-
netic parameters of atenolol during the second and third
trimesters are within the ranges reported in nonpreg-
Adverse Reactions Percentages as reported in chil-
nant patients (Hebert 2005). dren and adults; some adverse reactions may be
Untreated chronic maternal hypertension and pree- increased in "poor metabolizers" (CYP2D6). Frequency
clampsia are associated with adverse events in the not always defined.
fetus, infant, and mother (ACOG 2015; Magee 2014). >10%:
Although beta-blockers may be used when treatment of Central nervous system: Headache (19%; children
hypertension in pregnancy is indicated, agents other and adolescents), insomnia (1% to 19%), drowsiness
than atenolol are preferred (ACOG 2013; Magee 2014; (8% to 11%)
Regitz-Zagrosek 2011). Dermatologic: Hyperhidrosis (4% to 15%)
172
ATORVASTATIN
Gastrointestinal: Xerostomia (17% to 35%), nausea

(7% to 26%), decreased appetite (15% to 23%), AtorvaSTATin (a TORE va sta tin)
abdominal pain (7% to 18%), vomiting (4% to
11%), constipation (1% to 11%) Related Information
Genitourinary: Erectile dysfunction (8% to 21%) Cardiovascular Diseases on page 1442
1% to 10%: Brand Names: US Lipitor
Cardiovascular: Increased diastolic blood pressure Brand Names: Canada Lipitor
(5% to 9%; ≥15 mm Hg), systolic hypertension (4% Pharmacologic Category Antilipemic Agent, HMG-
to 5%), palpitations (3%), cold extremities (1% to CoA Reductase Inhibitor
3%), syncope (≤3%), flushing (≥2%), orthostatic Use
hypotension (≤2%), tachycardia (≤2%), prolonged Dyslipidemias:
Q-T interval on ECG Dysbetalipoproteinemia: Treatment of primary dysbe-
Central nervous system: Fatigue (6% to 10%), dizzi- talipoproteinemia (Fredrickson type III).
ness (5% to 8%), depression (4% to 7%), disturbed Heterozygous familial and nonfamilial hypercholester-
sleep (3% to 7%), irritability (5% to 6%), jitteriness olemia and mixed dyslipidemia: To reduce elevated
(2% to 5%), abnormal dreams (4%), chills (3%), total cholesterol (total-C), low-density lipoprotein
paresthesia (adults 3%; postmarketing observation cholesterol (LDL-C), apolipoprotein B (apo B), and
in children), anxiety (≥2%), hostility (children and triglyceride levels, and to increase HDL-C in patients
adolescents 2%), emotional lability (1% to 2%), agi- with primary hypercholesterolemia (heterozygous
tation, restlessness, sensation of cold familial and nonfamilial) and mixed dyslipidemia
Dermatologic: Excoriation (2% to 4%), skin rash (2%), (Fredrickson type IIa and IIb).
pruritus, urticaria Heterozygous familial hypercholesterolemia: To
Endocrine & metabolic: Weight loss (2% to 7%), reduce total-C, LDL-C, and apo B levels in pediatric
decreased libido (3%), hot flash (3%), increased patients 10 to 17 years of age with heterozygous
thirst (2%), menstrual disease familial hypercholesterolemia with LDL-C
Gastrointestinal: Dyspepsia (4%), anorexia (3%), dys- ≥190 mg/dL, LDL-C ≥160 mg/dL with positive family
geusia, flatulence history of premature cardiovascular disease (CVD),
Genitourinary: Ejaculatory disorder (2% to 6%), uri- or LDL-C ≥160 mg/dL with two or more other CVD
nary retention (1% to 6%), dysmenorrhea (3%), risk factors.
dysuria (2%), orgasm abnormal, pollakiuria, prosta- Homozygous familial hypercholesterolemia: To reduce
titis, testicular pain, urinary frequency total-C and LDL-C in patients with homozygous
Neuromuscular & skeletal: Tremor (1% to 5%), muscle familial hypercholesterolemia as an adjunct to other
spasm, weakness lipid-lowering treatments (eg, LDL apheresis) or if
Ophthalmic: Blurred vision (1% to 4%), conjunctivitis such treatments are unavailable.
(1% to 3%), mydriasis Hypertriglyceridemia: Treatment of elevated serum
Respiratory: Pharyngolaryngeal pain triglyceride levels (Fredrickson type IV).
Mis cell aneou s: Therapeu tic respon se une x- Limitations of use: Has not been studied in conditions
pected (2%) where the major lipid abnormality is elevation of
<1%, postmarketing, and/or case reports: Aggressive chylomicrons (Fredrickson types I and V).
behavior, akathisia, alopecia, anaphylaxis, angioe- Prevention of cardiovascular disease (CVD):
dema, cerebrovascular accident, change in libido, Primary prevention of cardiovascular disease (high-
delusions, growth suppression (children), hallucina- risk for CVD): To reduce the risk of MI, stroke, and
tion, hepatotoxicity, hypersensitivity reaction, hypoes- revascularization procedures and angina in adult
thesia, hypomania, impulsivity, jaundice, lethargy, patients without clinically evident coronary heart dis-
mania, myocardial infarction, panic attack, pelvic pain, ease (CHD) who have multiple CHD risk factors (eg,
priapism, Raynaud's phenomenon, rhabdomyolysis, age, smoking, hypertension, low high-density lipo-
seizure (including patients with no prior history or protein cholesterol [HDL-C], family history of early
known risk factors for seizure), severe hepatic dis- CHD); to reduce the risk of MI and stroke in patients
ease, suicidal ideation, tics with type 2 diabetes and without clinically evident
Mechanism of Action Selectively inhibits the reuptake CHD but with multiple risk factors for CHD (eg,
of norepinephrine (Ki 4.5 nM) with little to no activity at retinopathy, albuminuria, smoking, hypertension).
the other neuronal reuptake pumps or receptor sites. Secondary prevention of cardiovascular disease: To
Pharmacodynamics/Kinetics reduce the risk of nonfatal MI, fatal and nonfatal
Duration of Action Up to 24 hours (Jain 2017) stroke, revascularization procedures, hospitalization
Half-life Elimination Atomoxetine: 5 hours (up to 24 for decompensated heart failure, and angina in
hours in poor metabolizers); Active metabolites: 4- patients with clinically evident CHD.
hydroxyatomoxetine: 6-8 hours; N-desmethylatomox- Local Anesthetic/Vasoconstrictor Precautions
etine: 6-8 hours (34-40 hours in poor metabolizers) No information available to require special precautions
Time to Peak Plasma: 1-2 hours; delayed 3 hours by Effects on Dental Treatment Key adverse event(s)
high-fat meal related to dental treatment: Assess unusual presenta-
Pregnancy Risk Factor C tions of muscle weakness or myopathy resulting from
Pregnancy Considerations Adverse events have lipid therapy such as patient having a difficult time
been observed in animal reproduction studies. Informa- brushing teeth or weakness with chewing. Refer patient
tion related to atomoxetine use in pregnancy is limited; back to their physician for evaluation and adjustment of
appropriate contraception is recommended for sexually lipid therapy.
active women of childbearing potential (Heiligenstein, Effects on Bleeding No information available to
2003). require special precautions
173
ATORVASTATIN
Adverse Reactions Pregnancy Considerations

>10%: Atorvastatin is contraindicated in pregnant females or
Gastrointestinal: Diarrhea (7% to 14%) those who may become pregnant.
Neuromuscular & skeletal: Arthralgia (9% to 12%)
There are reports of congenital anomalies following
Respiratory: Nasopharyngitis (13%)
maternal use of HMG-CoA reductase inhibitors in preg-
1% to 10%:
nancy; however, maternal disease, differences in spe-
Cardiovascular: Hemorrhagic stroke (2%)
cific agents used, and the low rates of exposure limit the
Central nervous system: Insomnia (5%), malaise
interpretation of the available data (Godfrey 2012;
(<2%), nightmares (<2%) Lecarpentier 2012). Cholesterol biosynthesis may be
Dermatologic: Urticaria (<2%) important in fetal development; serum cholesterol and
Endocrine & metabolic: Diabetes mellitus (6%), hyper- triglycerides increase normally during pregnancy. The
glycemia (<2%) discontinuation of lipid-lowering medications tempora-
Gastrointestinal: Nausea (7%), dyspepsia (6%), rily during pregnancy is not expected to have significant
abdominal distress (<2%), cholestasis (<2%), eruc- impact on the long-term outcomes of primary hyper-
tation (<2%), flatulence (<2%) cholesterolemia treatment.
Genitourinary: Urinary tract infection (7% to 8%), urine
abnormality (white blood cells positive in urine: <2%) Atorvastatin should be discontinued immediately if an
Hepatic: Increased serum transaminases (≤2%), unplanned pregnancy occurs during treatment.
abnormal hepatic function tests (<2%), hepatitis Adequate contraception is recommended if an HMG-
(<2%), increased serum alkaline phosphatase (<2%) CoA reductase inhibitor is required in females of repro-
Neuromuscular & skeletal: Limb pain (9%), myalgia ductive potential. Females planning a pregnancy should
(4% to 8%), musculoskeletal pain (5%), muscle discontinue the HMG-CoA reductase inhibitor 1 to 2
spasm (4% to 5%), increased creatine phosphoki- months prior to attempting to conceive (AHA/ACC
nase (<2%), joint swelling (<2%), muscle fatigue [Grundy 2018]).
(<2%), neck pain (<2%)
Ophthalmic: Blurred vision (<2%)
Otic: Tinnitus (<2%) Atovaquone (a TOE va kwone)
Respiratory: Pharyngolaryngeal pain (3% to 4%), epis-
Related Information
taxis (<2%)
Miscellaneous: Fever (<2%) Systemic Viral Diseases on page 1496
Frequency not defined: Central nervous system: Myas- Brand Names: US Mepron
thenia Brand Names: Canada Mepron
<1%, postmarketing, and/or case reports: Abdominal Pharmacologic Category Antiprotozoal
pain, alopecia, amnesia (reversible), anaphylaxis, Use
anemia, angioedema, anorexia, back pain, bullous Pneumocystis jirovecii pneumonia (PCP), prophylaxis:
rash, chest pain, cognitive dysfunction (reversible), Prevention of PCP in adults and adolescents 13 years
confusion (reversible), cystitis (interstitial; Huang and older who are intolerant to trimethoprim-sulfame-
2015), depression, dizziness, dysgeusia, elevated gly- thoxazole (TMP-SMZ)
cosylated hemoglobin (HbA1c), erythema multiforme, Pneumocystis jirovecii pneumonia (PCP), treatment:
fatigue, gynecomastia, hepatic failure, hypoesthesia, Acute oral treatment of mild to moderate PCP in adults
increased serum glucose, interstitial pulmonary dis- and adolescents 13 years and older who are intolerant
ease, jaundice, memory impairment (reversible), myo- to TMP-SMZ
pathy, myositis, pancreatitis, paresthesia, peripheral Local Anesthetic/Vasoconstrictor Precautions
edema, peripheral neuropathy, pruritus, rhabdomyol- No information available to require special precautions
ysis, rupture of tendon, Stevens-Johnson syndrome, Effects on Dental Treatment Key adverse event(s)
thrombocytopenia, toxic epidermal necrolysis, vomit- related to dental treatment: Oral Candida infection
ing, weight gain Effects on Bleeding No information available to
Mechanism of Action Inhibitor of 3-hydroxy-3-meth- require special precautions
ylglutaryl coenzyme A (HMG-CoA) reductase, the rate- Adverse Reactions Frequency not always defined.
limiting enzyme in cholesterol synthesis (reduces the Adverse reaction statistics have been compiled from
production of mevalonic acid from HMG-CoA); this then studies including patients with advanced HIV disease.
results in a compensatory increase in the expression of Consequently, it is difficult to distinguish reactions attrib-
LDL receptors on hepatocyte membranes and a stim- uted to atovaquone from those caused by the under-
ulation of LDL catabolism. In addition to the ability of lying disease or a combination thereof.
HMG-CoA reductase inhibitors to decrease levels of >10%:
high-sensitivity C-reactive protein (hsCRP), they also Central nervous system: Headache (16% to 31%),
possess pleiotropic properties including improved endo- insomnia (10% to 19%), depression, pain
thelial function, reduced inflammation at the site of the Dermatologic: Skin rash (22% to 46%), pruritus (5% to
coronary plaque, inhibition of platelet aggregation, and ≥10%), diaphoresis
anticoagulant effects (de Denus 2002; Ray 2005). Gastrointestinal: Diarrhea (19% to 42%), nausea (21%
Pharmacodynamics/Kinetics to 32%), vomiting (14% to 22%), abdominal pain (4%
Onset of Action Initial changes: 3 to 5 days; Maximal to 21%)
reduction in plasma cholesterol and triglycerides: 2 to Infection: Infection (18% to 22%)
4 weeks; LDL reduction: 10 mg/day: 39% (for each Neuromuscular & skeletal: Weakness (8% to 31%),
doubling of this dose, LDL is lowered approximately myalgia
6%) Respiratory: Cough (14% to 25%), rhinitis (5% to
Half-life Elimination Parent drug: ~14 hours; Equi- 24%), dyspnea (15% to 21%), sinusitis (7% to
potent metabolites: 20 to 30 hours ≥10%), flu-like symptoms
Time to Peak Serum: 1 to 2 hours Miscellaneous: Fever (14% to 40%)
174
AVANAFIL
1% to 10%: Hepatic: Increased serum ALT (27%; increased liver

Cardiovascular: Hypotension (≤1%) function test values typically normalized after ~4
Central nervous system: Dizziness (3% to 8%), anxi- weeks), increased serum AST (17%; increased liver
ety (≤7%) function test values typically normalized after ~4
Endocrine & metabolic: Hyponatremia (7% to 10%), weeks)
hyperglycemia (≤9%), increased amylase (7% to 1% to 10%:
8%), hypoglycemia (≤1%) Central nervous system: Headache (10%), dizzi-
Gastrointestinal: Oral candidiasis (5% to 10%), ano- ness (5%)
rexia (≤7%), dyspepsia (≤5%), constipation (≤3%), Dermatologic: Pruritus (children: 6%)
dysgeusia (≤3%) Gastrointestinal: Diarrhea (children: 6%; adults: 8%),
Hematologic & oncologic: Anemia (4% to 6%), neu- anorexia (5%)
tropenia (3% to 5%) Neuromuscular & skeletal: Weakness (8%)
Hepatic: Increased liver enzymes (4% to 8%) <1%, postmarketing, and/or case reports: Anaphylaxis
Renal: Increased blood urea nitrogen (≤1%), (rare), anemia (rare), angioedema, cholestasis, eryth-
increased serum creatinine (≤1%) ema multiforme (rare), hallucination, hepatic failure
Respiratory: Bronchospasm (2% to 4%) (case report), hepatitis (rare), neutropenia, pancyto-
<1%, postmarketing, and/or case reports: Acute renal penia (with severe renal impairment), psychotic reac-
failure, angioedema, constriction of the pharynx, cor- tion (rare), seizure (rare), skin photosensitivity, skin
neal disease (vortex keratopathy), desquamation, rash, Stevens-Johnson syndrome (rare), stomatitis,
erythema multiforme, hepatic failure (rare), hepatitis urticaria, vasculitis (rare)
(rare), hypersensitivity reaction, methemoglobinemia, Mechanism of Action
pancreatitis, Stevens-Johnson syndrome, thrombocy- Atovaquone: Selectively inhibits parasite mitochondrial
topenia, urticaria electron transport.
Mechanism of Action Inhibits electron transport in Proguanil: The metabolite cycloguanil inhibits dihydro-
mitochondria resulting in the inhibition of key metabolic folate reductase, disrupting deoxythymidylate synthe-
enzymes responsible for the synthesis of nucleic acids sis. Together, atovaquone/cycloguanil affect the
and ATP erythrocytic and exoerythrocytic stages of devel-
Pharmacodynamics/Kinetics opment.
Half-life Elimination Range: 67 ± 33.4 hours to 77.6 Pharmacodynamics/Kinetics
± 23.1 hours Half-life Elimination
Pregnancy Considerations Atovaquone: 2-3 days (adults), 1-2 days (children)
Information specific to the use of atovaquone in preg- Proguanil: 12-21 hours
nancy is limited. Pregnancy Considerations
Outcome information following maternal use of atova-
Diagnosis and treatment of Pneumocystis jirovecii quone and proguanil in pregnancy is limited (Andrejko
pneumonia (PCP) in pregnant women is the same as 2019; Mayer 2018; Pasternak 2011).
in nonpregnant women. Atovaquone may be used as an
alternative agent for PCP and Toxoplasma gondii infec- The pharmacokinetics of atovaquone and proguanil
tions when needed in pregnancy (HHS [OI adult 2017]). may be altered during pregnancy (Burger 2016).
Malaria infection in pregnant women may be more
severe than in nonpregnant women. Because P. falci-
Atovaquone and Proguanil parum malaria can cause maternal death and fetal loss,
(a TOE va kwone & pro GWA nil)
pregnant women traveling to malaria-endemic areas
Related Information must use personal protection against mosquito bites.
Atovaquone on page 174 Atovaquone/proguanil may be used as an alternative
Brand Names: US Malarone treatment of malaria in pregnant women; consult cur-
rent CDC guidelines (CDC 2013).
Brand Names: Canada Malarone; Malarone Pediatric
Pharmacologic Category Antimalarial Agent
Use Avanafil (a VAN a fil)
Malaria due to Plasmodium falciparum, prevention:
Brand Names: US Stendra
Prophylaxis of P. falciparum malaria, including areas
where chloroquine resistance has been reported Pharmacologic Category Phosphodiesterase-5
Malaria (uncomplicated) due to P. falciparum, treat- Enzyme Inhibitor
ment: Treatment of acute, uncomplicated P. falcipa- Use Erectile dysfunction: Treatment of erectile dys-
rum malaria function
Local Anesthetic/Vasoconstrictor Precautions Local Anesthetic/Vasoconstrictor Precautions
No information available to require special precautions No information available to require special precautions
Effects on Dental Treatment No significant effects or Effects on Dental Treatment No significant effects or
complications reported complications reported
Adverse Reactions The following adverse reactions Adverse Reactions
>10%: Central nervous system: Headache (1% to 12%)
were reported in patients being treated for malaria.
2% to 10%:
When used for prophylaxis, reactions are similar to
Cardiovascular: Flushing (3% to 10%), ECG abnor-
those seen with placebo.
mality (1% to 3%)
>10%: Central nervous system: Dizziness (1% to 2%)
Gastrointestinal: Abdominal pain (17%), nausea Gastrointestinal: Viral gastroenteritis (≤2%)
(12%), vomiting (children: 10% to 13%; adults: 12%) Neuromuscular & skeletal: Back pain (1% to 3%)
175
AVANAFIL
Respiratory: Nasopharyngitis (1% to 5%), nasal con- (thrombocytopenia 27%; grades 3/4: 1%) and altered
gestion (1% to 3%), upper respiratory tract infection hemostasis. In patients who are under active treat-
(1% to 3%) ment with these agents, medical consult is sug-
<2%, postmarketing, and/or case reports: Abdominal gested.
distress, angina pectoris, anterior ischemic optic neu- Adverse Reactions
ropathy (nonarteritic), arthralgia, balanitis, bronchitis, >10%:
constipation, cough, deep vein thrombosis, depres- Cardiovascular: Peripheral edema (17% to 20%),
sion, diarrhea, drowsiness, dyspepsia, dyspnea on hypertension (10% to 13%)
exertion, epistaxis, fatigue, gastritis, gastroesopha- Central nervous system: Fatigue (41% to 50%), dizzi-
geal reflux disease, hearing loss, hematuria, hyper- ness (14%)
glycemia, hypertension, hypoglycemia, hypotension, Dermatologic: Skin rash (15% to 22%)
increased serum ALT, influenza, insomnia, limb pain, Endocrine & metabolic: Weight loss (15% to 19%),
muscle spasm, musculoskeletal pain, myalgia, nau- hyponatremia (grades 3/4: 16%), increased gamma-
sea, nephrolithiasis, oropharyngeal pain, palpitations, glutamyl transferase (grades 3/4: 12%)
peripheral edema, pollakiuria, priapism, pruritus, sinus Gastrointestinal: Nausea (22% to 24%), diarrhea (18%
congestion, sinusitis, skin rash, tinnitus, urinary tract to 23%), decreased appetite (20% to 21%), abdomi-
infection, vertigo, vision color changes, vision loss nal pain (16% to 19%), constipation (17% to 18%),
(temporary or permanent), vomiting, wheezing increased serum lipase (14%), vomiting (13%
Mechanism of Action Does not directly cause penile to 14%)
erections, but affects the response to sexual stimula- Genitourinary: Urinary tract infection (21%)
tion. The physiologic mechanism of erection of the Hematologic & oncologic: Lymphocytopenia (49%;
penis involves release of nitric oxide (NO) in the corpus grades 3/4: 11% to 19%), anemia (35%; grades
cavernosum during sexual stimulation. NO then acti- 3/4: 6% to 9%), thrombocytopenia (27%; grades
vates the enzyme guanylate cyclase, which results in 3/4: 1%)
increased levels of cyclic guanosine monophosphate Hepatic: Increased serum AST (34%), increased
(cGMP), producing smooth muscle relaxation and serum ALT (20%)
inflow of blood to the corpus cavernosum. Avanafil Neuromuscular & skeletal: Musculoskeletal pain (25%
enhances the effect of NO by inhibiting phosphodiester- to 32%), arthralgia (16%)
ase type 5 (PDE-5), which is responsible for degrada- Renal: Increased serum creatinine (≤16%), renal fail-
tion of cGMP in the corpus cavernosum; when sexual ure (≤16%)
stimulation causes local release of NO, inhibition of Respiratory: Cough (14% to 18%), dyspnea (11%
PDE-5 by avanafil causes increased levels of cGMP to 17%)
in the corpus cavernosum, resulting in smooth muscle Miscellaneous: Infusion-related reaction (14% to
relaxation and inflow of blood to the corpus caverno- 30%), fever (16%)
sum; at recommended doses, it has no effect in the 1% to 10%:
absence of sexual stimulation. Central nervous system: Headache (10%)
Pharmacodynamics/Kinetics Dermatologic: Pruritus (10%), cellulitis (>1%)
Half-life Elimination Terminal: ~5 hours Endocrine & metabolic: Hyperglycemia (grades 3/4:
Time to Peak Plasma: 30 to 45 minutes (fasting); 1.12 3% to 9%), increased amylase (8%), hypothyroidism
to 1.25 hours (high-fat meal) (immune-mediated: 5%)
Pregnancy Considerations Adverse events were not Gastrointestinal: Colitis (immune-mediated: 2%),
observed in animal reproduction studies. This product is intestinal obstruction (≥2%)
not indicated for use in females. Hematologic & oncologic: Neutropenia (6%; grades
3/4: 1%)
Hepatic: Increased serum alkaline phosphatase
Avelumab (a VEL ue mab) (grades 3/4: 7%), increased serum bilirubin (6%),
increased serum bilirubin (grades 3/4: 1%)
Brand Names: US Bavencio Immunologic: Antibody development (4%)
Brand Names: Canada Bavencio Neuromuscular & skeletal: Weakness (>1%)
Pharmacologic Category Antineoplastic Agent, Anti- Renal: Acute renal failure (>1%)
PD-L1 Monoclonal Antibody; Antineoplastic Agent, Respiratory: Pneumonitis (immune-mediated: 1%)
Monoclonal Antibody Frequency not defined: Cardiovascular: Pericardial
Use effusion
Merkel cell carcinoma, metastatic: Treatment of <1%, postmarketing, and/or case reports: Adrenocort-
metastatic Merkel cell carcinoma (MCC) in adults ical insufficiency (immune-mediated), arthritis
and children ≥12 years of age. (immune-mediated), erythema multiforme (immune-
Urothelial carcinoma, locally advanced or meta- mediated), exfoliative dermatitis (immune-mediated),
static: Treatment of locally advanced or metastatic Guillain-Barré syndrome (immune-mediated), hepati-
urothelial carcinoma in patients who have disease tis (immune-mediated), hyperthyroidism (immune-
progression during or following platinum-containing mediated), myocarditis (immune-mediated), myositis
chemotherapy or have disease progression within 12 (immune-mediated), nephritis (immune-mediated),
months of neoadjuvant or adjuvant treatment with pemphigoid (immune-mediated), pituitary insufficiency
platinum-containing chemotherapy (immune-mediated), psoriasis (immune-mediated),
Local Anesthetic/Vasoconstrictor Precautions sepsis (systemic inflammatory response; immune-
No information available to require special precautions mediated), thyroiditis (immune-mediated), type 1 dia-
Effects on Dental Treatment No significant effects or betes mellitus (immune-mediated), uveitis (immune-
complications reported mediated)
Effects on Bleeding Chemotherapy may result in Mechanism of Action Avelumab is a fully human
significant myelosuppression, potentially including monoclonal antibody that binds to programmed death
significant reduction in platelet counts ligand 1 (PD-L1) to selectively prevent the interaction
176
AXICABTAGENE CILOLEUCEL
between the programmed cell death-1 (PD-1) and B7.1 Infection: Infection (26%), viral infection (16%), bacte-
receptors, while still allowing interaction between PD-L2 rial infection (13%)
and PD-1 (Kaufman 2016). PD-L1 is an immune check Neuromuscular & skeletal: Tremor (31%), limb pain
point protein expressed on tumor cells and tumor infil- (17%), back pain (15%), myalgia (14%)
trating cells and down regulates anti-tumor t-cell func- Renal: Renal insufficiency (12%)
tion by binding to PD-1 and B7.1; blocking PD-1 and Respiratory: Hypoxia (32%), cough (30%), dyspnea
B7.1 interactions restores antitumor t-cell function (Feh- (19%), pleural effusion (13%)
renbacher 2016, Rosenberg 2016). Miscellaneous: Fever (86%)
Half-life Elimination 6.1 days Central nervous system: Anxiety (9%), insomnia (9%),
Pregnancy Considerations Immunoglobulins are ataxia (6%), seizure (4%), cognitive dysfunction
known to cross the placenta and fetal exposure to (comprehending mathematics: 2%), myoclonus (2%)
avelumab is expected. Based on the mechanism of Dermatologic: Skin rash (9%)
action, avelumab may cause fetal harm. Immune-medi- Endocrine & metabolic: Hypokalemia (grade 3 or
ated fetal rejection causing increased abortion or still- 4: 10%)
birth was observed in animal reproduction studies. Genitourinary: Urinary tract infection (>2%)
Females of reproductive potential should use effective Hematologic & oncologic: Blood coagulation disorder
contraception during therapy and for at least 1 month (2%), natural killer cell count increased (hemopha-
after treatment is complete. gocytic lymphohistiocytosis/macrophage activation
syndrome: 1%)
Axicabtagene Ciloleucel Hepatic: Increased serum ALT (grade 3 or 4: 10%)
(ax i CAB tay jeen sye LO loo sel) Hypersensitivity: Hypersensitivity reaction (1%)
Infection: Fungal infection (5%), clostridium infec-
Brand Names: US Yescarta tion (>2%)
Pharmacologic Category Antineoplastic Agent, Anti- Neuromuscular & skeletal: Arthralgia (10%)
CD19; Antineoplastic Agent, CAR-T Immunotherapy; Respiratory: Pulmonary edema (9%), pulmonary
CAR-T Cell Immunotherapy; Cellular Immunotherapy, infection (>2%)
Autologous; Chimeric Antigen Receptor T-Cell Immu- Frequency not defined: Central nervous system: Cere-
notherapy bral edema, leukoencephalopathy, seizure
Use Mechanism of Action Axicabtagene ciloleucel is a
Large B-cell lymphoma, relapsed or refractory: CD19-directed genetically modified autologous T cell
Treatment of relapsed or refractory large B-cell lym- immunotherapy in which a patient's T cells are reprog-
phoma after 2 or more lines of systemic therapy, rammed with a transgene encoding a chimeric antigen
including diffuse large B-cell lymphoma (DLBCL) not receptor (CAR) to identify and eliminate CD19-express-
otherwise specified, primary mediastinal large B-cell ing malignant and normal cells. The CAR is comprised
lymphoma, high grade B-cell lymphoma, and DLBCL
of a murine single-chain antibody fragment which rec-
arising from follicular lymphoma
ognizes CD19 and is fused to CD28 and CD3 zeta. CD3
Limitations of use: Not indicated for the treatment of
zeta is a critical component for initiating T-cell activation
patients with primary CNS lymphoma
and antitumor activity. After binding to CD19-expressing
Local Anesthetic/Vasoconstrictor Precautions cells, the CD28 and CD3-zeta co-stimulatory domains
activate downstream signaling cascades, which results
Effects on Dental Treatment Xerostomia, normal in T cell activation, proliferation, acquisition of effector
salivary flow with discontinuation
functions, and secretion of inflammatory cytokines and
Effects on Bleeding No information available to chemokines, leading to destruction of CD19-expressing
cells. Axicabtagene ciloleucel is prepared from the
Adverse Reactions patient's peripheral blood cells obtained via leukaphe-
>10%: resis.
Cardiovascular: Hypotension (57%), tachycardia Pharmacodynamics/Kinetics
(57%), cardiac arrhythmia (23%), edema (19%),
Onset of Action Median time to response: 1 month
hypertension (15%), thrombosis (10%), cardiac fail-
(range: 0.8 to 6 months) (Neelapu 2017)
ure (6%), capillary leak syndrome (3%)
Central nervous system: Brain disease (57%; lasted
Duration of Action Anti-CD19 CAR T cells displayed
an initial rapid expansion followed by a decline to near
up to 173 days), fatigue (46%), headache (44% to
45%), chills (40%), dizziness (21%), motor dysfunc- baseline levels by 3 months post axicabtagene cilo-
tion (19%), aphasia (18%), delirium (17%) leucel infusion
Endocrine & metabolic: Hypophosphatemia (grade 3 Time to Peak Peak levels of anti-CD19 CAR T cells
or 4: 50%), hyponatremia (grade 3 or 4: 19%), weight occurred within the first 7 to 14 days after infusion
loss (16%), increased uric acid (grade 3 or 4: 13%), Pregnancy Considerations
dehydration (11%) Animal reproduction studies have not been conducted.
Gastrointestinal: Decreased appetite (44%), diarrhea Treatment with axicabtagene ciloleucel is not recom-
(38%), nausea (34%), vomiting (26%), constipation mended during pregnancy. If placental transfer were to
(23%), abdominal pain (14%), xerostomia (11%) occur, fetal toxicity, including B-cell lymphocytopenia,
Hematologic & oncologic: Lymphocytopenia (grade 3 may occur.
or 4: 100%), leukopenia (grade 3 or 4: 96%), neu- Pregnancy testing is recommended prior to therapy in
tropenia (grade 3 or 4: 93%), anemia (grade 3 or 4: sexually active women of reproductive potential. Refer
66%), thrombocytopenia (grade 3 or 4: 58%), febrile to the cyclophosphamide and fludarabine monographs
neutropenia (36%), hypogammaglobulinemia (15%) for information related to use of effective contraception
Hepatic: Increased direct serum bilirubin (grade 3 or in patients using these medications for lymphodeplet-
4: 13%) ing chemotherapy. The duration of contraception
Hypersensitivity: Cytokine release syndrome (94%) needed following axicabtagene ciloleucel
177
AXICABTAGENE CILOLEUCEL
administration is not known. Potential pregnancies Dermatologic: Xeroderma (10%), pruritus (7%), alope-
(following treatment) should be discussed with the cia (4%), erythema (2%)
prescriber. Endocrine & metabolic: Dehydration (6%), hyperthyr-
oidism (1%)
Axitinib (ax I ti nib) Gastrointestinal: Dyspepsia (10%), hemorrhoids (4%),
gastrointestinal fistula (1%), gastrointestinal perfora-
Brand Names: US Inlyta tion (≤1%)
Brand Names: Canada Inlyta Genitourinary: Hematuria (3%)
Pharmacologic Category Antineoplastic Agent, Tyro- Hematologic and Oncologic: Increased hemoglobin
sine Kinase Inhibitor; Antineoplastic Agent, Vascular (9%), rectal hemorrhage (2%), polycythemia (1%)
Endothelial Growth Factor (VEGF) Inhibitor Neuromuscular & skeletal: Myalgia (7%)
Use Renal cell carcinoma, advanced: Treatment of Otic: Tinnitus (3%)
advanced renal cell carcinoma after failure of one prior Respiratory: Epistaxis (6%), hemoptysis (2%)
systemic therapy. <1%, postmarketing, and/or case reports: Cardiac fail-
Local Anesthetic/Vasoconstrictor Precautions ure, cerebral hemorrhage, cerebrovascular accident,
Significant hypertension can occur with the use of this fever, hypertensive crisis, neutropenia, reversible pos-
drug; monitor for hypertension prior to using local terior leukoencephalopathy syndrome
anesthetic with vasoconstrictor; medical consult if nec- Mechanism of Action Axitinib is a selective second-
essary generation tyrosine kinase inhibitor which blocks angio-
Effects on Dental Treatment Key adverse event(s) genesis and tumor growth by inhibiting vascular endo-
related to dental treatment: Oral mucosal inflammation, thelial growth factor receptors (VEGFR-1, VEGFR-2,
stomatitis, and taste alteration have been reported and VEGFR-3).
Effects on Bleeding Chemotherapy may result in Pharmacodynamics/Kinetics
significant myelosuppression, potentially including sig- Half-life Elimination 2.5 to 6.1 hours
nificant reduction in platelet counts and altered hemo- Time to Peak 2.5 to 4 hours
stasis. Hemorrhagic events have been reported. In
patients who are under active treatment with axitinib,
Based on its mechanism of action and findings from
medical consult is suggested.
animal reproduction studies, adverse effects on preg-
Adverse Reactions
nancy would be expected.
>10%:
Cardiovascular: Hypertension (40%; grades 3/4: 16%) Females of childbearing potential should have a preg-
Central nervous system: Fatigue (39%), voice disorder nancy test prior to therapy; effective contraception
(31%), headache (14%) should be used during axitinib therapy and for 1 week
Dermatologic: Palmar-plantar erythrodysesthesia after the final axitinib dose. Males with female partners
(27%; grades 3/4: 5%), skin rash (13%; grades of reproductive potential should also use effective con-
3/4: <1%) traception during axitinib therapy and for 1 week after
Endocrine & metabolic: Decreased serum bicarbonate the final axitinib dose.
(44%), hypocalcemia (39%), hyperglycemia (28%), Prescribing and Access Restrictions Available
weight loss (25%), hypothyroidism (19%; grades 3/4:
from select specialty pharmacies. Further information
<1%), hypernatremia (17%), hyperkalemia (15%),
may be obtained at 877-744-5675 or www.inlytahcp.
hypoalbuminemia (15%), hyponatremia (13%), hypo-
com.
phosphatemia (13%), hypoglycemia (11%)
Gastrointestinal: Diarrhea (55%; grades 3/4: 11%),
decreased appetite (34%), nausea (32%; grades AzaCITIDine (ay za SYE ti deen)
3/4: 3%), increased serum lipase (3% to 27%),
increased serum amylase (25%), vomiting (24%; Brand Names: US Vidaza
grades 3/4: 3%), constipation (20%), mucosal inflam- Brand Names: Canada Vidaza
mation (15%), stomatitis (15%), abdominal pain (8% Pharmacologic Category Antineoplastic Agent, Anti-
to 14%), dysgeusia (11%) metabolite; Antineoplastic Agent, DNA Methylation
Genitourinary: Proteinuria (11%; grade 3: 3%) Inhibitor
Hematologic and oncologic: Anemia (4% to 35%; Use Myelodysplastic syndromes: Treatment of mye-
grades 3/4: <1%), lymphocytopenia (33%; grades lodysplastic syndromes (MDS) in patients with the
3/4: 3%), hemorrhage (16%; grades 3/4 1%), throm- following French-American-British (FAB) classification
bocytopenia (15%; grades 3/4: <1%), leukope- subtypes: Refractory anemia or refractory anemia with
nia (11%) ringed sideroblasts (if accompanied by neutropenia or
Hepatic: Increased serum alkaline phosphatase thrombocytopenia or requiring transfusions), refractory
(30%), increased serum ALT (22%; grades 3/4: anemia with excess blasts, refractory anemia with
<1%), increased serum AST (20%; grades 3/4: <1%)
excess blasts in transformation, and chronic myelomo-
Neuromuscular & skeletal: Weakness (21%), arthral-
nocytic leukemia.
gia (15%), limb pain (13%)
Renal: Increased serum creatinine (55%) Local Anesthetic/Vasoconstrictor Precautions
Respiratory: Cough (15%), dyspnea (15%) No information available to require special precautions
1% to 10%: Effects on Dental Treatment Key adverse event(s)
Cardiovascular: Venous thrombosis (grades 3/4: 3%), related to dental treatment: Mucositis, gingival bleeding,
arterial thrombosis (2%; grade 3/4: 1%), pulmonary oral mucosal petechiae, stomatitis, oral hemorrhage,
embolism (2%) deep vein thrombosis (1%), transient and tongue ulceration.
ischemic attack (1%), retinal vein occlusion (≤1%), Effects on Bleeding Gingival bleeding is reported in
retinal thrombosis (≤1%) 10% of patients. Thrombocytopenia is reported in 66%
Central nervous system: Dizziness (9%) to 70% of patients receiving azacitidine subcutaneously.
178
AZATHIOPRINE
Adverse Reactions <5%, postmarketing, and/or case reports: Abscess

>10%: (limb, perirectal), aggravated bone pain, agranulocy-
Cardiovascular: Peripheral edema (7% to 19%), chest tosis, anaphylactic shock, atrial fibrillation, azotemia,
pain (16%) bacterial infection, blastomycosis, bone marrow fail-
Central nervous system: Fatigue (13% to 36%), rigors ure, cardiac failure, catheter site hemorrhage, celluli-
(26%), headache (22%), dizziness (19%), anxiety t i s , c e r e b r a l h e m o r r h a g e , c h o l e c y s t e c t o m y,
(5% to 13%), depression (12%), malaise (11%), pain cholecystitis, congestive cardiomyopathy, decreased
(11%), insomnia (9% to 11%) serum bicarbonate, dehydration, diverticulitis, fibrosis
Dermatologic: Erythema (7% to 17%), pallor (16%), (interstitial and alveolar), gastrointestinal hemorrhage,
skin lesion (15%), skin rash (10% to 14%), pruritus glycosuria, hemophthalmos, hemoptysis, hepatic
(12%), diaphoresis (11%) coma, hypersensitivity reaction, hypophosphatemia,
Endocrine & metabolic: Weight loss (≤16%), pitting increased serum creatinine, injection site infection,
edema (15%), hypokalemia (6% to 13%) interstitial pulmonary disease, intracranial hemor-
Gastrointestinal: Nausea (48% to 71%), vomiting rhage, leukemia cutis, melena, necrotizing fasciitis,
(27% to 54%), constipation (34% to 50%), diarrhea neutropenic sepsis, orthostatic hypotension, pancyto-
(36%), anorexia (13% to 21%), abdominal pain (11% penia, pneumonitis, polyuria, pulmonary infiltrates,
to 16%), abdominal tenderness (12%) pyoderma gangrenosum, renal failure, renal tubular
Hematologic & oncologic: Thrombocytopenia (66% to acidosis, respiratory distress, seizure, sepsis, sepsis
70%; grades 3/4: 58%), anemia (51% to 70%; syndrome, septic shock, splenomegaly, Sweet's syn-
grades 3/4: 14%), neutropenia (32% to 66%; grades drome, tissue necrosis at injection site, toxoplasmosis,
3/4: 61%), leukopenia (18% to 48%; grades 3/4: tumor lysis syndrome
15%), bruise (19% to 31%), petechia (11% to Mechanism of Action Antineoplastic effects may be a
24%), febrile neutropenia (14% to 16%; grades 3/4: result of azacitidine's ability to promote hypomethylation
13%), bone marrow depression (nadir: days 10 to 17; of DNA, restoring normal gene differentiation and pro-
recovery: days 28 to 31) liferation. Azacitidine also exerts direct toxicity to abnor-
Local: Injection site reactions (14% to 29%): Erythema
mal hematopoietic cells in the bone marrow.
(35% to 43%; more common with IV administration), Pharmacodynamics/Kinetics
pain (19% to 23%; more common with IV adminis-
Half-life Elimination IV, SubQ: ~4 hours
tration), bruising (5% to 14%)
Neuromuscular & skeletal: Weakness (29%), arthral-
Time to Peak SubQ: 30 minutes
gia (22%), limb pain (20%), back pain (19%), myal- Pregnancy Considerations Adverse events were
gia (16%) observed in animal reproduction studies. Based on its
Respiratory: Cough (11% to 30%), dyspnea (5% to mechanism of action, azacitidine may cause fetal harm
29%), pharyngitis (20%), epistaxis (16%), nasophar- if administered during pregnancy. Women of childbear-
yngitis (15%), upper respiratory infection (9% to ing potential should be advised to avoid pregnancy
13%), pneumonia (11%), rales (9% to 11%) during treatment; verify pregnancy status prior to ther-
Miscellaneous: Fever (30% to 52%) apy initiation. In addition, males should be advised to
5% to 10%: avoid fathering a child while on azacitidine therapy and
Cardiovascular: Heart murmur (10%), tachycardia should use effective contraception during therapy.
(9%), hypertension (≤9%), hypotension (7%), syn-
cope (6%), chest wall pain (5%) AzaTHIOprine (ay za THYE oh preen)
Central nervous system: Lethargy (7% to 8%), hypo-
esthesia (5%), postoperative pain (5%) Brand Names: US Azasan; Imuran
Dermatologic: Night sweats (9%), cellulitis (8%), rash Brand Names: Canada Imuran
at injection site (6%), urticaria (6%), skin nodules Pharmacologic Category Immunosuppressant Agent
(5%), xeroderma (5%) Use
Gastrointestinal: Gingival hemorrhage (10%), stoma- Renal transplantation: Adjunctive therapy in preven-
titis (8%), hemorrhoids (7%), dyspepsia (6% to 7%), tion of rejection of kidney transplants
abdominal distention (6%), loose stools (6%), dys-
Guideline recommendations: While azathioprine is
phagia (5%), tongue ulcer (5%)
FDA approved for adjunctive therapy in prevention
Genitourinary: Urinary tract infection (8% to 9%),
of rejection after renal transplantation, it is no longer
dysuria (8%), hematuria (≤6%)
recommended as a first-line agent. The KDIGO
Hematologic & oncologic: Lymphadenopathy (10%),
clinical practice guidelines for care of kidney trans-
hematoma (9%), oral mucosal petechiae (8%), post-
plant recipients recommend a combination of main-
procedural hemorrhage (6%), oral hemorrhage (5%)
tenance immunosuppressive medications as
Hypersensitivity: Transfusion reaction (7%)
Infection: Herpes simplex infection (9%) maintenance therapy, including a calcineurin inhibitor
Local: Itching at injection site (7%), hematoma at and an antiproliferative agent (mycophenolate pre-
injection site (6%), induration at injection site (5%), ferred) with or without corticosteroids. Azathioprine is
injection site granuloma (5%), skin discoloration at recommended as a second-line antiproliferative
injection site (5%), swelling at injection site (5%) agent for prevention of acute rejection (KDIGO
Neuromuscular & skeletal: Muscle cramps (6%) [Kasiske 2010]).
Respiratory: Rhinorrhea (10%), wheezing (9%), Rheumatoid arthritis: Treatment of active rheumatoid
abnormal breath sounds (8%), nasal congestion arthritis (RA), to reduce signs and symptoms
(6%), pharyngolaryngeal pain (6%), pleural effusion Local Anesthetic/Vasoconstrictor Precautions
(6%), post nasal drip (6%), rhinitis (6%), rhonchi No information available to require special precautions
(6%), atelectasis (5%), sinusitis (5%) Effects on Dental Treatment No significant effects or
Miscellaneous: Lymphadenopathy (10%), herpes sim- complications reported
plex (9%), night sweats (9%), transfusion reaction Effects on Bleeding Thrombocytopenia and bleeding
(7%), mouth hemorrhage (5%) may occur.
179
AZATHIOPRINE
Adverse Reactions Frequency not always defined; Available guidelines suggest that use of azathioprine is
dependent upon dose, duration, indication, and con- acceptable for the treatment of rheumatoid arthritis in
comitant therapy. pregnant females (Flint 2016), although use for this
Central nervous system: Malaise indication is contraindicated by the manufacturer. Aza-
Gastrointestinal: Nausea and vomiting (rheumatoid thioprine may also be used for the adjunctive treatment
arthritis: 12%), diarrhea of lupus nephritis in pregnant females (Hahn 2012).
Hematologic & oncologic: Leukopenia (renal transplant: Females with Crohn disease or ulcerative colitis who
>50%; rheumatoid arthritis: 28%), neoplasia (renal are on maintenance therapy with azathioprine may
transplant 3% [other than lymphoma], 0.5% [lym- continue treatment during pregnancy (Nguyen 2016).
phoma]), thrombocytopenia Agents other than azathioprine are recommended for
Hepatic: Hepatotoxicity, increased serum alkaline phos- the treatment of immune thrombocytopenia in pregnant
phatase, increased serum bilirubin, increased serum females (Neunert 2011).
transaminases The manufacturer recommends that females of repro-
Infection: Increased susceptibility to infection (renal ductive potential should avoid becoming pregnant dur-
transplant 20%; rheumatoid arthritis <1%; includes ing treatment. Azathioprine is compatible for use in
bacterial, fungal, protozoal, viral, opportunistic, and males with female partners of reproductive potential
reactivation of latent infections) (Flint 2016).
Neuromuscular & skeletal: Myalgia
Miscellaneous: Fever The Transplant Pregnancy Registry International (TPR)
<1%, postmarketing and/or case reports: Abdominal is a registry that follows pregnancies that occur in
pain, acute myelocytic leukemia, alopecia, anemia, maternal transplant recipients or those fathered by male
arthralgia, bone marrow depression, hemorrhage, transplant recipients. The TPR encourages reporting of
hepatic sinusoidal obstruction syndrome (formerly pregnancies following solid organ transplant by contact-
known as hepatic veno-occlusive disease), hepatos- ing them at 1-877-955-6877 or https://www.-
plenic T-cell lymphomas, hepatotoxicity (idiosyncratic) transplantpregnancyregistry.org.
(Chalasani, 2014), hypersensitivity, hypotension, inter-
stitial pneumonitis (reversible), JC virus infection, Azelastine (Nasal) (a ZEL as teen)
macrocytic anemia, malignant lymphoma, malignant
neoplasm of skin, negative nitrogen balance, pancrea- Brand Names: US Astepro
titis, pancytopenia, progressive multifocal leukoence- Brand Names: Canada Astelin
phalopathy, skin rash, steatorrhea, Sweet's syndrome Pharmacologic Category Histamine H1 Antagonist;
(acute febrile neutrophilic dermatosis) Histamine H1 Antagonist, Second Generation
Mechanism of Action Azathioprine is an imidazolyl Use
derivative of mercaptopurine; metabolites are incorpo- Perennial allergic rhinitis (Astepro 0.1% and 0.15%
rated into replicating DNA and halt replication; also solution only): Relief of symptoms of perennial aller-
block the pathway for purine synthesis (Taylor 2005). gic rhinitis in adults and pediatric patients ≥6 months.
The 6-thioguanine nucleotide metabolites appear to Seasonal allergic rhinitis: Relief of symptoms of sea-
mediate the majority of azathioprine’s immunosuppres- sonal allergic rhinitis in adults and pediatric patients ≥2
sive and toxic effects. years (Astepro 0.1% and 0.15% solution) and ≥5
Pharmacodynamics/Kinetics years (azelastine [generic] 0.1% solution).
Onset of Action Immune thrombocytopenia (oral): Vasomotor rhinitis (azelastine [generic] 0.1% solu-
Initial response: 30 to 90 days; Peak response: 30 to tion): Relief of symptoms of vasomotor rhinitis in
120 days (Neunert 2011) adults and adolescents ≥12 years.
Half-life Elimination Azathioprine and mercaptopur- Local Anesthetic/Vasoconstrictor Precautions
ine: Variable: ~2 hours (Taylor 2005) No information available to require special precautions
Time to Peak Oral: 1 to 2 hours (including metabo- Effects on Dental Treatment Key adverse event(s)
lites) related to dental treatment: Bitter taste, xerostomia
Pregnancy Risk Factor D (normal salivary flow resumes upon discontinuation),
Pregnancy Considerations aphthous stomatitis, glossitis, and burning sensation
Azathioprine crosses the placenta. in throat. Chronic use of antihistamines will inhibit
salivary flow, particularly in elderly patients. May con-
Product labeling notes congenital anomalies, immuno- tribute to periodontal disease and oral discomfort.
suppression, hematologic toxicities (lymphopenia, pan- Effects on Bleeding No information available to
cytopenia), and intrauterine growth retardation from require special precautions
case reports following use in maternal renal allograft Adverse Reactions Adverse reactions may be dose-,
recipients (based on additional data, this may, in part, indication-, or product-dependent:
be dose related [Colla 2018]). Intrauterine growth retar- >10%:
dation and preterm delivery are also reported in preg- Central nervous system: Bitter taste (4% to 20%),
nancies following a kidney transplant. In addition, fetal headache (1% to 15%), drowsiness (≤12%)
immunosuppression and hematologic toxicities are Infection: Cold symptoms (children ≤17%)
decreased when maintaining appropriate maternal leu- Respiratory: Rhinitis (exacerbation; ≤17%), cough
kocyte counts. Stable immunosuppression is required in (children: 11%; infants and children: ≥2%)
pregnant females who have had a kidney transplant 2% to 10%:
and an increased risk of fetal malformations has not Central nervous system: Dysesthesia (8%), dizziness
been observed with azathioprine. Azathioprine therapy (2%), fatigue (2%)
is considered acceptable in pregnant patients with Dermatologic: Contact dermatitis
kidney transplants; lower doses (<2 mg/kg/day) are Endocrine & metabolic: Weight gain (2%)
recommended (Colla 2018; Durst 2015; Gonzalez Gastrointestinal: Dysgeusia (children: 2% to 4%),
Suarez 2018; Hou 2013; KDIGO 2009). nausea (3%), xerostomia (3%), vomiting
180
AZILSARTAN
Infection: Upper respiratory tract infection (children:

≥2% to 3%) Azilsartan (ay zil SAR tan)
Neuromuscular & skeletal: Myalgia (≤2%)
Ophthalmic: Conjunctivitis (<2% to 5%)
Related Information
Otic: Otitis media (infants & children: ≥2%) Cardiovascular Diseases on page 1442
Respiratory: Epistaxis (2% to 7%), asthma (5%), Brand Names: US Edarbi
sinusitis (3% to >5%), burning sensation of the nose Brand Names: Canada Edarbi
(4%), pharyngitis (4%), nasal discomfort (≤4%), Pharmacologic Category Angiotensin II Receptor
sneezing (1% to 3%), sore nose (infants and chil- Blocker; Antihypertensive
dren: ≥2%), nasal mucosa ulcer (≤2%), pharyngolar- Use
yngeal pain Hypertension: Management of hypertension
Guideline recommendations:
The 2017 Guideline for the Prevention, Detection,
<2%:
Evaluation, and Management of High Blood Pres-
Cardiovascular: Flushing, hypertension, tachycardia
sure in Adults recommends if monotherapy is war-
Central nervous system: Abnormality in thinking, anxi- ranted, in the absence of comorbidities (eg,
ety, depersonalization, depression, hypoesthesia, cerebrovascular disease, chronic kidney disease,
malaise, nervousness, sleep disorder, vertigo diabetes, heart failure, ischemic heart disease,
Dermatologic: Eczema, folliculitis, furunculosis etc.), that thiazide-like diuretics or dihydropyridine
Endocrine & metabolic: Albuminuria, amenorrhea calcium channel blockers may be preferred options
Gastrointestinal: Abdominal pain, ageusia, aphthous due to improved cardiovascular endpoints (eg, pre-
stomatitis, constipation, diarrhea, gastroenteritis, vention of heart failure and stroke). ACE inhibitors
glossitis, increased appetite, toothache and ARBs are also acceptable for monotherapy.
Genitourinary: Hematuria, mastalgia Combination therapy may be required to achieve
Hepatic: Increased serum ALT blood pressure goals and is initially preferred in
Hypersensitivity: Hypersensitivity reaction patients at high risk (stage 2 hypertension or athero-
Infection: Herpes simplex infection, viral infection sclerotic cardiovascular disease [ASCVD] risk ≥10%)
Neuromuscular & skeletal: Back pain, dislocation of (ACC/AHA [Whelton 2017]).
temporomandibular joint, hyperkinesia, limb pain, Local Anesthetic/Vasoconstrictor Precautions
rheumatoid arthritis No information available to require special precautions
Ophthalmic: Eye pain, watery eyes Effects on Dental Treatment Key adverse event(s)
Renal: Polyuria related to dental treatment: Patients may experience
Respiratory: Bronchitis, bronchospasm, laryngitis, orthostatic hypotension as they stand up after treat-
nasal congestion, paranasal sinus hypersecretion, ment; especially if lying in dental chair for extended
paroxysmal nocturnal dyspnea, postnasal drip, sore periods of time. Use caution with sudden changes in
throat
Miscellaneous: Laceration
<1%, postmarketing, and/or case reports: Altered sense
Adverse Reactions
of smell, anaphylactoid reaction, anosmia, application
1% to 10%: Gastrointestinal: Diarrhea (≤2%)
site irritation, atrial fibrillation, blurred vision, chest
pain, confusion, drug tolerance, dyspnea, facial
Cardiovascular: Hypotension, orthostatic hypotension
edema, increased serum transaminases, insomnia, Central nervous system: Dizziness, fatigue, orthostatic
muscle spasm, nasal sores, palpitations, paresthesia, dizziness
pruritus, skin rash, urinary retention, visual disturb- Gastrointestinal: Nausea
ance, xerophthalmia Neuromuscular & skeletal: Asthenia, muscle spasm
Mechanism of Action Competes with histamine for Renal: Increased serum creatinine
H1-receptor sites on effector cells and inhibits the Respiratory: Cough
release of histamine and other mediators involved in <1%, postmarketing, and/or case reports: Angioedema,
the allergic response; when used intranasally, reduces decreased hematocrit, decreased hemoglobin,
hyper-reactivity of the airways; increases the motility of decreased red blood cells, leukocytosis, pruritus, skin
bronchial epithelial cilia, improving mucociliary transport rash, thrombocytopenia
Pharmacodynamics/Kinetics Mechanism of Action Angiotensin II (which is formed
Onset of Action 30 minutes (Wallace 2008); max- by enzymatic conversion from angiotensin I) is the
imum effect: 3 hours primary pressor agent of the renin-angiotensin system.
Duration of Action 12 hours Effects of angiotensin II include vasoconstriction, stim-
Half-life Elimination Azelastine: 22 hours (0.1% sol- ulation of aldosterone synthesis/release, cardiac stim-
ution), 25 hours (0.15% solution); Desmethylazelas- ulation, and renal sodium reabsorption. Azilsartan
inhibits angiotensin II’s vasoconstrictor and aldoster-
tine: 52 hours (0.1% solution), 57 hours (0.15%
one-secreting effects by selectively blocking the binding
solution)
of angiotensin II to the AT1 receptor in vascular smooth
Time to Peak 2 to 3 hours (Azelastine [generic] 0.1% muscle and adrenal gland tissues (azilsartan has a
solution); 3 to 4 hours (Astepro) stronger affinity for the AT1 receptor than the AT2
Pregnancy Considerations Azelastine is systemi- receptor). The action is independent of the angiotensin
cally absorbed following nasal inhalation and may have II synthesis pathways. Azilsartan does not inhibit ACE
side effects similar to other antihistamines. However, (kininase II), therefore it does not affect the response to
data related to the use of azelastine in pregnancy is bradykinin (the clinical relevance of this is unknown)
limited; if treatment for rhinitis in a pregnant woman is and does not bind to or inhibit other receptors or ion
needed, other agents are preferred (Wallace 2008). channels of importance in cardiovascular regulation.
181
AZILSARTAN
Pharmacodynamics/Kinetics combination with rifabutin) in patients with advanced

Half-life Elimination ~11 hours HIV infection; treatment of disseminated MAC (in
Time to Peak Serum: 1.5-3 hours combination with ethambutol) in patients with
Pregnancy Risk Factor D advanced HIV infection
Pregnancy Considerations [US Boxed Warning]: Otitis media, acute: Treatment of acute otitis media
Drugs that act on the renin-angiotensin system due to H. influenzae, M. catarrhalis, or S. pneu-
can cause injury and death to the developing fetus. moniae
Discontinue as soon as possible once pregnancy is Pneumonia, community-acquired: Treatment of
detected. The use of drugs which act on the renin- community-acquired pneumonia (CAP) due to Chla-
angiotensin system are associated with oligohydram- mydophila pneumoniae, H. influenzae, Legionella
nios. Oligohydramnios, due to decreased fetal renal pneumophila, M. catarrhalis, Mycoplasma pneumo-
function, may lead to fetal lung hypoplasia and skeletal niae, or S. pneumoniae
malformations. Use is also associated with anuria, Skin and skin structure infection, uncomplicated:
hypotension, renal failure, skull hypoplasia, and death Treatment of uncomplicated skin and skin structure
in the fetus/neonate. The exposed fetus should be infections due to Staphylococcus aureus, Strepto-
monitored for fetal growth, amniotic fluid volume, and coccus pyogenes, or Streptococcus agalactiae
organ formation. Infants exposed in utero should be Streptococcal pharyngitis (group A): Treatment of
monitored for hyperkalemia, hypotension, and oliguria pharyngitis/tonsillitis due to S. pyogenes as an alter-
(exchange transfusions or dialysis may be needed). native to first-line therapy
These adverse events are generally associated with Urethritis/cervicitis: Treatment of urethritis and cer-
maternal use in the second and third trimesters. vicitis due to Chlamydia trachomatis or Neisseria
gonorrhoeae
Untreated chronic maternal hypertension is also asso- Local Anesthetic/Vasoconstrictor Precautions
ciated with adverse events in the fetus, infant, and Azithromycin is one of the drugs confirmed to prolong
mother. The use of angiotensin II receptor blockers is the QT interval and is accepted as having a risk of
not recommended to treat chronic uncomplicated causing torsade de pointes. The risk of drug-induced
hypertension in pregnant women and should generally torsade de pointes is extremely low when a single QT
be avoided in women of reproductive potential interval prolonging drug is prescribed. In terms of epi-
(ACOG 2013). nephrine, it is not known what effect vasoconstrictors in
Azithromycin (Systemic) (az ith roe MYE sin) known history of congenital prolonged QT interval or in
Related Information interval. Until more information is obtained, it is sug-
Antibiotic Prophylaxis on page 1502 gested that the clinician consult with the physician prior
Bacterial Infections on page 1525 to the use of a vasoconstrictor in suspected patients,
Clinical Risk Related to Drugs Prolonging QT Interval and that the vasoconstrictor (epinephrine, mepivacaine
on page 1462 and levonordefrin [Carbocaine® 2% with Neo-Cobe-
Periodontal Diseases on page 1534 frin®]) be used with caution. See Dental Health Pro-
Sexually-Transmitted Diseases on page 1494 fessional Considerations.
Related Sample Prescriptions Effects on Dental Treatment Key adverse event(s)
related to dental treatment: Rare occurrence of muco-
Bacterial Infections and Periodontal Diseases - Sample
sitis, oral candidiasis, tongue discoloration
Prescriptions on page 36
Prevention of Endocarditis and to Reduce the Risk of
Late Infections of Joint Prostheses - Sample Prescrip-
Adverse Reactions
tions on page 41
>10%: Gastrointestinal: Loose stools (≤14%; single-
Sinus Infection Treatment - Sample Prescriptions on
dose regimens tend to be associated with increased
page 42
incidence), vomiting (children, single-dose regimens
Brand Names: US Zithromax; Zithromax Tri-Pak; tend to be associated with increased incidence: 1% to
Zithromax Z-Pak; Zmax [DSC] 14%; adults: ≤2%; adults, single 2 g dose: 1% to 7%),
Brand Names: Canada Zithromax; Zmax SR diarrhea (2% to 9%; single-dose regimens 4% to
Generic Availability (US) Yes 14%), nausea (≤7%; high single-dose regimens 4%
Pharmacologic Category Antibiotic, Macrolide to 18%)
Dental Use Alternate oral antibiotic for prevention of 1% to 10%:
infective endocarditis in individuals allergic to penicillins Cardiovascular: Chest pain (≤1%), palpitations (≤1%)
or ampicillin, when amoxicillin cannot be used; alternate Central nervous system: Dizziness (≤1%), drowsiness
antibiotic in the treatment of common orofacial infec- (≤1%), fatigue (≤1%), headache (≤1%), ver-
tions caused by aerobic gram-positive cocci and sus- tigo (≤1%)
ceptible anaerobes Dermatologic: Skin rash (≤5%; single-dose regimens
Use tend to be associated with increased incidence),
Oral, IV: dermatitis (children: ≤2%), pruritus (≤2%), skin pho-
Chancroid: Treatment of genital ulcer disease (in tosensitivity (≤1%)
men) due to Haemophilus ducreyi (chancroid) Endocrine & metabolic: Increased lactate dehydrogen-
Chronic obstructive pulmonary disease, bacterial ase (1% to 3%), increased gamma-glutamyl trans-
exacerbations: Treatment of acute bacterial exac- ferase (1% to 2%), increased serum potassium (1%
erbations of chronic obstructive pulmonary disease to 2%), decreased serum bicarbonate (adults: ≥1%),
(COPD) due to Haemophilus influenzae, Moraxella decreased serum glucose (adults: >1%)
catarrhalis, or Streptococcus pneumoniae Gastrointestinal: Abdominal pain (1% to 7%; single-
Mycobacterium avium complex: Prevention of dose regimens tend to be associated with increased
Mycobacterium avium complex(MAC) (alone or in incidence), anorexia (≤2%), dysgeusia (≤1%),
182
AZITHROMYCIN (SYSTEMIC)
dyspepsia (≤1%), flatulence (≤1%), gastritis (≤1%), Adolescents ≥16 years and Adults: 500 mg 30-60
melena (adults, multiple-dose regimens: ≤1%), minutes prior to the procedure. Note: American
mucositis (≤1%), oral candidiasis (≤1%) Heart Association (AHA) guidelines now recommend
Genitourinary: Vaginitis (≤3%), genital candidiasis prophylaxis only in patients undergoing invasive
(adults, multiple-dose regimens: ≤1%) procedures and in whom underlying cardiac condi-
Hematologic & oncologic: Decrease in absolute neu- tions may predispose to a higher risk of adverse
trophil count (children: 15% to 16%; 500 to 1,500 outcomes should infection occur. As of April 2007,
cells/mm3), decreased hematocrit (adults: >1%), routine prophylaxis for GI/GU procedures is no lon-
decreased hemoglobin (adults: >1%), increased ger recommended by the AHA.
neutrophils (adults: >1%), thrombocythemia (adults: Bacterial sinusitis: Oral:
>1%), change in neutrophil count (children: ≥1%), Children ≥6 months: 10 mg/kg once daily for 3 days
eosinophilia (≥1%), lymphocytopenia (≥1%) (maximum: 500 mg/day)
Hepatic: Increased serum ALT (≤6%), increased Adolescents ≥16 years and Adults: 500 mg/day for a
serum AST (≤6%), increased serum bilirubin (≤3%), total of 3 days
cholestatic jaundice (≤1%) Extended release suspension (Zmax): 2 g as a sin-
Local (adults with IV administration): Pain at injection gle dose
site (7%), local inflammation (3%) Orofacial infections: Adolescents ≥16 years and Adults:
Neuromuscular & skeletal: Increased creatine phos- Oral: 500 mg/day, then 250 mg days 2-5
phokinase (1% to 2%) Treatment of periodontal disease: 500 mg once daily for
Renal: Increased serum creatinine (≤6%), increased 4-7 days
blood urea nitrogen (≤1%), nephritis (adults, multiple- Dosing
dose regimens: ≤1%) Adult & Geriatric Note: Zmax suspension has been
Respiratory: Bronchospasm (≤1%) discontinued in the US for more than 1 year.
Miscellaneous: Fever (children: (≤2%) Note: Extended-release suspension (Zmax) is not
<1%, postmarketing, and/or case reports: Abnormal interchangeable with immediate-release formula-
stools, acute generalized exanthematous pustulosis, tions. Use should be limited to approved indications.
acute renal failure, ageusia, aggressive behavior, agi- All doses are expressed as immediate-release azi-
tation, alteration in sodium, altered sense of smell, thromycin unless otherwise specified.
altered serum glucose, anaphylaxis, anemia, angioe- Acne vulgaris, inflammatory (moderate to severe)
dema, anosmia, anxiety, arthralgia, asthma, baso- (off-label use): Note: Use as an adjunct to topical
philia, bronchitis, cardiac arrhythmia, chills, acne therapy (AAD [Zaenglein 2016]). Oral: Dosing
Clostridioides (formerly Clostridium) difficile-associ- regimens used in clinical trials have varied greatly. All
ated diarrhea, conjunctivitis (children), constipation, trials used pulse-dosing regimens; regimens
convulsions, cough, deafness, decreased serum included: 500 mg once daily for 4 consecutive days
potassium (children), decreased serum sodium, diaper month for 3 consecutive months (Babaeinejad
phoresis, DRESS syndrome, dyspnea, dysuria, 2011; Parsad 2001) or 500 mg once daily for 3 days
eczema, edema, emotional lability, enteritis, erythema in the first week, followed by 500 mg once weekly
multiforme, exacerbation of myasthenia gravis, facial until week 10 (Maleszka 2011) or 500 mg once daily
edema, flu-like symptoms, fungal dermatitis, fungal for 3 consecutive days each week in month 1,
infection, gastrointestinal disease, hearing loss, hep- followed by 500 mg once daily for 2 consecutive
atic failure, hepatic insufficiency, hepatic necrosis, days each week in month 2, then 500 mg once daily
hepatitis, hepatotoxicity (idiosyncratic) (Chalasani for 1 day each week in month 3 (Kus 2005). The
2014), hostility, hyperactivity, hyperkinesia, hypersen- shortest possible duration should be used to mini-
sitivity reaction, hypotension, increased monocytes, mize development of bacterial resistance; reevaluate
increased serum alkaline phosphatase, increased at 3 to 4 months (AAD [Zaenglein 2016]).
serum bicarbonate, increased serum glucose, Babesiosis (off-label use):
increased serum phosphate, interstitial nephritis, Mild to moderate disease: Oral: 500 mg on day 1,
insomnia, irritability, jaundice, Lambert-Eaton syn- followed by 250 mg once daily in combination with
drome, leukopenia, maculopapular rash, malaise, atovaquone for 7 to 10 days in immunocompetent
nervousness, neutropenia, otitis media, pain, pancrea- patients (IDSA [Wormser 2006]; Krause 2000; Van-
titis, paresthesia, pharyngitis, pleural effusion, pro- nier 2012); higher doses of azithromycin may be
longed Q-T interval on ECG, pseudomembranous used in immunocompromised patients (600 to
colitis, pyloric stenosis, pyloric stenosis (infantile 1,000 mg daily) (IDSA [Wormser 2006]; Weiss
hypertrophic), rhinitis, seizure, Stevens-Johnson syn- 2001; Wormser 2010).
drome, syncope, thrombocytopenia, tinnitus, tongue Severe disease: IV: 500 mg daily in combination with
discoloration, torsades de pointes toxic epidermal atovaquone for 7 to 10 days (Kletsova 2017; San-
necrolysis, urticaria, ventricular tachycardia, vesiculo- chez 2016); a longer duration is needed for those at
bullous dermatitis, weakness high risk for relapse (Krause 2008; Sanchez 2016;
Dental Usual Dosage Vannier 2012). Note: May switch to oral azithromy-
Prophylaxis against infective endocarditis (off-label cin (at the same dose) following improvement on IV
use): Oral: therapy (Sanchez 2016); when switching to oral
Children: 15 mg/kg 30-60 minutes before procedure treatment in immunocompromised patients, a
(maximum: 500 mg). Note: American Heart Associ- higher dose (600 to 1,000 mg daily) has been used
ation (AHA) guidelines now recommend prophylaxis (IDSA [Wormser 2006]; Sanchez 2016;
only in patients undergoing invasive procedures and Weiss 2001).
in whom underlying cardiac conditions may predis- Bronchiectasis (non-cystic fibrosis), prevention of
pose to a higher risk of adverse outcomes should pulmonary exacerbations (off-label use): Oral:
infection occur. As of April 2007, routine prophylaxis 500 mg 3 times weekly (Wong 2012) or 250 mg once
for GI/GU procedures is no longer recommended by daily (Altenburg 2013). Note: Recommended for
the AHA. patients with ≥2 (Barker 2018) or ≥3 (ERS [Polverino
183
2017]) exacerbations per year; for those who do not may occur with the 1 g single-dose regimen (Trib-
have Pseudomonas aeruginosa infection, have P. ble 2007), which may be reduced by administering
aeruginosa but cannot take an inhaled antibiotic, or azithromycin as 2 divided doses on the same day
continue to have exacerbations despite an inhaled (CDC 2018; Riddle 2017).
antibiotic. Patients should be screened for nontuber- Endocarditis prophylaxis, dental or invasive res-
culous mycobacterial infection prior to treatment and piratory tract procedure (alternative agent for
azithromycin should not be given if present (ERS penicillin-allergic patients) (off-label use): Oral:
[Polverino 2017]). 500 mg 30 to 60 minutes prior to procedure. Note:
Bronchiolitis obliterans syndrome in lung trans- Only recommended for patients with cardiac condi-
plant recipients (off-label use): Oral: 250 mg daily tions associated with the highest risk of an adverse
for 5 days, followed by 250 mg 3 times weekly for at outcome from endocarditis and who are undergoing
least a 3-month trial (ISHLT/ATS/ERS [Meyer 2014]); a procedure likely to result in bacteremia with an
some experts continue indefinitely, regardless of organism that has the potential to cause endocardi-
response to therapy (Pilewski 2018). tis. (AHA [Wilson 2007]).
Cat scratch disease (lymphadenitis) (off-label
Lyme disease (erythema migrans or borrelial lym-
use): Oral: 500 mg as a single dose, then 250 mg
phocytoma) (alternative agent) (off-label use):
once daily for 4 additional days (Bass 1998; IDSA
Oral: 500 mg once daily for 7 to 10 days. Note:
[Stevens 2014]; Psarros 2012)
Use with caution and only when recommended
Cesarean delivery (intrapartum or after rupture of
agents cannot be used (due to decreased efficacy
membranes), preoperative prophylaxis (off-label
compared to other agents) (IDSA [Wormser 2006]).
use): IV: 500 mg as a single dose 1 hour prior to
surgical incision; use in combination with standard Mycobacterial (nontuberculous) infection:
preoperative antibiotics (Tita 2016) Mycobacterium avium complex (MAC) infection:
Chronic obstructive pulmonary disease (COPD): Disseminated disease in HIV-infected patients
Bacterial exacerbation, treatment: Oral: 500 mg in a (HHS [OI adult] 2018):
single loading dose on day 1, followed by 250 mg Treatment: Oral: 500 to 600 mg daily as part of a
once daily on days 2 to 5 (Castaldo 2003) or combination therapy regimen
500 mg once daily for 3 days (Swanson 2005). Primary prophylaxis (patients with CD4 count <50
Prevention of exacerbations (off-label use): Oral: cells/mm3): Oral: 1,200 mg once weekly (pre-
250 to 500 mg 3 times weekly (Berkhof 2013; Uzun ferred) or 600 mg twice weekly; may discontinue
2014) or 250 mg once daily (Albert 2011) prophylaxis when CD4 count >100 cells/mm3 for
Cystic fibrosis, anti-inflammatory (off-label use): ≥3 months in response to antiretroviral therapy
Oral: 250 mg (<40 kg) or 500 mg (≥40 kg) 3 times (ART). Note: If effective ART is initiated imme-
weekly (Saiman 2003) or 250 mg once daily (Wolter diately and viral suppression is achieved, some
2002). Note: Patients should be screened for non- experts do not recommend routine initiation of
tuberculous mycobacterial infection prior to treat- MAC primary prophylaxis, regardless of initial
ment and azithromycin should not be given if CD4 count (IAS-USA [Gunthard 2016]).
present (Mogayzel 2013; Saiman 2003). Secondary prophylaxis: Oral: 500 to 600 mg daily
Diarrhea, infectious (off-label use): as part of an appropriate combination regimen;
Campylobacter infection: Oral: 1 g as a single dose may discontinue when patient has completed
or 500 mg once daily for 3 days (ACG [Riddle ≥12 months of therapy, has no signs/symptoms
2016]; Tribble 2007). If symptoms have not of MAC disease, and has sustained (>6 months)
resolved after 24 hours following single-dose ther- CD4 count >100 cells/mm3 in response to ART
apy, continue with 500 mg once daily for 2 more Pulmonary disease (nodular/bronchiectatic dis-
days (ACG [Riddle 2016]). For HIV-infected ease) (off-label use): Oral: 500 to 600 mg 3 times
patients, 500 mg once daily for 5 days is recom- weekly as part of an appropriate combination
mended (HHS [OI adult] 2018). Note: Increased regimen; continue treatment until patient is culture
nausea may occur with the 1 g single-dose regimen negative on therapy for ≥1 year (ATS/IDSA [Grif-
(Tribble 2007), which may be reduced by adminis- fith 2007]); some experts prefer 500 mg 3 times
tering azithromycin as 2 divided doses on the same weekly due to improved tolerability (BTS
day (CDC 2018; Riddle 2017). [Haworth 2017])
Cholera (alternative agent): Oral: 1 g as a single
Pulmonary disease (severe nodular/bronchiectatic
dose (Saha 2006)
or cavitary disease) (off-label use): Oral: 250 to
Shigella infection: Note: Confirm susceptibility if
500 mg once daily as part of an appropriate
possible (Agha 2018; HHS [OI adult] 2018; WHO
combination regimen (ATS/IDSA [Griffith 2007];
2005). Oral: 500 mg once daily for 3 days (ACG
BTS [Haworth 2017]; Deshpande 2016; van Ingen
[Riddle 2016]); 5 days of therapy should be given
2012); continue treatment until patient is culture
for Shigella dysenteriae type 1 infection or for
negative on therapy for ≥1 year (ATS/IDSA [Grif-
patients with HIV coinfection (Agha 2018; HHS
fith 2007]; BTS [Haworth 2017]). Preliminary data
[OI adult] 2018).
suggest a relationship between peak concentra-
Travelers' diarrhea , empiric treatment: Oral: 1 g as a
tion and clinical outcome among patients receiv-
single dose or 500 mg once daily for 3 days (ACG
ing daily therapy for pulmonary MAC (Jeong
[Riddle 2016]; CDC 2018; Riddle 2017; Tribble
2016); as such, some experts recommend check-
2007). If symptoms have not resolved after 24
ing levels and/or using higher doses of azithromy-
hours following single-dose therapy, continue with
cin (Kasperbauer 2018).
500 mg once daily for 2 more days. A 3-day course
of 500 mg once daily is the preferred regimen for Pulmonary disease in patients with cystic fibrosis
dysentery or febrile diarrhea (ACG [Riddle 2016]). (off-label use): Oral: 250 to 500 mg once daily as
Note: Most cases are self-limited and may not part of an appropriate combination regimen; con-
warrant antimicrobial therapy. Increased nausea tinue treatment until patient is culture negative on
184
therapy for ≥1 year. Note: Intermittent dosing (3 Gonococcal infection, expedited partner therapy (off-
times weekly) is not recommended for patients label use): Oral: 1 g as a single dose in combination
with cystic fibrosis (CFF/ECFS [Floto 2016]). with cefixime. Note: Clinical evaluation and pre-
Mycobacterium abscessus infection (off-label use): sumptive treatment is preferred for sexual partners
Note: Presence of inducible erm gene can result in of patients with gonorrhea. Alternatively, expedited
decreased susceptibility even with a "susceptible" partner therapy for gonorrhea can be used for
MIC result; perform susceptibility testing before heterosexual partners if the provider is concerned
and after ≥14 days of clarithromycin incubation that the partner will otherwise not be promptly
to evaluate for the presence of an active erm evaluated and treated; state laws regarding expe-
gene, which may preclude use of azithromycin dited partner therapy vary (CDC [Workow-
(CFF/ECFS [Floto 2016]; Griffith 2018). ski 2015]).
Pulmonary, skin, soft tissue, or bone infection: Oral: Gonococcal infection, uncomplicated (infection of the
250 to 500 mg once daily as part of an appropriate cervix, urethra, rectum, or pharynx; conjunctivitis):
combination regimen and continued for ≥6 to 12 Oral:
months for pulmonary and bone infections, and ≥4 Dual-therapy regimen (off-label): 1 g as a single
months for skin/soft tissue infections (ATS/IDSA dose in combination with ceftriaxone (CDC [Work-
[Griffith 2007]; CFF/ECFS [Floto 2016]; Griffith owski 2015])
2018). Note: Patients should be under the care Patients with severe cephalosporin allergy (off-
of a clinician with expertise in managing myco- label): 2 g as a single dose in combination with
bacterial infection. gemifloxacin (not available in the US) or gentami-
Pertussis (off-label use): Oral: 500 mg on day 1, cin IM (CDC [Workowski 2015]). Note: Patients
followed by 250 mg once daily on days 2 to 5 with pharyngeal infection treated with an alterna-
(CDC [Tiwari 2005]) tive regimen should have a 14-day test-of-cure
Pneumonia, community-acquired: Note: For performed. Consult an infectious diseases spe-
empiric therapy, may need to use in combination with cialist when treatment failure is suspected and
other appropriate agents (depending on disease report failures to the CDC through state and local
severity and/or risk factors for drug-resistant patho- health departments within 24 hours of diagnosis
gens, particularly Streptococcus pneumoniae). Dura- (CDC [Workowski 2015]).
tion of therapy may vary based on disease severity Granuloma inguinale (donovanosis) (off-label use):
and response to therapy. Patients should be afebrile Oral: 1 g once weekly or 500 mg once daily for ≥3
for ≥48 hours and clinically stable prior to discontin- weeks and until lesions have healed. Note: If
uation (IDSA/ATS [Mandell 2007]). symptoms do not improve within the first few days
Outpatient: Oral: 500 mg on day 1, followed by of therapy, the addition of gentamicin may be con-
250 mg once daily for 4 days or 500 mg once daily sidered (CDC [Workowski 2015]).
for 3 days (Amsden 1999; IDSA/ATS [Mandell Mycoplasma genitalium (off-label use) (CDC [Work-
2007]; Schönwald 1991) owski 2015]; Falk 2015): Oral:
ER suspension (Zmax): 2 g as a single dose Note: Azithromycin resistance is rapidly emerging;
Inpatient: Oral, IV: 500 mg once daily for a minimum consider alternative therapy.
of 3 days (File 2018; IDSA/ATS [Mandell 2007]) Single-dose regimen: 1 g as a single dose
Sexually transmitted infections: Extended-dose regimen: 500 mg on day 1, followed
Cervicitis, empiric therapy: Oral: 1 g as a single by 250 mg once daily on days 2 through 5
dose, preferably under direct observation; give in Prophylaxis against sexually transmitted infections
combination with ceftriaxone if the patient is at high following sexual assault (off-label use): Oral: 1 g
risk for gonorrhea, if follow-up is a concern, or if the as a single dose in combination with ceftriaxone
local prevalence of gonorrhea is high (eg, >5%) (plus metronidazole or tinidazole) (CDC [Workow-
(CDC [Workowski 2015]; Marrazzo 2018) ski 2015])
Chancroid (due to Haemophilus ducreyi): Oral: 1 g Syphilis, primary and secondary (alternative agent
as a single dose. Note: Data are limited concerning for penicillin-allergic patients) (off-label use): Oral:
efficacy in HIV infected patients (CDC [Workow- 2 g as a single dose. Note: Limited data support
ski 2015]). the use of alternatives to penicillin; close serologic
Chlamydia trachomatis infection of the cervix, ure- and clinical follow-up is warranted. Use only if no
thra, or pharynx (off-label use [pharynx]): Oral: 1 g other options are available due to the potential for
as a single dose, preferably under direct observa- rapid emergence of macrolide resistance in Trepo-
tion (CDC [Workowski 2015]) nema pallidum and treatment failure; do not use to
Chlamydia trachomatis infection, expedited partner treat syphilis in patients with HIV, pregnant women,
therapy (off-label use): Oral: 1 g as a single dose, or the men who have sex with men (MSM) pop-
preferably under direct observation. Note: Clinical ulation (CDC [Workowski 2015]).
evaluation and presumptive treatment is preferred Urethritis, empiric therapy: Oral: 1 g as a single
for sexual partners of patients with chlamydia. dose, preferably under direct observation; give in
Alternatively, expedited partner therapy for chlamy- combination with ceftriaxone if there is microscopic
dia can be used for heterosexual partners if the evidence of gonococcal urethritis or if there is high
provider is concerned that the partner will otherwise clinical suspicion for gonococcal infection (Bach-
not be promptly evaluated and treated; state laws mann 2018; CDC [Workowski 2015])
regarding expedited partner therapy vary (CDC Streptococcal pharyngitis (group A) (alternative
[Workowski 2015]). agent for severely penicillin-allergic patients):
Gonococcal infection, disseminated (arthritis, arthri- Oral: 500 mg on day 1, followed by 250 mg once
tis-dermatitis, meningitis, endocarditis) (off-label daily on days 2 through 5 (IDSA [Shulman 2012]) or
use): Oral: 1 g as a single dose in combination with 500 mg once daily for 3 days (Casey 2005)
ceftriaxone, preferably under direct observation Surgical prophylaxis, uterine evacuation (induced
(CDC [Workowski 2015]) abortion or pregnancy loss) (alternative agent)
185
(off-label use): Oral: 500 mg as a single dose 1 hour Pneumonia, community-acquired (Bradley 2011):
before the procedure (may be administered up to 12 Infants >3 months, Children, and Adolescents:
hours before the procedure) (Shih 2019) Mild infection or step-down therapy: Oral: 10 mg/kg
Renal Impairment: Adult once on day 1 (maximum dose: 500 mg/dose)
Use with caution in patients with GFR <10 mL/minute followed by 5 mg/kg once daily on days 2 to 5
(AUC increased by 35% compared to patients with (maximum dose: 250 mg/dose)
normal renal function); however, no dosage adjust- Severe infection: IV: 10 mg/ kg once daily for at
ment is provided in the manufacturer's labeling. least 2 days, then transition to oral route with a
No supplemental dose or dosage adjustment neces- single daily dose of 5 mg/kg to complete course of
sary, including patients on intermittent hemodialysis, therapy; maximum dose: 500 mg/dose
peritoneal dialysis, or continuous renal replacement Cystic fibrosis; improve lung function, reduce
therapy (eg, CVVHD) (Aronoff 2007; Heintz 2009). exacerbation frequency: Limited data available;
Hepatic Impairment: Adult Azithromycin is predom- dosing regimen variable (Mogayzel 2013; Saiman
inantly hepatically eliminated; however, there is no 2003; Saiman 2010): Children ≥6 years and Adoles-
dosage adjustment provided in the manufacturer's cents: Oral:
labeling. Use with caution due to potential for hepato- 18 to 35.9 kg: 250 mg three times weekly (Monday,
toxicity (rare); discontinue immediately for signs or Wednesday, Friday)
symptoms of hepatitis. ≥36 kg: 500 mg three times weekly (Monday, Wed-
Pediatric Note: Zmax 2 g extended-release oral sus- nesday, Friday)
pension has been discontinued in the US for more Diarrhea, infectious:
than 1 year. Campylobacter: Infants, Children, and Adolescents:
Note: Extended-release suspension (Zmax) is not Oral: 10 mg/kg once daily for 3 days; maximum
interchangeable with immediate-release formula- dose: 500 mg/dose (Red Book [AAP] 2012)
tions. All doses are expressed as immediate-release Shigellosis: Infants, Children, and Adolescents: Oral:
azithromycin unless otherwise specified. AAP Recommendation: 12 mg/kg once on day 1
General dosing, susceptible infection (Red Book (maximum dose: 500 mg/dose), followed by
[AAP] 2012): Infants, Children, and Adolescents: 6 mg/kg once daily on days 2 to 5 (maximum
Mild to moderate infection: Oral: 5 to 12 mg/kg/dose; dose: 250 mg/dose) (Red Book [AAP] 2012)
typically administered as 10 to 12 mg/kg/dose on Alternate dosing: 10 mg/kg once daily for 3 days
day 1 followed by 5 to 6 mg/kg once daily for (Dupont 2009; Mackell 2005); WHO Guidelines
remainder of treatment duration; usual maximum recommend up to 20 mg/kg/dose and in some
dose for the total course: 1,500 to 2,000 mg cases, a wider range of duration of therapy (eg,
Serious infection: IV: 10 mg/kg once daily; maximum 1 to 5 days) (WHO 2005)
dose: 500 mg/dose Endocarditis; prophylaxis: Infants, Children, and
Babesiosis: Infants, Children, and Adolescents: Oral: Adolescents: Oral: 15 mg/kg/dose 30 to 60 minutes
10 mg/kg once on day 1 (maximum dose: 500 mg/
before procedure; maximum dose: 500 mg/dose
dose), then 5 mg/kg once daily on days 2 to 10
(Wilson 2007)
(maximum dose: 250 mg/dose) in combination with
Gonococcal infection; uncomplicated (cervicitis,
atovaquone; longer duration of therapy may be nec-
urethritis, anorectal): Oral:
essary in some cases; in immunocompromised
Children <45 kg: 20 mg/kg as a single dose; max-
patients, higher doses (eg, adults: 600 to 1,000 mg
imum dose: 1,000 mg/dose (Red Book [AAP] 2012)
daily) may be required (Red Book [AAP] 2012; IDSA
Children >8 years and ≥45 kg and Adolescents:
[Wormser 2006])
1,000 mg as a single dose (CDC 2012; Red Book
Bartonellosis: Oral:
Cat scratch disease (B. henselae) with extensive [AAP] 2012)
lymphadenopathy (IDSA [Stevens] 2014): Non- Group A streptococcal infection; treatment of
HIV-exposed/-positive: streptococcal tonsillopharyngitis:
Infants, Children, and Adolescents ≤45 kg: Manufacturer's labeling and AHA recommendations:
10 mg/kg once on day 1 (maximum dose: Infants, Children, and Adolescents: Oral: 12 mg/kg/
500 mg/dose), followed by 5 mg/kg once daily dose once daily for 5 days; maximum dose:
on days 2 to 5 (maximum dose: 250 mg/dose) 500 mg/dose (AHA [Gerber 2009])
Children and Adolescents >45 kg: 500 mg as a Alternate dosing:
single dose on day 1, then 250 mg once daily IDSA recommendations: Note: Recommended as
for 4 additional days an alternative agent for group A streptococcal
Cutaneous bacillary angiomatosis (B. henselae or B. pharyngitis in penicillin-allergic patients. Infants,
quintana): HIV-exposed/-positive: Infants, Chil- Children, and Adolescents: Oral: 12 mg/kg (max-
dren, and Adolescents: 5 to 12 mg/kg once daily; imum: 500 mg/dose) on day 1 followed by
maximum dose: 600 mg/dose; usual treatment 6 mg/kg/dose (maximum: 250 mg/dose) once
duration: 3 months (CDC 2009) daily on days 2 through 5 (IDSA [Shulman 2012]).
Chancroid (CDC 2010; Red Book [AAP] 2012): Oral: Three-day regimen: Limited data available: Chil-
<45 kg: 20 mg/kg as a single dose; maximum dose: dren and Adolescents: Oral: 20 mg/kg/dose once
1,000 mg/dose daily for 3 days; maximum dose: 1,000 mg/dose
≥45 kg: 1,000 mg as a single dose (Cohen 2004; O'Doherty 1996)
Chlamydial infections: Meningococcal disease, chemoprophylaxis of
Cervicitis, urethritis (C. trachomatis): Children and high-risk contacts: Infants, Children, and Adoles-
Adolescents ≥45 kg: Oral: 1,000 mg as a single cents: Oral: 10 mg/kg as a single dose; maximum
dose (CDC 2010; Red Book [AAP] 2012) dose: 500 mg/dose; Note: Not routinely recom-
Conjunctivitis: Infants: Oral, IV: 20 mg/kg once daily mended; may consider if fluoroquinolone resistance
for 3 days (Red Book [AAP] 2012) detected (Red Book [AAP] 2012)
186
Mycobacterium avium complex (MAC) infection Pneumonia, community acquired; mycoplasma

(HIV-exposed/-positive): pneumoniae, or chlamydial infection (Bradley
Infants and Children (DHHS [pediatric] 2013): Oral: 2011): Infants >3 months, Children, and Adoles-
Treatment: 10 to 12 mg/kg once daily in combina- cents:
tion with ethambutol, with or without rifabutin; Mild infection or step-down therapy: Oral: 10 mg/kg
maximum dose: 500 mg/dose; treatment duration once on day 1 (maximum dose: 500 mg/dose)
at least 12 months; dependent upon clinical followed by 5 mg/kg once daily on days 2 to 5
response (maximum dose: 250 mg/dose)
Primary prevention of first episode: Preferred: Severe infection: IV: 10 mg/kg once daily for at least
2 0 m g /k g on c e w ee k ly (m ax i m um d os e : 2 days (maximum dose: 500 mg/dose), then tran-
1,200 mg/dose) or alternatively, 5 mg/kg once sition to oral route with a single daily dose of
daily (maximum dose: 250 mg/dose) 5 mg/kg to complete course of therapy (maximum
Secondary prevention of recurring episodes: dose: 250 mg/dose)
5 mg/kg once daily in combination with ethambu- Rhinosinusitis, bacterial: Oral: Infants ≥6 months,
tol, with or without rifabutin; maximum dose: Children, and Adolescents: 10 mg/kg once daily for 3
250 mg/dose days; maximum dose: 500 mg/dose; Note: Although
Adolescents (DHHS [adult] 2013): Oral: FDA approved, macrolides are not recommended for
Treatment: 500 to 600 mg daily in combination with empiric therapy due to high rates of resistance
ethambutol (Chow 2012).
Primary prophylaxis: 1,200 mg once weekly or Sexual victimization, prophylaxis: Oral: Note: Use
alternatively, 600 mg twice weekly in combination with cefixime or ceftriaxone and com-
Secondary prophylaxis: 500 to 600 mg daily in pletion of hepatitis B virus immunization; also con-
combination with ethambutol sider prophylaxis for trichomoniasis and bacterial
Otitis media, acute (AOM): Infants ≥6 months, Chil- vaginosis (CDC 2010; Red Book [AAP] 2012).
dren, and Adolescents: Oral: Note: Due to increased Children <45 kg: 20 mg/kg as a single dose
S pneumonia and H. influenzae resistance, azithro- Children ≥45 kg and Adolescents: 1,000 mg as a
mycin is not routinely recommended as a treatment single dose
option (AAP [Lieberthal 2013]) Toxoplasma gondii, encephalitis (HIV-exposed/-
Single-dose regimen: 30 mg/kg as a single dose; positive); treatment and prevention: Oral: Adoles-
maximum dose: 1,500 mg/dose; if patient vomits cents: 900 to 1,200 mg once daily in combination
within 30 minutes of dose, repeat dosing has been with pyrimethamine/leucovorin; treatment duration: 6
administered although limited data available on weeks or longer if extensive disease or incomplete
safety response at 6 weeks (DHHS [adult] 2013)
Three-day regimen: 10 mg/kg once daily for 3 days; Renal Impairment: Pediatric
maximum dose: 500 mg/dose Infants ≥6 months, Children, and Adolescents:
Five-day regimen: 10 mg/kg once on day 1 (max- Use with caution in patients with GFR <10 mL/minute
imum dose: 500 mg/dose), followed by 5 mg/kg (AUC increased by 35% compared to patients with
(maximum dose: 250 mg/dose) once daily on days normal renal function); however, no dosage adjust-
2 to 5 ment is provided in the manufacturer's labeling.
Peritonitis (peritoneal dialysis), prophylaxis for No supplemental dose or dosage adjustment neces-
patients receiving peritoneal dialysis who require sary, including patients on intermittent hemodialy-
dental procedures: Infants, Children, and Adoles- sis, peritoneal dialysis, or continuous renal
cents: Oral: 15 mg/kg administered 30 to 60 minutes replacement therapy (eg, CVVHD) (Aronoff 2007;
before dental procedure; maximum dose: 500 mg/ Heintz 2009).
dose (Warady [ISPD 2012]) Hepatic Impairment: Pediatric Azithromycin is pre-
Pertussis (CDC 2005; Red Book [AAP] 2012): Oral, dominantly hepatically eliminated; however, there is
IV: no dosage adjustment provided in the manufacturer's
Infants 1 to 5 months: 10 mg/kg/dose once daily for labeling. Use with caution due to potential for hepato-
5 days toxicity (rare); discontinue immediately for signs or
Infants ≥6 months, Children, and Adolescents: symptoms of hepatitis.
10 mg/kg once on day 1 (maximum dose: Mechanism of Action Inhibits RNA-dependent protein
500 mg/dose), followed by 5 mg/kg once daily on synthesis at the chain elongation step; binds to the 50S
days 2 to 5 (maximum dose: 250 mg/dose) ribosomal subunit resulting in blockage of transpeptida-
Pneumonia, community-acquired (excluding tion
mycobacterial [mycoplasma pneumoniae] and Contraindications
chlamydial infections): Hypersensitivity to azithromycin, erythromycin, other
Oral: macrolide (eg, azalide or ketolide) antibiotics, or any
Immediate release: Infants >3 months, Children, component of the formulation; history of cholestatic
and Adolescents: 10 mg/kg once on day 1 (max- jaundice/hepatic dysfunction associated with prior azi-
imum dose: 500 mg/dose), followed by 5 mg/kg thromycin use
(maximum dose: 250 mg/dose) once daily on Note: The manufacturer does not list concurrent use of
days 2 to 5 (Bradley 2011) pimozide as a contraindication; however, azithromycin
Extended-release oral suspension (Zmax): Infants is listed as a contraindication in the manufacturer's
≥6 months, Children, and Adolescents: 60 mg/kg labeling for pimozide.
as a single dose; maximum dose: 2,000 mg/dose Warnings/Precautions Use with caution in patients
IV: Infants >3 months, Children, and Adolescents: with preexisting liver disease; hepatocellular and/or
10 mg/kg once daily for at least 2 days, follow IV cholestatic hepatitis (with or without jaundice), hepatic
therapy by the oral route with a single daily dose of necrosis, failure and death have occurred. Discontinue
5 mg/kg to complete a 5-day course of therapy; immediately if symptoms of hepatitis occur (malaise,
maximum dose: 500 mg/dose (Bradley 2011) nausea, vomiting, abdominal colic, fever). Allergic
187
(hypersensitivity) reactions (eg, angioedema, anaphy- Inhibitors (Moderate Risk); QT-prolonging Strong
laxis, Stevens-Johnson syndrome, toxic epidermal nec- CYP3A4 Inhibitors (Moderate Risk)
rolysis and drug reaction with eosinophilia and systemic Decreased Effect
symptoms [DRESS]) have been reported (rare), includ- Azithromycin (Systemic) may decrease the levels/
ing fatalities; reappearance of allergic reaction may effects of: BCG (Intravesical); BCG Vaccine (Immuni-
occur shortly after discontinuation without further azi- zation); Cholera Vaccine; Lactobacillus and Estriol;
thromycin exposure. May mask or delay symptoms of Sincalide; Sodium Picosulfate; Typhoid Vaccine
incubating gonorrhea or syphilis, so appropriate culture Food Interactions Rate and extent of GI absorption
and susceptibility tests should be performed prior to may be altered depending upon the formulation. Azi-
initiating a treatment regimen. Prolonged use may thromycin suspension, not tablet form, has significantly
result in fungal or bacterial superinfection, including C. increased absorption (46%) with food. Management:
difficile-associated diarrhea (CDAD); CDAD has been Immediate release suspension and tablet may be taken
observed >2 months postantibiotic treatment. Use cau- without regard to food; extended release suspension
tion with renal dysfunction. Macrolides (especially eryth- should be taken on an empty stomach (at least 1 hour
romycin) have been associated with rare QTc before or 2 hours following a meal).
prolongation and ventricular arrhythmias, including tor- Dietary Considerations
sades de pointes; consider avoiding use in patients with Some products may contain sodium and/or sucrose.
prolonged QT interval, congenital long QT syndrome, Oral suspension, immediate release, may be adminis-
history of torsades de pointes, bradyarrhythmias, uncor- tered with or without food.
rected hypokalemia or hypomagnesemia, clinically sig- Oral suspension, extended release, should be taken on
nificant bradycardia, uncompensated heart failure, or an empty stomach (at least 1 hour before or 2 hours
concurrent use of Class IA (eg, quinidine, procaina- following a meal).
mide) or Class III (eg, amiodarone, dofetilide, sotalol) Tablet may be administered with food to decrease GI
antiarrhythmic agents or other drugs known to prolong effects.
the QT interval. Use with caution in patients with Pharmacodynamics/Kinetics
myasthenia gravis. Use of azithromycin in neonates Half-life Elimination Terminal: Oral, IV: Infants and
and infants (treatment up to 42 days of life) has been Children 4 months to 15 years: 54.5 hours; Adults:
associated with infantile hypertrophic pyloric stenosis Immediate release: 68 to 72 hours; Extended release:
(IHPS); observe for non-bilious vomiting or irritability 59 hours
with feeding (Eberly 2015). Time to Peak Oral: Serum: Immediate release: ~2 to 3
Oral suspensions (immediate release and extended hours; Extended release: 3 to 5 hours
release) are not interchangeable. Pregnancy Risk Factor B
Drug Interactions Pregnancy Considerations Adverse events were not
Metabolism/Transport Effects Substrate of observed in animal reproduction studies. Azithromycin
CYP3A4 (minor); Note: Assignment of Major/Minor crosses the placenta (Ramsey 2003). The maternal
substrate status based on clinically relevant drug serum half-life of azithromycin is unchanged in early
interaction potential; Inhibits P-glycoprotein/ABCB1 pregnancy and decreased at term; however, high con-
Avoid Concomitant Use centrations of azithromycin are sustained in the myo-
Avoid concomitant use of Azithromycin (Systemic) metrium and adipose tissue (Fischer 2012; Ramsey
with any of the following: BCG (Intravesical); Cholera 2003). Azithromycin is recommended for the treatment
Vaccine; Mizolastine; PAZOPanib; Pimozide; QT-pro- of several infections, including chlamydia, gonococcal
longing Strong CYP3A4 Inhibitors (Moderate Risk); infections, and Mycobacterium avium complex (MAC) in
Topotecan; VinCRIStine (Liposomal) pregnant patients (consult current guidelines) (CDC
Increased Effect/Toxicity [Workowski 2015]; HHS [opportunistic; adult] 2015).
Azithromycin (Systemic) may increase the levels/ Breastfeeding Considerations
effects of: Afatinib; AtorvaSTATin; Betrixaban; Bilas- Azithromycin is excreted in breast milk.
tine; Brentuximab Vedotin; Cardiac Glycosides; Cel- The relative infant dose (RID) of azithromycin is 4% to
iprolol; Chloroquine; Clofazimine; Colchicine; 8% when calculated using the highest breast milk
CycloSPORINE (Systemic); Dabigatran Etexilate; concentration located and compared to an infant ther-
Domperidone; DOXOrubicin (Conventional); Edoxa- apeutic dose of 5 to 10 mg/kg/day. In general, breast-
ban; Everolimus; Gadobenate Dimeglumine; Halofan- feeding is considered acceptable when the RID is
tri ne; Ha lo peri do l; In otu zu ma b O zo ga mic in ; <10% (Anderson 2016; Ito 2000). Using the highest
Ivermectin (Systemic); Larotrectinib; Lofexidine; Lov- milk concentration (2.8 mcg/mL), the estimated daily
astatin; Midostaurin; Mizolastine; Naldemedine; infant dose via breast milk is 0.42 mg/kg/day. This milk
Naloxegol; Ondansetron; PAZOPanib; Pentamidine concentration was obtained following maternal admin-
(Systemic); P-glycoprotein/ABCB1 Substrates; Piper- istration of oral azithromycin as a 1 g loading dose
aquine; Probucol; Prucalopride; QT-prolonging Anti- followed in 48 hours by azithromycin 500 mg for 3
psychotics (Moderate Risk); QT-prolonging Class IC days; milk concentrations increased over time and
Antiarrhythmics (Moderate Risk); QT-prolonging Qui- reached a peak 30 hours after the last oral dose
nolone Antibiotics (Moderate Risk); Ranolazine; (Kelsey 1994).
Following a single dose of IV azithromycin 500 mg,
RifAXIMin; Silodosin; Simvastatin; Sodium Stibogluc-
azithromycin was measurable in breast milk for up to
onate; Tacrolimus (Systemic); Tacrolimus (Topical);
48 hours. The median half-life in breast milk was 15.6
Talazoparib; Topotecan; Toremifene; VinCRIStine
hours (Sutton 2015).
(Liposomal); Vitamin K Antagonists
Decreased appetite, diarrhea, rash, and somnolence
The levels/effects of Azithromycin (Systemic) may be have been reported in nursing infants exposed to
increased by: Nelfinavir; Pimozide; QT-prolonging macrolide antibiotics (Goldstein 2009). In general,
Agents (Highest Risk); QT-prolonging Antidepressants antibiotics that are present in breast milk may cause
(Moderate Risk); QT-prolonging Kinase Inhibitors non-dose-related modification of bowel flora. Monitor
(Moderate Risk); QT-prolonging Moderate CYP3A4 infants for GI disturbances (WHO 2002). In addition,
188
AZTREONAM (SYSTEMIC)
an increased risk for infantile hypertrophic pyloric Effects on Dental Treatment No significant effects or
stenosis (IHPS) may be present in infants who are complications reported
exposed to macrolides via breast milk, especially Effects on Bleeding No information available to
during the first 2 weeks of life (Lund 2014); however, require special precautions
data is conflicting (Goldstein 2009). The manufacturer Adverse Reactions
recommends that caution be exercised when admin- >10%:
istering azithromycin to breastfeeding women. Hematologic & oncologic: Neutropenia (children 3% to
The CDC's Sexually Transmitted Diseases Treatment 11%; adults <1%)
Guidelines state that azithromycin is one of the rec- Hepatic: Increased serum transaminases (children,
ommended agents for the treatment of granuloma high dose: >3 times ULN: 15% to 20%; children,
inguinale in lactating women. For lymphogranuloma standard dose: increased serum AST 4%, increased
venereum, azithromycin may be considered as an serum ALT 7%)
alternative agent in this patient population (CDC Local: Pain at injection site (children 12%, adults 2%)
[Workowski 2015]). 1% to 10%:
Product Availability Zmax suspension has been dis- Cardiovascular: Phlebitis (intravenous: ≤2%), throm-
continued in the US for more than 1 year. bophlebitis (intravenous: ≤2%)
Dosage Forms: US Dermatologic: Skin rash (children 4%, adults ≤1%)
Packet, Oral: Gastrointestinal: Diarrhea (≤1%), nausea (≤1%), vom-
Zithromax: 1 g (3 ea, 10 ea) iting (≤1%)
Generic: 1 g (3 ea, 10 ea) Hematologic & oncologic: Eosinophilia (children 6%,
Solution Reconstituted, Intravenous: adults <1%), thrombocythemia (children 4%,
Zithromax: 500 mg (1 ea) adults <1%)
Generic: 500 mg (1 ea) Local: Erythema at injection site (intravenous: Chil-
Solution Reconstituted, Intravenous [preservative dren 3%, adults <1%), discomfort at injection site
free]: (intramuscular: ≤2%), swelling at injection site (intra-
Generic: 500 mg (1 ea) muscular: ≤2%)
Suspension Reconstituted, Oral: Renal: Increased serum creatinine (children 6%)
Zithromax: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 Miscellaneous: Fever (≤1%)
mL, 22.5 mL, 30 mL) <1%, postmarketing, and/or case reports: Abdominal
Generic: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 mL, cramps, anaphylaxis, anemia, angioedema, breast
22.5 mL, 30 mL) tenderness, bronchospasm, chest pain, Clostridioides
Tablet, Oral: (formerly Clostridium) difficile-associated diarrhea,
Zithromax: 250 mg, 500 mg, 600 mg confusion, diaphoresis, diplopia, dizziness, dysgeusia,
Zithromax Tri-Pak: 500 mg dyspnea, erythema multiforme, exfoliative dermatitis,
Zithromax Z-Pak: 250 mg flushing, gastrointestinal hemorrhage, halitosis, head-
Generic: 250 mg, 500 mg, 600 mg ache, hepatitis, hepatobiliary disease, hypotension,
Dental Health Professional Considerations There increased serum alkaline phosphatase, increased
is evidence that azithromycin is proarrhythmic (see serum ALT (adults), increased serum AST (adults),
Local Anesthetic/Vasoconstrictor Precautions) induration at injection site, insomnia, jaundice, leuko-
cytosis, malaise, myalgia, nasal congestion, numb-
A recent large retrospective review of the cardiovascu- ness of tongue, oral mucosa ulcer, pancytopenia,
lar risks of azithromycin was published. Researchers paresthesia, petechia, positive direct Coombs test,
reviewed a Tennessee Medicaid cohort of patients to prolonged partial thromboplastin time, prolonged pro-
evaluate cardiovascular mortality in patients taking azi- thrombin time, pruritus, pseudomembranous colitis,
thromycin, amoxicillin, ciprofloxacin, levofloxacin, or no purpura, seizure, sneezing, thrombocytopenia, tinni-
antibiotic. The cohort included patients who took azi- tus, toxic epidermal necrolysis, urticaria, vaginitis,
thromycin (347,795 prescriptions); propensity-score- ventricular bigeminy (transient), ventricular premature
matched persons who took no antibiotics (1,391,180 contractions (transient), vertigo, vulvovaginal candi-
control periods); and patients who took amoxicillin diasis, weakness, wheezing
(1,348,672 prescriptions), ciprofloxacin (264,626 pre- Mechanism of Action Inhibits bacterial cell wall syn-
scriptions), or levofloxacin (193,906 prescriptions). thesis by binding to one or more of the penicillin-binding
The risk of cardiovascular death was greater with proteins (PBPs) which in turn inhibits the final trans-
azithromycin than with ciprofloxacin, but similar to levo- peptidation step of peptidoglycan synthesis in bacterial
floxacin. Amoxicillin showed no increase in risk of cell walls, thus inhibiting cell wall biosynthesis. Bacteria
cardiovascular death. The estimated risk for azithromy- eventually lyse due to ongoing activity of cell wall
cin was 47 additional cardiovascular deaths per million autolytic enzymes (autolysins and murein hydrolases)
courses of treatment (Ray 2012). while cell wall assembly is arrested. Monobactam struc-
ture makes cross-allergenicity with beta-lactams
Aztreonam (Systemic) (AZ tree oh nam) unlikely.
Brand Names: US Azactam; Azactam in Dextrose Half-life Elimination
[DSC] Neonates: <7 days, ≤2.5 kg: 5.5 to 9.9 hours; <7 days,
Pharmacologic Category Antibiotic, Monobactam >2.5 kg: 2.6 hours; 1 week to 1 month: 2.4 hours
Use Treatment of patients with urinary tract infections, Children 2 months to 12 years: 1.7 hours
lower respiratory tract infections, septicemia, skin/skin Children with cystic fibrosis: 1.3 hours
structure infections, intra-abdominal infections, and Adults: Normal renal function: 1.5 to 2 hours
gynecological infections caused by susceptible gram- End-stage renal disease: 6 to 8.4 hours (Brog-
negative bacilli den 1986)
Local Anesthetic/Vasoconstrictor Precautions Time to Peak IM: Within 60 minutes (Mattie 1988)
No information available to require special precautions Pregnancy Risk Factor B
189
AZTREONAM (SYSTEMIC)
Pregnancy Considerations Adverse events have not 1-877-7CAYSTON (1-877-722-9786) or at www.-

been observed in animal reproduction studies. Aztreo- cayston.com. In Canada, Cayston is distributed by
nam crosses the placenta and can be detected in the Innomar Solutions specialty pharmacy; Canadian
fetus. healthcare providers and patients may obtain additional
information at http://cayston.ca/
Aztreonam (Oral Inhalation) (AZ tree oh nam)
Bacitracin (Topical) (bas i TRAY sin)
Brand Names: US Cayston
Brand Names: Canada Cayston Brand Names: Canada Bacitin
Pharmacologic Category Antibiotic, Monobactam Pharmacologic Category Antibiotic, Topical
Use Cystic fibrosis: Improve respiratory symptoms in Use Topical infection prevention: Prevention of infec-
cystic fibrosis (CF) patients with pulmonary Pseudomo- tion in minor cuts, scrapes, or burns.
nas aeruginosa infections Local Anesthetic/Vasoconstrictor Precautions
Local Anesthetic/Vasoconstrictor Precautions No information available to require special precautions
No information available to require special precautions Effects on Dental Treatment No significant effects or
Effects on Dental Treatment No significant effects or complications reported
complications reported Effects on Bleeding No information available to
Effects on Bleeding No information available to require special precautions
require special precautions Adverse Reactions Postmarketing and/or case
Adverse Reactions reports: Anaphylaxis (Elsner, 1990; Farley, 1995)
>10%: Mechanism of Action Inhibits bacterial cell wall syn-
Gastrointestinal: Pharyngolaryngeal pain (12%) thesis by preventing transfer of mucopeptides into the
Respiratory: Cough (54%), nasal congestion (16%), growing cell wall
wheezing (16%) Pregnancy Considerations Although large studies
Miscellaneous: Fever (13%; more common in have not been conducted, absorption is limited follow-
children) ing topical application; use during pregnancy has not
1% to 10%: been associated with an increased risk of adverse fetal
Cardiovascular: Chest discomfort (8%) events (Leachman, 2006; Murase, 2014).
Gastrointestinal: Abdominal pain (7%), vomiting (6%) Baclofen (BAK loe fen)
Respiratory: Bronchospasm (3%; patients experi-
enced ≥15% reduction in FEV1) Brand Names: US Gablofen; Lioresal; Lioresal Intra-
<1%, postmarketing, and/or case reports: Arthralgia, thecal
facial rash, facial swelling, hypersensitivity reaction, Brand Names: Canada Lioresal; Lioresal D.S.; Lior-
joint swelling, pharyngeal edema esal Intrathecal
Mechanism of Action Inhibits bacterial cell wall syn- Pharmacologic Category Skeletal Muscle Relaxant
thesis by binding to one or more of the penicillin-binding Use
proteins (PBPs), which in turn inhibits the final trans- Spasticity:
peptidation step of peptidoglycan synthesis in bacterial Oral: Management of reversible spasticity associated
cell walls, thus inhibiting cell wall biosynthesis. Bacteria with multiple sclerosis or spinal cord lesions
eventually lyse due to ongoing activity of cell wall Intrathecal: Management of severe spasticity of spinal
autolytic enzymes (autolysins and murein hydrolases), cord origin (eg, spinal cord injury, multiple sclerosis)
while cell wall assembly is arrested. Monobactam struc- or cerebral origin (eg, cerebral palsy, traumatic brain
ture makes cross-allergenicity with beta-lactams injury) in patients ≥4 years; may be considered as an
unlikely. alternative to destructive neurosurgical procedures.
Pharmacodynamics/Kinetics Limitations of use: Patients should first respond to a
Half-life Elimination Adults: 2.1 hours screening dose of intrathecal baclofen prior to con-
Pregnancy Risk Factor B sideration for long term infusion via an implantable
Pregnancy Considerations Animal reproduction pump. For spasticity of spinal cord origin, chronic
studies have not been conducted with aztreonam sol- infusion via an implantable pump should be
ution for inhalation; however, adverse events were not reserved for patients unresponsive to oral baclofen
observed in animal reproduction studies conducted with therapy, or those who experience intolerable CNS
the injection. Aztreonam crosses the placenta and side effects at effective doses. Patients with spas-
reaches the fetal circulation following IV administration; ticity due to traumatic brain injury should wait at
however, peak plasma concentrations following inhala- least one year after the injury before consideration
tion of aztreonam are significantly less than those of long term intrathecal baclofen therapy.
observed following aztreonam IV. Local Anesthetic/Vasoconstrictor Precautions
Prescribing and Access Restrictions Cayston No information available to require special precautions
(aztreonam inhalation solution) is only available through Effects on Dental Treatment No significant effects or
a select group of specialty pharmacies and cannot be complications reported
obtained through a retail pharmacy. Because Cayston Effects on Bleeding No information available to
may only be used with the Altera Nebulizer System, it require special precautions
can only be obtained from the following specialty phar- Adverse Reactions
macies; IV Solutions/Maxor; Foundation Care; Pharma- >10%:
ceutical Specialties Inc; TLCRx/ModernHEALTH; and Central nervous system: Hypotonia (2% to 35%),
Walgreens Specialty Pharmacy. This network of spe- drowsiness (6% to 21%), confusion (1% to 11%),
cialty pharmacies ensures proper access to both the headache (2% to 11%)
drug and device. To obtain the medication and proper Gastrointestinal: Nausea (1% to 12%), vomiting (2%
nebulizer, contact the Cayston Access Program at to 11%)
190
BALSALAZIDE
1% to 10%: Freeman 2016; Ratnayaka 2001). Use of intrathecal

Cardiovascular: Hypotension (≤9%), peripheral baclofen in pregnant females has been described (Dal-
edema (≤3%) ton 2008; Hara 2018; Méndez-Lucena 2016; Tandon
Central nervous system: Seizure (≤10%), dizziness 2010). Maternal plasma concentrations following
(2% to 8%), insomnia (≤7%), paresthesia (≤7%), administration of intrathecal baclofen are significantly
hypertonia (≤6%), pain (≤4%), speech disturbance less than those with oral doses; exposure to the fetus is
(≤4%), depression (2%), coma (≤2%), abnormality in expected to be limited and adverse neonatal events
thinking (≤1%), agitation (≤1%), chills (≤1%) have not been noted in available reports (Morton 2009).
Dermatologic: Pruritus (4%), urticaria (≤1%)
Gastrointestinal: Constipation (≤6%), sialorrhea
(≤3%), xerostomia (≤3%), diarrhea (≤2%)
Baloxavir Marboxil (ba LOX A veer mar BOX el)
Genitourinary: Urinary retention (≤8%), urinary fre- Brand Names: US Xofluza
quency (≤6%), difficulty in micturition (2%), impo- Pharmacologic Category Antiviral Agent; Endonu-
tence (≤2%), urinary incontinence (≤2%) clease Inhibitor
Neuromuscular & skeletal: Asthenia (≤2%), back pain
Use
(≤2%), tremor (≤1%)
Influenza, treatment: Treatment of acute uncompli-
Ophthalmic: Amblyopia (≤2%)
cated influenza in patients ≥12 years who have been
Respiratory: Hypoventilation (≤4%), pneumonia
symptomatic for no more than 48 hours.
(≤2%), dyspnea (≤1%)
Limitations of use: Influenza viruses change over time,
Miscellaneous: Accidental injury (≤4%)
and factors such as the virus type or subtype, emer-
gence of resistance, or changes in viral virulence may
pain, accommodation disturbance, akathisia, albumi-
diminish the clinical benefit of antiviral drugs. Consider
nuria, alopecia, amnesia, ankle edema, anorexia,
available information on drug susceptibility patterns for
anxiety, apnea, ataxia, blurred vision, bradycardia,
carcinoma, chest pain, contact dermatitis, decreased circulating influenza virus strains when deciding
libido, deep vein thrombophlebitis, dehydration, der- whether to use baloxavir marboxil.
mal ulcer, diaphoresis, diplopia, dysarthria, dysauto- Local Anesthetic/Vasoconstrictor Precautions
nomia, dysgeusia, dysphagia, dystonia, dysuria, No information available to require special precautions
epilepsy, erectile dysfunction, euphoria, excitement, Effects on Dental Treatment Key adverse event(s)
facial edema, fecal incontinence, fever, gastrointesti- related to dental treatment: Nasopharyngitis has been
nal hemorrhage, hallucination, hematuria, hyperglyce- reported
mia, hyperhidrosis, hypertension, hyperventilation, Effects on Bleeding No information available to
hypothermia, hysteria, inhibited ejaculation, intestinal require special precautions
obstruction, leukocytosis, loss of postural reflex, Adverse Reactions
malaise, miosis, muscle rigidity, myalgia, mydriasis, 1% to 10%:
nasal congestion, nephrolithiasis, nocturia, nystagmus Gastrointestinal: Diarrhea (2%; Hayden 2018)
disorder, occult blood in stools, oliguria, opisthotonus, Respiratory: Nasopharyngitis (2%; Hayden 2018)
orgasm disturbance, pallor, palpitations, paranoid Mechanism of Action Baloxavir marboxil is an oral
ideation, personality disorder, petechial rash, priap- prodrug that is converted to baloxavir, an inhibitor of the
ism, pulmonary embolism, scoliosis, scoliosis progres- endonuclease activity of a selective polymerase acidic
sion, sedated state, sexual disorder, skin rash, slurred (PA) protein, which is required for viral gene transcrip-
speech, strabismus, suicidal ideation, syncope, taste tion, resulting in inhibition of influenza virus replication.
disorder, tinnitus, tongue irritation, vaginitis, vasodila- Baloxavir has demonstrated antiviral activity against
tation, weight gain, weight loss influenza A and B viruses, including strains resistant
Mechanism of Action Inhibits the transmission of both to standard current antiviral agents (Hayden 2018).
monosynaptic and polysynaptic reflexes at the spinal Pharmacodynamics/Kinetics
cord level, possibly by hyperpolarization of primary Half-life Elimination 79.1 hour
afferent fiber terminals, with resultant relief of muscle Time to Peak 4 hours
spasticity Pregnancy Considerations
Pharmacodynamics/Kinetics Adverse events were not observed in animal reproduc-
Onset of Action tion studies.
Intrathecal bolus: 30 minutes to 1 hour; Continuous
infusion: 6 to 8 hours after infusion initiation Untreated influenza infection is associated with an
Peak effect: Intrathecal bolus: 4 hours (effects may increased risk of adverse events to the fetus and an
last 4 to 8 hours); Continuous infusion: 24 to 48 increased risk of complications or death to the mother.
hours Other agents are currently recommended for the treat-
Half-life Elimination ment of influenza in pregnant females and females up
Oral: to 2 weeks postpartum (ACOG 2018; CDC
Pediatric patients with cerebral palsy (age range: 2 to [Fiore] 2011).
17 years): 4.5 hours (He 2014)
Adults: 3.75 ± 0.96 hours (Brunton 2011) Balsalazide (bal SAL a zide)
Intrathecal: CSF elimination half-life: 1.5 hours over
the first 4 hours Brand Names: US Colazal; Giazo [DSC]
Time to Peak Serum: Oral: 1 hour (0.5 to 4 hours) Pharmacologic Category 5-Aminosalicylic Acid
(Brunton 2011) Derivative; Anti-inflammatory Agent
Pregnancy Considerations Use
Feeding difficulties, high-pitched cry, hyperthermia, Ulcerative colitis: Treatment of mildly- to moderately-
hypertonicity, loose stools, tremors, and seizures have active ulcerative colitis
been reported in newborns following maternal use of Limitations of use: Efficacy of Giazo has not been
oral baclofen throughout pregnancy (Duncan 2013; demonstrated in females.
191
BALSALAZIDE
Local Anesthetic/Vasoconstrictor Precautions placenta. Refer to the mesalamine monograph for addi-
No information available to require special precautions tional information.
complications reported Baricitinib (bar i SYE ti nib)
require special precautions Brand Names: US Olumiant
Adverse Reactions Pharmacologic Category Antirheumatic Miscellane-
>10%: ous; Antirheumatic, Disease Modifying; Janus Associ-
Central nervous system: Headache (children: 15%; ated Kinase Inhibitor
adults: 8%) Use
Gastrointestinal: Abdominal pain (children: 12% to Rheumatoid arthritis: Treatment of adult patients with
13%; adults: ≤6%) moderately to severely active rheumatoid arthritis who
1% to 10%: have had an inadequate response to one or more
Central nervous system: Fatigue (children: 4%; adults: tumor necrosis factor antagonist therapies.
≤2%), insomnia (adults: 2%) Limitation of use: Use of baricitinib in combination with
Gastrointestinal: Vomiting (children: 10%; adults: other JAK inhibitors, biologic DMARDs, or with potent
≤4%), diarrhea (children: 9%; adults: ≤5%), exacer- immunosuppressants such as azathioprine and cyclo-
bation of ulcerative colitis (children: 6%; adults: 1%), sporine is not recommended.
nausea (adults: 5%; children: 4%), hematochezia Local Anesthetic/Vasoconstrictor Precautions
(children: 4%), stomatitis (children: 3%), anorexia Prolongation of the EKG QT interval has been reported
(adults: 2%), dyspepsia (adults: 2%), flatulence as a rare occurrence associated with other Janus
(adults: ≤2%), abdominal cramps (adults: 1%), con- kinase inhibitors (see ruxolitinib). Assuming the patient
stipation (adults: ≤1%), xerostomia (adults: ≤1%) has no history of arrhythmia or not taking any medi-
Genitourinary: Urinary tract infection (adults: 1% to cations which are associated with prolongation of the
4%), dysmenorrhea (children: 3%) QT interval, there is nothing to suggest that baricitinib
Hematologic & oncologic: Anemia (4%) will increase the risk of an arrhythmia.
Neuromuscular & skeletal: Arthralgia (adults: ≤4%), Effects on Dental Treatment Key adverse event(s)
musculoskeletal pain (adults: 2%), myalgia related to dental treatment: Opportunistic infections are
(adults: ≤1%) possible; rare occurrence of esophageal candidiasis
Respiratory: Pharyngitis (children: 6%; adults: 2%), and fungal infections have been reported. Although
flu-like symptoms (children: 4%; adults: 1%), respi- there are no specific reports, patients may be at risk
ratory infection (adults: ≤4%), cough (children: 3%; for candida albicans infections in the oral cavity.
adults: 2%), pharyngolaryngeal pain (adults: 4%, Effects on Bleeding Active therapy with immunosup-
children: 3%), rhinitis (adults: 2%) pressants such as baricitinib may result in myelosup-
Miscellaneous: Fever (children: 6%; adults: 2%) pression; medical consult suggested. Baricitinib
<1%, postmarketing, and/or case reports: Alopecia, labeling reports the occurrence of anemia and lympho-
back pain, bowel urgency, bronchopneumonia, cho- cytopenia; rare occurrence of deep vein thrombosis.
lestatic jaundice, dizziness, dyspnea, edema, eryth- Adverse Reactions
ema nodosum, facial edema, fecal impaction, >10%: Respiratory: Upper respiratory tract infection
gastroenteritis, gastroesophageal reflux disease, hep- (16%)
atic cirrhosis, hepatic failure, hepatic injury, hepatic 1% to 10%:
necrosis, hepatotoxicity, hyperbilirubinemia, hyper- Gastrointestinal: Nausea (3%)
sensitivity reaction, increased blood pressure, Hepatic: Increased serum alanine aminotransferase
increased heart rate, increased liver enzymes, (≥3 x ULN) (2%), increased serum aspartate amino-
increased serum AST, interstitial nephritis, jaundice, transferase (≥3 x ULN) (1%)
Kawasaki-like syndrome, lethargy, malaise, myocardi- Infection: Herpes zoster infection (1%)
tis, pain, pancreatitis, pericarditis, pleural effusion, Frequency not defined:
Endocrine & metabolic: Increased HDL cholesterol,
pneumonia (with and without eosinophilia), pruritus,
increased LDL cholesterol, increased serum choles-
renal failure, skin rash, vasculitis
terol, increased serum triglycerides
Mechanism of Action Balsalazide is a prodrug, con- Hematologic & oncologic: Anemia, lymphocytopenia
verted by bacterial azoreduction to 5-aminosalicylic acid
Hepatic: Increased liver enzymes
(mesalamine, active), 4-aminobenzoyl-β-alanine (inert), Neuromuscular & skeletal: Increased creatine phos-
and their metabolites. 5-aminosalicylic acid may phokinase
decrease inflammation by blocking the production of Renal: Increased serum creatinine
arachidonic acid metabolites topically in the colon <1%, postmarketing, and/or case reports: Acne, arterial
mucosa. thrombosis, bacterial infection, BK virus, CMV viremia,
Pharmacodynamics/Kinetics cryptococcosis, deep vein thrombosis, esophageal
Half-life Elimination Primary effect is topical (colonic candidiasis, fungal infection, gastrointestinal perfora-
mucosa); therapeutic effect appears not to be influ- tion, herpes virus infection, histoplasmosis, neutrope-
enced by the systemic half-life of balsalazide (1.9 nia, malignant neoplasm, mycobacterium infection,
hours) or its metabolites (5-ASA [9.5 hours], N-Ac-5- opportunistic infection, pneumonia, pneumonia due
ASA [10.4 hours]) to Pneumocystis jirovecii, pulmonary embolism, skin
Time to Peak Balsalazide: Capsule: 1 to 2 hours; carcinoma, tuberculosis, urinary tract infection,
Tablet: 0.5 hours venous thromboses, viral infection
Pregnancy Risk Factor B Mechanism of Action Baricitinib inhibits Janus kinase
Pregnancy Considerations Adverse events have not (Jak) enzymes, which are intracellular enzymes
been observed in animal reproduction studies. Mesal- involved in stimulating hematopoiesis and immune cell
amine (5-aminosalicylic acid) is the active metabolite of function through a signaling pathway. In response to
balsalazide; mesalamine is known to cross the extracellular cytokine or growth factor signaling, Jaks
192
BASILIXIMAB
activate signal transducers and activators of transcrip- Effects on Bleeding No information available to
tion (STATs), which regulate gene expression and intra- require special precautions
cellular activity. Inhibition of Jaks prevents the activation Adverse Reactions Frequency not defined. Adminis-
of STATs and reduces serum IgG, IgM, IgA, and C- tration of basiliximab did not appear to increase the
reactive protein. incidence or severity of adverse effects in clinical trials.
Pharmacodynamics/Kinetics Adverse events were reported in 96% of both the
Half-life Elimination ~12 hours placebo and basiliximab groups.
Time to Peak ~1 hour
>10%:
Pregnancy Considerations Adverse events were Cardiovascular: Hypertension, peripheral edema
observed in animal reproduction studies. Central nervous system: Headache, insomnia, pain
Dental Health Professional Considerations The Dermatologic: Acne vulgaris
actions of baricitinib in treating rheumatoid arthritis is Endocrine & metabolic: Hypercholesterolemia, hyper-
due to its ability to inhibit cytokines, including some in glycemia, hyperkalemia, hyperuricemia, hypokale-
the interleukin family, from attaching to receptors that mia, hypophosphatemia
exacerbate arthritic symptoms. The receptors rely on Gastrointestinal: Abdominal pain, constipation, diar-
the Janus kinase family of enzymes for receptor activa- rhea, dyspepsia, nausea, vomiting
tions. These activations occur because the kinases Genitourinary: Urinary tract infection
phosphorylate receptor components (definition of kin- Hematologic & oncologic: Anemia
ases is enzymes that phosphorylate substrates). Janus Infection: Viral infection
kinases are members of the larger family of tyrosine Neuromuscular & skeletal: Tremor
kinases. Janus kinases, sometimes referred to as Jaks, Respiratory: Dyspnea, upper respiratory infection
due to the phosphorylation, recruit signal transducers Miscellaneous: Fever, postoperative wound compli-
and activators of transcription (STATs) which regulate cation
intracellular activity. Drugs, such as baricitinib, that 3% to 10%:
inhibit the activity of the Janus kinases block the Cardiovascular: Abnormal heart sounds, angina pec-
receptor activations. Unfortunately, one undesired toris, atrial fibrillation, cardiac arrhythmia, cardiac
result is suppression of immune responses, leading to failure, chest pain, hypotension, tachycardia, throm-
increased risk of infections. A US Boxed Warning bosis
reminds the clinician of the increased risk of serious Central nervous system: Agitation, anxiety, depres-
infections in patients receiving baricitinib. Infections can sion, dizziness, fatigue, hypoesthesia, malaise,
often develop in patients receiving concomitant immu- rigors
nosuppressive agents, such as corticosteroids or Dermatologic: Dermal ulcer, dermatological disease,
methotrexate. It is suggested to closely monitor patients hypertrichosis, pruritus, skin rash
for the development of signs/symptoms of infection Endocrine & metabolic: Acidosis, albuminuria, ana-
during and after baricitinib treatment. sarca, dehydration, diabetes mellitus, hypercalce-
mia, hyperlipidemia, hypertriglyceridemia,
hypervolemia, hypocalcemia, hypoglycemia, hypo-
Basiliximab (ba si LIK si mab)
magnesemia, hyponatremia, increased nonprotein
Brand Names: US Simulect nitrogen, increased serum glucocorticoids,
Brand Names: Canada Simulect weight gain
Gastrointestinal: Enlargement of abdomen, esophagi-
Pharmacologic Category Immunosuppressant
tis, flatulence, gastroenteritis, gastrointestinal hem-
Agent; Monoclonal Antibody
orrhage, GI moniliasis, gingival hyperplasia, hernia,
Use melena, stomatitis (including ulcerative)
Renal transplant (prophylaxis of acute rejection):
Genitourinary: Bladder dysfunction, dysuria, genital
Prophylaxis of acute organ rejection in renal trans- edema (male), hematuria, impotence, oliguria, ure-
plantation in combination with cyclosporine (modified) teral disease, urinary frequency, urinary retention
and corticosteroids Hematologic & oncologic: Hematoma, hemorrhage,
Guideline recommendations: While basiliximab is FDA- hypoproteinemia, leukopenia, polycythemia, pur-
approved for prophylaxis of acute organ rejection in pura, thrombocytopenia
renal transplantation in combination with cyclosporine Infection: Cytomegalovirus disease, herpes virus
(modified) and corticosteroids, cyclosporine is no lon- infection (simplex and zoster), infection, sepsis
ger recommended as the first line agent of choice. The Neuromuscular & skeletal: Arthralgia, arthropathy,
Kidney Disease: Improving Global Outcomes (KDIGO) back pain, bone fracture, leg pain, muscle cramps,
clinical practice guidelines for care of kidney trans- myalgia, neuropathy, paresthesia, weakness
plant recipients recommend induction as part of the Ophthalmic: Cataract, conjunctivitis, visual dis-
initial immunosuppressive regimen for all kidney trans- turbance
plants to reduce the risk of acute rejection. KDIGO Renal: Renal insufficiency, renal tubular necrosis
recommends an interleukin 2 receptor antagonist (eg, Respiratory: Bronchitis, bronchospasm, cough, phar-
basiliximab) as the first line induction agent for acute yngitis, pneumonia, pulmonary edema, rhinitis,
rejection prophylaxis except in those patients at high sinusitis
immunologic risk. (KDIGO [Kasiske 2009]). Miscellaneous: Accidental injury, cyst
Local Anesthetic/Vasoconstrictor Precautions <1%, postmarketing, and/or case reports: Anaphylaxis,
No information available to require special precautions capillary leak syndrome, cytokine release syndrome,
Effects on Dental Treatment Key adverse event(s) diabetes (new onset), hypersensitivity reaction
related to dental treatment: Facial edema and ulcerative (includes bronchospasm, cardiac failure, dyspnea,
stomatitis. Causes gingival hypertrophy (GH) similar to hypotension, pruritus, pulmonary edema, respiratory
that caused by cyclosporine; early reports indicate that failure, skin rash, sneezing, tachycardia, urticaria),
frequency/incidence of basiliximab-induced GH not as impaired glucose tolerance, increase in fasting plasma
high as cyclosporine-induced GH. glucose, lymphoproliferative disorder
193
BASILIXIMAB
Mechanism of Action Basiliximab is a chimeric (mur-

ine/human) immunosuppressant monoclonal antibody Beclomethasone (Nasal) (be kloe METH a sone)
which blocks the alpha-chain of the interleukin-2 (IL-2)
receptor complex; this receptor is expressed on acti- Brand Names: US Beconase AQ; Qnasl; Qnasl Child-
vated T lymphocytes and is a critical pathway for rens
activating cell-mediated allograft rejection Brand Names: Canada Apo-Beclomethasone; Mylan-
Pharmacodynamics/Kinetics Beclo AQ; Rivanase AQ
Duration of Action Mean: 36 ± 14 days (determined Pharmacologic Category Corticosteroid, Nasal
by IL-2R alpha saturation in patients also on cyclo- Use
sporine and corticosteroids) Nasal polyps Beconase AQ only: Prevention of recur-
Half-life Elimination Children 1 to 11 years: 9.5 ± 4.5 rence of nasal polyps following surgical removal
days; Adolescents 12 to 16 years: 9.1 ± 3.9 days; Rhinitis:
Adults: Mean: 7.2 ± 3.2 days Beconase AQ: Relief of symptoms of seasonal or
Pregnancy Considerations perennial allergic rhinitis and nonallergic (vasomotor)
Adverse effects were not observed in animal reproduc- rhinitis
Qnasl: Treatment of the nasal symptoms associated
tion studies. Basiliximab is a monoclonal IgG antibody
with seasonal or perennial allergic rhinitis in patients
which targets IL-2 receptors. IgG is known to cross the
4 years and older.
placenta; IL-2 receptors play an important role in the
development of the immune system. Local Anesthetic/Vasoconstrictor Precautions
Women of childbearing potential should use effective Effects on Dental Treatment No significant effects or
contraceptive measures before beginning treatment, complications reported
during, and for 4 months after completion of basiliximab Effects on Bleeding No information available to
treatment. require special precautions
The Transplant Pregnancy Registry International (TPR) Adverse Reactions Frequency not always defined.
is a registry that follows pregnancies that occur in >10%: Respiratory: Nasopharyngitis (≤24%; children:
maternal transplant recipients or those fathered by male 2%), epistaxis (2% to 11%)
transplant recipients. The TPR encourages reporting of 1% to 10%:
pregnancies following solid organ transplant by contact- Central nervous system: Dizziness (≤5%), head-
ache (≤5%)
ing them at 1-877-955-6877 or https://www.-
Endocrine & metabolic: Adrenal suppression (at high
transplantpregnancyregistry.org.
doses or in susceptible individuals), hypercorticoid-
ism (at high doses or in susceptible individuals)
Becaplermin (be KAP ler min) Gastrointestinal: Nausea (≤5%), oral candidiasis (rare;
more likely with aqueous solution)
Brand Names: US Regranex Immunologic: Immunosuppression
Pharmacologic Category Growth Factor, Platelet- Neuromuscular & skeletal: Decreased linear skeletal
Derived; Topical Skin Product growth rate
Use Diabetic ulcers: Adjunctive treatment of lower Ophthalmic: Intraocular pressure increased (5%), lac-
extremity diabetic neuropathic ulcers that extend into rimation (≤3%)
the subcutaneous tissue or beyond and have an Respiratory: Sneezing (4%), upper respiratory tract
adequate blood supply. infection (children: 3%), nasal congestion (≤3%),
rhinorrhea (≤3%), nasal mucosa irritation (erosion)
Limitations of use: Efficacy has not been established for
(≤1%), nasal candidiasis (rare; more likely with aque-
pressure and venous stasis ulcers; has not been
ous solution), pharyngeal candidiasis (rare; more
evaluated for diabetic neuropathic ulcers that do not
likely with aqueous solution)
extend through the dermis into subcutaneous tissue
Miscellaneous: Fever (children: 3%), wound healing
(stage I or II, International Association of Enterostomal
impairment
Therapy [IAET] staging classification) or ischemic
<1%, postmarketing, and/or case reports: Ageusia,
diabetic ulcers. altered sense of smell, anaphylactoid reaction, ana-
Local Anesthetic/Vasoconstrictor Precautions phylaxis, angioedema, anosmia, blurred vision, bron-
No information available to require special precautions chospasm, burning sensation, cataract, chorioretinitis,
Effects on Dental Treatment No significant effects or dry nose, glaucoma, hypersensitivity reaction, nasal
complications reported mucosa ulcer, nasal septum perforation, skin rash,
Effects on Bleeding No information available to unpleasant taste, urticaria, wheezing
require special precautions Mechanism of Action Controls the rate of protein
Adverse Reactions synthesis; depresses the migration of polymorphonu-
1% to 10%: Dermatologic: Erythematous rash (2%) clear leukocytes, fibroblasts; reverses capillary perme-
<1%, postmarketing, and/or case reports: Connective ability and lysosomal stabilization at the cellular level to
tissue disorder (excessive granulation tissue), dermal prevent or control inflammation
ulcer (with or without tunneling), erythema (with puru- Pharmacodynamics/Kinetics
lent discharge), local pain Onset of Action Within a few days up to 2 weeks
Mechanism of Action Recombinant B-isoform homo- Half-life Elimination BDP: 0.5 hours; 17-BMP: 2.7
dimer of human platelet-derived growth factor (rPDGF- hours
BB) which enhances formation of new granulation Pregnancy Considerations Intranasal corticosteroids
tissue, induces fibroblast proliferation and differentiation may be acceptable for the treatment of rhinitis during
to promote wound healing; also promotes angiogene- pregnancy when used at recommended doses (Lal
sis. 2016; Wallace 2008). Pregnant females adequately
Pregnancy Considerations Animal reproduction controlled on beclomethasone may continue therapy;
studies have not been conducted. if initiating treatment during pregnancy, use of an agent
194
BECLOMETHASONE (ORAL INHALATION)
with more data in pregnant females and less systemic (early in the course of illness) in patients with mild
absorption may be preferred (Alhussien 2017; Namazy to moderate asthma with a mild flare in symptoms.
2016; Wallace 2008). Reserve this approach for patients with no prior
history of life-threatening asthma exacerbations,
and in those with good self-management skills;
Beclomethasone (Oral Inhalation) return to baseline dose after normalization of symp-
(be kloe METH a sone)
toms or at a maximum of 14 days of the quadrupled
Related Information dose (Fanta 2019; GINA 2018; McKeever 2018).
Respiratory Diseases on page 1467 US labeling: Metered-dose inhaler:
Brand Names: US Qvar RediHaler; Qvar [DSC] QVAR/QVAR RediHaler: Note: Dosing based on
Brand Names: Canada QVAR previous asthma therapy and asthma severity.
Generic Availability (US) No May increase dose after 2 weeks of therapy in
Pharmacologic Category Corticosteroid, Inhalant patients who are not adequately controlled.
(Oral) Patients not currently on inhaled corticosteroids:
Initial: 40 to 80 mcg twice daily; maximum dose:
Use
320 mcg twice daily
Asthma: Maintenance and prophylactic treatment of
Patients previously on inhaled corticosteroids: Ini-
asthma in patients ≥5 years of age (QVAR) or ≥4
tial: 40 to 320 mcg twice daily; maximum dose:
years of age (QVAR RediHaler).
320 mcg twice daily
Limitations of use: Not for relief of acute bronchospasm.
Canadian labeling: Metered-dose inhaler:
Guideline recommendations: A low-dose inhaled cor-
Mild asthma: 50 to 100 mcg twice daily; maximum
ticosteroid (in addition to an as-needed short acting
dose: 100 mcg twice daily
beta2-agonist) is the initial preferred long-term control
Moderate asthma: 100 to 250 mcg twice daily;
medication for children, adolescents, and adult
maximum dose: 250 mcg twice daily
patients with persistent asthma who are candidates
Severe asthma: 300 to 400 mcg twice daily; max-
for treatment according to a step-wise treatment
imum dose: 400 mcg twice daily
approach (GINA 2018; NAEPP 2007).
Asthma Guidelines:
Local Anesthetic/Vasoconstrictor Precautions National Asthma Education and Prevention Pro-
gram guidelines (NAEPP 2007): Metered-dose
Effects on Dental Treatment Key adverse event(s) inhaler:
related to dental treatment: Oral candidiasis, xerosto- Low-dose therapy: 80 to 240 mcg/day
mia (normal salivary flow resumes upon discontinua- Medium-dose therapy: >240 to 480 mcg/day
tion), nasal dryness, and dry throat. Localized infections High-dose therapy: >480 mcg/day
with Candida albicans or Aspergillus niger occur fre- Global Initiative for Asthma guidelines (GINA 2018):
quently in the mouth and pharynx with repetitive use of Metered-dose inhaler:
an oral inhaler; may require treatment with appropriate Low-dose therapy: 100 to 200 mcg/day
antifungal therapy or discontinuance of inhaler use. Medium-dose therapy: >200 to 400 mcg/day
Effects on Bleeding No information available to High-dose therapy: >400 mcg/day
Adverse Reactions Chronic obstructive pulmonary disease (stable)
>10%: (off-label use): Oral inhalation: 50 to 400 mcg daily
Central nervous system: Headache (1% to 25%) in combination with a long-acting bronchodilator
Respiratory: Pharyngitis (3% to 27%) (GOLD 2014; GOLD 2018).
1% to 10%: Renal Impairment: Adult There are no dosage
Central nervous system: Pain (1% to 5%), voice adjustments provided in the manufacturer's labeling
disorder (4%) (has not been studied).
Gastrointestinal: Oral candidiasis (1% to 8%), vomiting Hepatic Impairment: Adult There are no dosage
(children: 3%), diarrhea (children: 1% to 3%), nausea adjustments provided in the manufacturer's labeling
(1% to 3%) (has not been studied).
Genitourinary: Dysmenorrhea (1% to 3%), viral gastro- Pediatric Note: Doses should be titrated to the lowest
enteritis (children: 1% to 3%) effective dose once asthma is controlled:
Infection: Influenza (children: 1% to 3%) Asthma, maintenance therapy: Inhalation, oral:
Neuromuscular & skeletal: Back pain (1% to 4%), Manufacturer's labeling (Qvar):
myalgia (children: 1% to 3%) Children 5 to 11 years: Initial: 40 mcg twice daily;
Otic: Otitis (children: 1% to 3%) maximum dose: 80 mcg twice daily
Respiratory: Nasopharyngitis (2% to 9%), upper res- Children ≥12 years and Adolescents:
piratory tract infection (3% to 8%), cough (1% to 7%), No previous inhaled corticosteroids: Initial: 40 to
viral upper respiratory tract infection (2% to 4%), 80 mcg twice daily; maximum dose: 320 mcg
oropharyngeal pain (1% to 4%), sinusitis (3%), aller- twice daily
gic rhinitis (≤3%) Previous inhaled corticosteroid use: Initial: 40 to
Miscellaneous: Fever (children: 3%) 160 mcg twice daily; maximum dose: 320 mcg
<1%, postmarketing, and/or case reports: Aggressive twice daily
behavior, blurred vision, depression, dysgeusia (Tuc- Note: Therapeutic ratio between Qvar and other
cori 2011), psychomotor agitation, retinopathy, sleep beclomethasone inhalers (eg, CFC formulations;
disorder, suicidal ideation however, none are currently available in US) has
Dosing not been established.
Adult & Geriatric Note: Titrate to the lowest effective Alternate dosing: NIH Asthma Guidelines (NAEPP
dose once asthma is controlled. 2007): HFA formulation (Qvar):
Asthma: Oral inhalation: Note: To decrease the Children 5 to 11 years: Administer in divided doses:
severity or duration of an asthma exacerbation, "Low" dose: 80 to 160 mcg/day (40 mcg/puff: 2 to
may consider temporarily quadrupling the dose 4 puffs/day or 80 mcg/puff: 1 to 2 puffs/day)
195
BECLOMETHASONE (ORAL INHALATION)
"Medium" dose: >160 to 320 mcg/day (40 mcg/ inhaled products due to possible adrenal insufficiency
puff: 4 to 8 puffs/day or 80 mcg/puff: 2 to 4 or withdrawal from steroids, including an increase in
puffs/day) allergic symptoms. Adult patients receiving ≥20 mg per
"High" dose: >320 mcg/day (40 mcg/puff: >8 puffs/ day of prednisone (or equivalent) may be most suscep-
day or 80 mcg/puff: >4 puff/day) tible. Fatalities have occurred due to adrenal insuffi-
Children ≥12 years and Adolescents: ciency in asthmatic patients during and after transfer
"Low" dose: 80 to 240 mcg/day (40 mcg/puff: 2 to from systemic corticosteroids to aerosol steroids; aero-
6 puffs/day or 80 mcg/puff: 1 to 3 puffs/day) sol steroids do not provide the systemic steroid needed
"Medium" dose: >240 to 480 mcg/day (40 mcg/ to treat patients having trauma, surgery, or infections
puff: 6 to 12 puffs/day or 80 mcg/puff: 3 to 6 (particularly gastroenteritis), or other conditions with
puffs/day) severe electrolyte loss. Select surgical patients on
"High" dose: >480 mcg/day (40 mcg/puff: >12 long-term, high-dose, inhaled corticosteroid should be
puffs/day or 80 mcg/puff: 6 puffs/day) given stress doses of hydrocortisone intravenously dur-
Canadian labeling: Metered-dose inhaler: ing the surgical period and the dose reduced rapidly
Children 5 to 11 years: Initial: 50 mcg twice daily; within 24 hours after surgery (NAEPP 2007).
maximum dose: 100 mcg twice daily Paradoxical bronchospasm that may be life-threatening
Children ≥12 years of age and Adolescents: may occur with use of inhaled bronchodilating agents;
Mild asthma: 50 to 100 mcg twice daily; maximum reaction should be distinguished from inadequate
dose: 100 mcg twice daily response. If paradoxical bronchospasm occurs, discon-
Moderate asthma: 100 to 250 mcg twice daily; tinue beclomethasone and institute alternative therapy.
maximum dose: 250 mcg twice daily Supplemental steroids (oral or parenteral) may be
Severe asthma: 300 to 400 mcg twice daily; needed during stress or severe asthma attacks. Short-
maximum dose: 400 mcg twice daily acting beta-2 agonist (eg, albuterol) should be used for
Conversion from oral systemic corticosteroid to orally acute symptoms and symptoms occurring between
inhaled corticosteroid: Initiation of oral inhalation treatments. Use is contraindicated in status asthmaticus
therapy should begin in patients whose asthma is or during other acute asthma episodes requiring inten-
reasonably stabilized on oral corticosteroids (OCS). sive measures. Hypersensitivity reactions (eg, angioe-
A gradual dose reduction of OCS should begin ~7 dema, bronchospasm, rash, and urticaria) may occur;
days after starting inhaled therapy. US labeling discontinue use if reaction occurs. Prolonged use of
recommends reducing prednisone dose no more corticosteroids may increase the incidence of secon-
rapidly than ≤2.5 mg/day (or equivalent of other dary infection, mask acute infection (including fungal
OCS) every 1 to 2 weeks in adolescents or adults. infections), prolong or exacerbate viral infections, or
If adrenal insufficiency occurs, temporarily increase limit response to vaccines. Avoid use, if possible, in
the OCS dose and follow with a more gradual patients with ocular herpes, active or quiescent respi-
withdrawal. Note: When transitioning from systemic ratory or untreated viral, fungal, parasitic or bacterial
to inhaled corticosteroids, supplemental systemic systemic infections. Exposure to chickenpox and mea-
corticosteroid therapy may be necessary during sles should be avoided; if the patient is exposed,
periods of stress or during severe asthma attacks. prophylaxis with varicella zoster immune globulin or
Renal Impairment: Pediatric There are no dosage pooled intramuscular immunoglobulin, respectively,
adjustments provided in the manufacturer's labeling. may be indicated; if chickenpox develops, treatment
Hepatic Impairment: Pediatric There are no dos- with antiviral agents may be considered. Local orophar-
age adjustments provided in the manufacturer's label- yngeal Candida albicans infections have been reported;
ing. if this occurs, treat appropriately while continuing ther-
Mechanism of Action Controls the rate of protein apy. Patients should be instructed to rinse mouth with
synthesis; depresses the migration of polymorphonu- water without swallowing after each use.
clear leukocytes, fibroblasts; reverses capillary perme- Use with caution in patients with major risk factors for
ability and lysosomal stabilization at the cellular level to decreased bone mineral count. Use with caution in
prevent or control inflammation patients with cataracts and/or glaucoma; blurred vision,
Contraindications increased intraocular pressure, glaucoma, and cata-
Hypersensitivity to beclomethasone or any component racts have occurred with prolonged use. Consider
of the formulation; status asthmaticus, or other acute routine eye exams in chronic users. Because of the risk
asthma episodes requiring intensive measures of adverse effects, systemic corticosteroids should be
Documentation of allergenic cross-reactivity for cortico- used cautiously in elderly patients in the smallest
steroids is limited. However, because of similarities in possible effective dose for the shortest duration.
chemical structure and/or pharmacologic actions, the
possibility of cross-sensitivity cannot be ruled out with Orally inhaled corticosteroids may cause a reduction in
certainty. growth velocity in pediatric patients (~1 centimeter per
year [range: 0.3 to 1.8 cm per year] and related to dose
Canadian labeling: Additional contraindications (not in and duration of exposure). To minimize the systemic
US labeling): Moderate to severe bronchiectasis effects of orally inhaled corticosteroids, each patient
requiring intensive measures; untreated fungal, bacte- should be titrated to the lowest effective dose. Growth
rial, or tubercular infections of the respiratory tract should be routinely monitored in pediatric patients. A
Warnings/Precautions May cause hypercortisolism or gradual tapering of dose may be required prior to
suppression of hypothalamic-pituitary-adrenal (HPA) discontinuing therapy; there have been reports of sys-
axis, particularly in younger children or in patients temic corticosteroid withdrawal symptoms (eg, joint/
receiving high doses for prolonged periods. HPA axis muscle pain, lassitude, depression) when withdrawing
suppression may lead to adrenal crisis. Withdrawal and oral inhalation therapy. When transferring to oral inha-
discontinuation of a corticosteroid should be done lation therapy from systemic corticosteroid therapy,
slowly and carefully. Particular care is required when previously suppressed allergic conditions (rhinitis, con-
patients are transferred from systemic corticosteroids to junctivitis, eczema, arthritis, and eosinophilic
196
BELATACEPT
conditions) may be unmasked. Withdraw systemic cor- Inhaled corticosteroids are recommended for the treat-
ticosteroid therapy by gradually tapering the dose. ment of asthma during pregnancy (ACOG 2008; GINA
Monitor lung function, beta-agonist use, asthma symp- 2018; Namazy 2016). Pregnant females adequately
toms, and for signs and symptoms of adrenal insuffi- controlled on beclomethasone for asthma may continue
ciency (eg, fatigue, lassitude, weakness, nausea/ therapy; if initiating treatment during pregnancy, use of
vomiting, hypotension) during withdrawal. an agent with more data in pregnant females may be
preferred (Namazy 2016).
Potentially significant drug-drug interactions may exist,
Breastfeeding Considerations It is not known if
requiring dose or frequency adjustment, additional mon-
beclomethasone is present in breast milk following oral
inhalation; however, other corticosteroids are present in
Warnings: Additional Pediatric Considerations breast milk. According to the manufacturer, the decision
Reduction in growth velocity may occur when cortico- to continue or discontinue breastfeeding during therapy
steroids are administered to pediatric patients, even at should take into account the risk of infant exposure, the
recommended doses via inhaled route; reduction in benefits of breastfeeding to the infant, and benefits of
growth velocity is related to dose and duration of treatment to the mother.
exposure; monitor growth. With beclomethasone-HFA
(Qvar), the mean reduction in growth velocity was 0.5 The use of inhaled corticosteroids is not considered a
cm/year less than that with the previous beclometha- contraindication to breastfeeding (ACOG 2008).
sone CFC inhaler formulation. Use of Qvar with a Females with asthma should be encouraged to breast-
spacer device is not recommended in children <5 years feed (GINA 2018).
of age due to the decreased amount of medication that Dosage Forms Considerations QVAR 8.7 g canis-
is delivered with increasing wait times; patients should ters contain 120 inhalations.
be instructed to inhale immediately if using a spacer Dosage Forms: US
device. Aerosol Breath Activated, Inhalation:
Drug Interactions Qvar RediHaler: 40 mcg/actuation (10.6 g); 80 mcg/
Metabolism/Transport Effects None known. actuation (10.6 g)
Avoid Concomitant Use Dosage Forms: Canada
Avoid concomitant use of Beclomethasone (Oral Inha- Aerosol, for oral inhalation:
lation) with any of the following: Aldesleukin; BCG QVAR: 50 mcg/inhalation (6.5 g, 12.4 g); 100 mcg/
(Intravesical); Cladribine; Desmopressin; Loxapine; inhalation (6.5 g, 12.4 g)
Natalizumab; Pimecrolimus; Tacrolimus (Topical)
Increased Effect/Toxicity Belatacept (bel AT a sept)
Beclomethasone (Oral Inhalation) may increase the
levels/effects of: Amphotericin B; Baricitinib; Defera- Brand Names: US Nulojix
sirox; Desmopressin; Fingolimod; Leflunomide; Loop Pharmacologic Category Selective T-Cell Costimula-
Diuretics; Loxapine; Natalizumab; Ritodrine; Siponi- tion Blocker
mod; Thiazide and Thiazide-Like Diuretics; Tofacitinib Use
The levels/effects of Beclomethasone (Oral Inhalation) Kidney transplant (de novo use): Prophylaxis of
may be increased by: Cladribine; Denosumab; Ocre- organ rejection concomitantly with basiliximab induc-
lizumab; Pimecrolimus; Tacrolimus (Topical); Trastu- tion, mycophenolate, and corticosteroids in adult
zumab Epstein-Barr virus (EBV) seropositive kidney trans-
Decreased Effect plant recipients
Beclomethasone (Oral Inhalation) may decrease the Limitations of use: Use only in EBV seropositive
levels/effects of: Aldesleukin; BCG (Intravesical); Coc- patients; use for prophylaxis of organ rejection in
cidioides immitis Skin Test; Corticorelin; Cosyntropin; transplanted organs other than the kidney has not
Hyaluronidase; Nivolumab; Pidotimod; Sipuleucel-T; been established.
Tertomotide; Vaccines (Inactivated) Local Anesthetic/Vasoconstrictor Precautions
The levels/effects of Beclomethasone (Oral Inhalation) Effects on Dental Treatment Key adverse event(s)
may be decreased by: Echinacea; Tobacco (Smoked) related to dental treatment: Stomatitis has been
Pharmacodynamics/Kinetics reported
Onset of Action Within 1 to 2 days in some patients; Effects on Bleeding No information available to
usually within 1 to 2 weeks; Maximum effect: 3 to 4 require special precautions
weeks Adverse Reactions Incidences reported as part of a
Half-life Elimination combination therapy regimen.
QVAR: BDP: 0.5 hours; 17-BMP: 2.8 hours >10%:
RediHaler: BDP: 2 minutes; 17-BMP: 4 hours Cardiovascular: Peripheral edema (34%), hyperten-
Time to Peak sion (32%), hypotension (18%)
Plasma: Inhalation: Central nervous system: Headache (21%), insom-
QVAR: BDP: 0.5 hours; 17-BMP: 0.7 hours nia (15%)
RediHaler: BDP: 2 minutes; 17-BMP: 10 minutes Endocrine & metabolic: Hypokalemia (21%), hyper-
Pregnancy Considerations Uncontrolled asthma is kalemia (20%), hypophosphatemia (19%), lipid
associated with adverse events on pregnancy metabolism disorder (19%), hyperglycemia (16%),
(increased risk of perinatal mortality, preeclampsia, hypocalcemia (13%), hypercholesterolemia (11%)
preterm birth, low birth weight infants). Poorly controlled Gastrointestinal: Diarrhea (39%), constipation (33%),
asthma or asthma exacerbations may have a greater na us ea (24 %), vo mi tin g (2 2% ), ab do mi na l
fetal/maternal risk than what is associated with appro- pain (19%)
priately used asthma medications (ACOG 2008; GINA Genitourinary: Urinary tract infection (37%), dysu-
2018). ria (11%)
197
BELATACEPT
Hematologic & oncologic: Anemia (45%), leukope- maternal transplant recipients or those fathered by male
nia (20%) transplant recipients. The TPR encourages reporting of
Infection: Infection (72% to 82%, serious infection pregnancies following solid organ transplant by contact-
24% to 36%), fungal infection (18%), herpes virus i n g t h e m a t 1 - 8 7 7 - 9 5 5 - 6 8 7 7 o r w w w. -
infection (7% to 14%), cytomegalovirus disease transplantpregnancyregistry.org.
(11% to 13%), influenza (11%) Prescribing and Access Restrictions
Neuromuscular & skeletal: Arthralgia (17%), back Patients (new and existing) must be registered in the
pain (13%) Nulojix Distribution Program. Additional information is
Renal: Proteinuria (16%; up to 33% 2+ proteinuria at 1 available by calling (855) 511-6180 or at http://www.-
month post-transplant), graft complications (renal: nulojixhcp.bmscustomerconnect.com/index.
25%), hematuria (16%), increased serum creati-
nine (15%)
Respiratory: Cough (24%), upper respiratory tract Belimumab (be LIM yoo mab)
infection (15%), nasopharyngitis (13%), dysp-
nea (12%) Brand Names: US Benlysta
Miscellaneous: Fever (28%) Brand Names: Canada Benlysta
1% to 10%: Pharmacologic Category Monoclonal Antibody
Cardiovascular: Arteriovenous fistula site complication Use
(thrombosis, <10%), atrial fibrillation (<10%) Systemic lupus erythematosus: Treatment of adult
Central nervous system: Anxiety (10%), Guillain-Barré patients with active, autoantibody-positive systemic
syndrome (<10%), dizziness (9%) lupus erythematosus (SLE) who are receiving stand-
Dermatologic: Alopecia (<10%), hyperhidrosis ard therapy.
(<10%), acne vulgaris (8%) Limitations of use: Use is not recommended in patients
Endocrine & metabolic: Diabetes mellitus (new onset, with severe active lupus nephritis, severe active CNS
5% to 8%), hypomagnesemia (7%), hyperurice- lupus, or in combination with other biologics, including
mia (5%) B-cell targeted therapies or intravenous (IV) cyclo-
Gastrointestinal: Stomatitis (<10%; including aphthous phosphamide.
stomatitis), upper abdominal pain (9%) Local Anesthetic/Vasoconstrictor Precautions
Genitourinary: Urinary incontinence (<10%) No information available to require special precautions
Hematologic & oncologic: Hematoma (<10%), lym- Effects on Dental Treatment No significant effects or
phocele (<10%), neutropenia (<10%), malignant complications reported
neoplasm (4%), malignant neoplasm of skin (non-
melanoma, 2%)
Immunologic: Antibody development (2%)
Infection: Polyoma virus infection (3% to 4%) Adverse Reactions
Neuromuscular & skeletal: Musculoskeletal pain >10%:
(<10%), tremor (8%) Gastrointestinal: Nausea (15%), diarrhea (12%)
Renal: Acute renal failure (<10%), hydronephrosis Hypersensitivity: Hypersensitivity (13%)
(<10%), kidney transplant dysfunction (chronic allog- Miscellaneous: Infusion related reaction (17%)
raft nephropathy: <10%), renal disease (renal artery ≥3% to 10%:
stenosis: <10%), renal insufficiency (<10%), renal Central nervous system: Insomnia (6% to 7%),
tubular necrosis (9%) depression (5% to 6%), migraine (5%), anxiety
Respiratory: Bronchitis (10%), tuberculosis (1% to 2%) (4%), headache (≥3%)
Miscellaneous: Infusion related reaction (5%) Dermatologic: Dermatological reaction (≥3%)
<1%, postmarketing, and/or case reports: Anaphylaxis, Gastrointestinal: Viral gastroenteritis (3%)
aspergillosis (cerebral; higher dosing regimen), ence- Genitourinary: Urinary tract infection (site not specified
phalitis (Chagas, West Nile; higher dosing regimen), >5%), cystitis (4%)
graft rejection (renal), lymphoproliferative disorder Hematologic & oncologic: Leukopenia (4%)
(post transplant; incidence is 9-fold higher in non- Infection: Influenza (>5%)
EBV seropositive patients), meningitis (cryptococcal), Local: Injection site reaction (6%; including erythema
nephropathy (polyoma virus-associated mainly BK), at injection site, hematoma at injection site, indu-
progressive multifocal leukoencephalopathy (higher ration at injection site, injection site pruritus, pain at
dosing regimen) injection site)
Mechanism of Action Fusion protein which acts as a Neuromuscular & skeletal: Limb pain (6%)
selective T-cell (lymphocyte) costimulation blocker by Respiratory: Bronchitis (9%), nasopharyngitis (9%),
binding to CD80 and CD86 receptors on antigen pre- sinusitis (>5%), upper respiratory tract infection
senting cells (APC), blocking the required CD28 medi- (>5%), pharyngitis (5%)
ated interaction between APCs and T cells needed to Miscellaneous: Fever (10%)
activate T lymphocytes. T-cell stimulation results in <3%, postmarketing, and/or case reports: Anaphylaxis,
cytokine production and proliferation, mediators in angioedema, antibody development, bradycardia, cel-
immunologic rejection associated with kidney transplan- lulitis, dyspnea, eyelid edema, hypotension, myalgia,
tation. pneumonia, progressive multifocal leukoencephalop-
Pharmacodynamics/Kinetics athy (immune compromised), pruritus, skin rash, sui-
Half-life Elimination ~10 days (healthy patients and cidal tendencies, urticaria
kidney transplant patients)
Mechanism of Action Belimumab is an IgG1-lambda
Pregnancy Considerations monoclonal antibody that prevents the survival of B
lymphocytes by blocking the binding of soluble human
duction studies.
B lymphocyte stimulator protein (BLyS) to receptors on
The Transplant Pregnancy Registry International (TPR) B lymphocytes. This reduces the activity of B-cell medi-
is a registry that follows pregnancies that occur in ated immunity and the autoimmune response.
198
BENAZEPRIL
Pharmacodynamics/Kinetics grades 3/4: 1%), diarrhea (23%; grades 3/4: 2%),

Onset of Action B cells: 8 weeks; Clinical improve- decreased appetite (15%; grades 3/4: 2%), abdomi-
ment (SLE Responder Index and flare reduction): 16 nal pain (11%; grades 3/4: 1%)
weeks (Navarra 2011) Hematologic & oncologic: Anemia (32%; grades 3/4:
Half-life Elimination Terminal: IV: 19.4 days; SubQ: 11%), thrombocytopenia (16%; grades 3/4: 7%)
18.3 days Local: Pain at injection site (14%)
Time to Peak SubQ: 2.6 days Respiratory: Dyspnea (22%; grades 3/4: 6%),
Pregnancy Considerations cough (19%)
IgG molecules are known to cross the placenta (beli- Miscellaneous: Fever (35%; grades 3/4: 2%)
mumab is an engineered IgG molecule) with increasing 1% to 10%:
amounts as pregnancy progresses. Effective contra- Cardiovascular: Hypotension (10%; grades 3/4: 3%),
ception should be used during and for at least 4 months phlebitis (10%; grades 3/4: 1%)
following treatment in women of childbearing potential. Central nervous system: Dizziness (10%)
If exposure occurs during pregnancy, monitor the new- Infection: Infection (>2%)
born for B-cell reduction and other immune dysfunction Renal: Increased serum creatinine (>2%)
and consider risks and benefits prior to administering Respiratory: Pneumonia (>2%)
live vaccines. Miscellaneous: Multi-organ failure (>2%)
Healthcare providers are encouraged to enroll women <1%, postmarketing, and/or case reports: Abnormal
exposed to belimumab during pregnancy in a preg- hepatic function tests, febrile neutropenia, hepatic fail-
nancy registry (877-681-6296); patients may also enroll ure, hepatotoxicity, leukopenia, sepsis, tumor lysis
themselves. syndrome, ventricular fibrillation
Mechanism of Action Belinostat is a histone deace-
tylase (HDAC) inhibitor which catalyzes acetyl group
Belinostat (be LIN oh stat) removal from protein lysine residues (of histone and
Brand Names: US Beleodaq some nonhistone proteins). Inhibition of histone deace-
tylase results in accumulation of acetyl groups, leading
Pharmacologic Category Antineoplastic Agent, His-
to cell cycle arrest and apoptosis. Belinostat has pref-
tone Deacetylase (HDAC) Inhibitor
erential cytotoxicity toward tumor cells versus normal
Use Peripheral T-cell lymphoma, relapsed or refrac-
cells.
tory: Treatment of relapsed or refractory peripheral T-
cell lymphoma (PTCL).
Half-life Elimination 1.1 hours
Belinostat is one of the drugs confirmed to prolong the Time to Peak At end of infusion (Steele 2011)
QT interval and is accepted as having a risk of causing Pregnancy Risk Factor D
torsade de pointes. The risk of drug-induced torsade de Pregnancy Considerations Animal reproduction
pointes is extremely low when a single QT interval studies have not been conducted. Belinostat is a gen-
prolonging drug is prescribed. In terms of epinephrine, otoxic drug that targets dividing cells; embryofetal tox-
it is not known what effect vasoconstrictors in the local icity is expected if exposure occurs during pregnancy.
anesthetic regimen will have in patients with a known Based on animal data, belinostat may also impair male
history of congenital prolonged QT interval or in patients fertility. Women of reproductive potential should avoid
taking any medication that prolongs the QT interval. pregnancy during treatment with belinostat.
Until more information is obtained, it is suggested that Dental Health Professional Considerations This
the clinician consult with the physician prior to the use of drug is known to prolong the QT interval (see Local
a vasoconstrictor in suspected patients, and that the Anesthetic/Vasocontrictor Precautions)
vasoconstrictor (epinephrine, mepivacaine and levonor-
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used
with caution.
Benazepril (ben AY ze pril)
Effects on Dental Treatment Key adverse event(s) Related Information

related to dental treatment: Hypotension reported (10% Cardiovascular Diseases on page 1442
incidence); monitor patient for dizziness when arising
Brand Names: US Lotensin
from dental chair
Effects on Bleeding Chemotherapy may result in Brand Names: Canada Lotensin
significant myelosuppression, potentially including sig- Pharmacologic Category Angiotensin-Converting
nificant reduction in platelet counts (thrombocytopenia Enzyme (ACE) Inhibitor; Antihypertensive
grades 3/4: 7%) and altered hemostasis. In patients Use
who are under active treatment with these agents, Hypertension: Management of hypertension
medical consult is suggested. Guideline recommendations: The 2017 Guideline for
Adverse Reactions the Prevention, Detection, Evaluation, and Manage-
>10%: ment of High Blood Pressure in Adults recommends
Cardiovascular: Peripheral edema (20%), prolonged if monotherapy is warranted, in the absence of
Q-T interval on ECG (11%; grades 3/4: 4%) comorbidities (eg, cerebrovascular disease, chronic
Central nervous system: Fatigue (37%; grades 3/4: kidney disease, diabetes, heart failure, ischemic
5%), chills (16%; grades 3/4: 1%), headache (15%) heart disease, etc.), that thiazide-like diuretics or
Dermatologic: Skin rash (20%; grades 3/4: 1%), pru- dihydropyridine calcium channel blockers may be
ritus (16%; grades 3/4: 3%) preferred options due to improved cardiovascular
Endocrine & metabolic: Increased lactate dehydrogen- endpoints (eg, prevention of heart failure and stroke).
ase (16%; grades 3/4: 2%), hypokalemia (12%; ACE inhibitors and ARBs are also acceptable for
grades 3/4: 4%) monotherapy. Combination therapy may be required
Gastrointestinal: Nausea (42%; grades 3/4: 1%), vom- to achieve blood pressure goals and is initially pre-
iting (29%; grades 3/4: 1%), constipation (23%; ferred in patients at high risk (stage 2 hypertension or
199
BENAZEPRIL
atherosclerotic cardiovascular disease [ASCVD] risk hypoplasia, and death in the fetus/neonate. Teratogenic
≥10%) (ACC/AHA [Whelton 2017]). effects may occur following maternal use of an ACE
Local Anesthetic/Vasoconstrictor Precautions inhibitor during the first trimester, although this finding
No information available to require special precautions may be confounded by maternal disease. Because
Effects on Dental Treatment Key adverse event(s) adverse fetal events are well documented with expo-
related to dental treatment: Patients may experience sure later in pregnancy, ACE inhibitor use in pregnant
orthostatic hypotension as they stand up after treat- women is not recommended (Seely 2014; Weber 2014).
ment; especially if lying in dental chair for extended Infants exposed to an ACE inhibitor in utero should be
periods of time. Use caution with sudden changes in monitored for hyperkalemia, hypotension, and oliguria.
position during and after dental treatment. Oligohydramnios may not appear until after irreversible
fetal injury has occurred. Exchange transfusions or
An angiotensin-converting enzyme (ACE) Inhibitor dialysis may be required to reverse hypotension or
cough is a dry, hacking, nonproductive cough that can improve renal function, although data related to the
potentially interfere with longer dental procedures if effectiveness in neonates is limited.
patient has this side effect.
Effects on Bleeding No information available to Chronic maternal hypertension itself is also associated
require special precautions with adverse events in the fetus/infant and mother. ACE
Adverse Reactions inhibitors are not recommended for the treatment of
1% to 10%: uncomplicated hypertension in pregnancy (ACOG
Cardiovascular: Hypotension 2013) and they are specifically contraindicated for the
Central nervous system: Headache (6%), dizziness treatment of hypertension and chronic heart failure
(4%), drowsiness (2%), orthostatic dizziness (2%) during pregnancy by some guidelines (Regitz-Zagrosek
<1%, postmarketing, and/or case reports: Alopecia, 2011). In addition, ACE inhibitors should generally be
angioedema, anxiety, arthralgia, arthritis, asthma, avoided in women of reproductive age (ACOG 2013). If
bronchitis, constipation, decreased libido, dermatitis, treatment for hypertension or chronic heart failure in
diaphoresis, dyspnea, ECG changes, eosinophilia, pregnancy is needed, other agents should be used
fatigue, flushing, gastritis, hemolytic anemia, hyper- (ACOG 2013; Regitz-Zagrosek 2011).
sensitivity, hypertonia, hyponatremia, impotence,
increased liver enzymes, increased serum bilirubin, Bendamustine (ben da MUS teen)
increased serum glucose, increased uric acid, infec-
tion, insomnia, melena, myalgia, nausea, nervous- Brand Names: US Bendeka; Treanda
ness, pancreatitis, paresthesia, pemphigus, Brand Names: Canada Treanda
proteinuria, pruritus, sinusitis, skin photosensitivity, Pharmacologic Category Antineoplastic Agent, Alky-
skin rash, Stevens-Johnson syndrome, thrombocyto- lating Agent; Antineoplastic Agent, Alkylating Agent
penia, urinary frequency, urinary tract infection, vomit- (Nitrogen Mustard)
ing, weakness Use
Mechanism of Action Competitive inhibition of angio- Chronic lymphocytic leukemia: Treatment of chronic
tensin I being converted to angiotensin II, a potent lymphocytic leukemia (CLL)
vasoconstrictor, through the angiotensin I-converting Non-Hodgkin lymphoma: Treatment of indolent B-cell
enzyme (ACE) activity, with resultant lower levels of non-Hodgkin lymphoma (NHL) which has progressed
angiotensin II which causes an increase in plasma renin during or within 6 months of rituximab treatment or a
activity and a reduction in aldosterone secretion rituximab-containing regimen
Onset of Action
Reduction in plasma angiotensin-converting enzyme
(ACE) activity: Peak effect: 1 to 2 hours after 2 to
related to dental treatment: Stomatitis, xerostomia (nor-
20 mg dose (Nussberger 1987; Nussberger 1989)
mal salivary flow resumes upon discontinuation).
Reduction in blood pressure: Peak effect: Single dose:
2 to 4 hours; Continuous therapy: 2 weeks Effects on Bleeding Thrombocytopenia has been
(Fogari 1990) reported in 77% to 86% (grade 3/4: 11% to 25%) of
patients.
Duration of Action Reduction in plasma angiotensin-
converting enzyme (ACE) activity: >90% inhibition for Adverse Reactions
24 hours after 5 to 20 mg dose (Balfour 1991) >10%:
Half-life Elimination Benazeprilat: Effective: 10 to 11 Cardiovascular: Peripheral edema (13%)
hours; Terminal: Children: 5 hours, Adults: 22 hours Central nervous system: Fatigue (9% to 57%), head-
ache (21%), dizziness (14%), chills (6% to 14%),
Time to Peak
insomnia (13%)
Parent drug: 0.5 to 1 hour
Dermatologic: Skin rash (8% to 16%)
Active metabolite (benazeprilat): Fasting: 1 to 2 hours;
Endocrine & metabolic: Weight loss (7% to 18%),
Nonfasting: 2 to 4 hours
dehydration (14%)
Gastrointestinal: Nausea (20% to 75%), vomiting
[US Boxed Warning]: Drugs that act on the renin-
(16% to 40%), diarrhea (9% to 37%), constipation
angiotensin system can cause injury and death to
(29%), anorexia (23%), stomatitis (15%; grades 3/4:
the developing fetus. Discontinue as soon as pos-
<1%), abdominal pain (13%), decreased appetite
sible once pregnancy is detected.
(13%), dyspepsia (11%)
Benazepril crosses the placenta. Drugs that act on the Hematologic & oncologic: Lymphocytopenia (68% to
renin-angiotensin system are associated with oligohy- 99%; grades 3/4: 47% to 94%), bone marrow
dramnios. Oligohydramnios, due to decreased fetal depression (grades 3/4: 98%; nadir in week 3),
renal function, may lead to fetal lung hypoplasia and leukopenia (61% to 94%; grades 3/4: 28% to 56%),
skeletal malformations. Their use in pregnancy is also decreased hemoglobin (88% to 89%; grades 3/4:
associated with anuria, hypotension, renal failure, skull 11% to 13%), decreased neutrophils (75% to 86%;
200
BENRALIZUMAB
grades 3/4: 43% to 60%), thrombocytopenia (77% to Pharmacodynamics/Kinetics

86%; grades 3/4: 11% to 25%) Half-life Elimination Bendamustine: ~40 minutes;
Hepatic: Increased serum bilirubin (34%) M3: ~3 hours; M4: ~30 minutes
Neuromuscular & skeletal: Back pain (14%), asthenia Time to Peak At end of infusion
(8% to 11%) Pregnancy Risk Factor D
Respiratory: Cough (4% to 22%), dyspnea (16%) Pregnancy Considerations Adverse events were
Miscellaneous: Fever (24% to 34%) observed in animal reproduction studies. May cause
1% to 10%: fetal harm if administered during pregnancy. For women
Cardiovascular: Tachycardia (7%), chest pain (6%), and men of reproductive potential, effective contracep-
hypotension (6%), exacerbation of hyperten- tion should be used during and for 3 months after
sion (3%) treatment.
Central nervous system: Anxiety (8%), depression Product Availability Treanda liquid solution formula-
(6%), pain (6%) tion (45 mg/0.5 mL and 180 mg/2 mL) has been dis-
Dermatologic: Pruritus (5% to 6%), hyperhidrosis continued in the US for more than 1 year.
(5%), night sweats (5%), xeroderma (5%)
Endocrine & metabolic: Hypokalemia (9%), hyperur-
icemia (7%), hyperglycemia (grades 3/4: 3%), hypo- Benralizumab (ben ra LIZ ue mab)
calcemia (grades 3/4: 2%), hyponatremia (grades
Brand Names: US Fasenra
3/4: 2%)
Gastrointestinal: Gastroesophageal reflux disease
Brand Names: Canada Fasenra
(10%), xerostomia (9%), dysgeusia (7%), oral candi- Pharmacologic Category Interleukin-5 Receptor
diasis (6%), abdominal distention (5%), upper Antagonist; Monoclonal Antibody, Anti-Asthmatic
abdominal pain (5%) Use
Genitourinary: Urinary tract infection (10%) Asthma: Add-on maintenance treatment of severe
Hematologic & oncologic: Febrile neutropenia (grades asthma in adults and children ≥12 years of age with
3/4: 6%) an eosinophilic phenotype
Hepatic: Increased serum alanine aminotransferase Limitations of use: Not indicated for treatment of other
(grades 3/4: 3%), increased serum aspartate trans- eosinophilic conditions or for the relief of acute bron-
aminase (grades 3/4: 1%) chospasm or status asthmaticus
Hypersensitivity: Hypersensitivity reaction (5%) Local Anesthetic/Vasoconstrictor Precautions
Infection: Herpes zoster infection (10%), infection No information available to require special precautions
(6%), herpes simplex infection (3%) Effects on Dental Treatment Key adverse event(s)
Local: Infusion site pain (6%), catheter pain (5%) related to dental treatment: Pharyngitis has been
Neuromuscular & skeletal: Arthralgia (6%), limb pain reported.
(5%), ostealgia (5%) Effects on Bleeding No information available to
Renal: Increased serum creatinine (grades 3/4: 2%) require special precautions
Respiratory: Upper respiratory tract infection (10%), Adverse Reactions
sinusitis (9%), pharyngolaryngeal pain (8%), pneu- >10%: Immunologic: Antibody development (13%; neu-
monia (8%), nasopharyngitis (6% to 7%), nasal con- tralizing: 12%)
gestion (5%), wheezing (5%) 1% to 10%:
Frequency not defined: Central nervous system: Headache (8%)
Central nervous system: Drowsiness, malaise Respiratory: Pharyngitis (5%)
Dermatologic: Dermatitis, skin necrosis Miscellaneous: Fever (3%)
Gastrointestinal: Mucositis Frequency not defined: Hypersensitivity: Hypersensitiv-
Hematologic & oncologic: Hemolysis ity reaction
<1%, postmarketing, and/or case reports: Acute renal Mechanism of Action Benralizumab, a humanized
failure, anaphylactoid shock, anaphylaxis, atrial fibril- monoclonal antibody (IgG1, kappa), is an interleukin-5
lation, bronchogenic carcinoma, bullous rash, cardiac antagonist. IL-5 is the major cytokine responsible for the
failure, dermatological reaction (toxic), DRESS syn- growth and differentiation, recruitment, activation, and
drome, erythema, extravasation injury, hepatitis, hep- survival of eosinophils (a cell type associated with
atotoxicity, injection site reaction, myelodysplastic inflammation and an important component in the patho-
syndrome, myeloid leukemia (acute), myocardial genesis of asthma). Benralizumab, by inhibiting IL-5
infarction, neutropenic sepsis, palpitations, pancyto- signaling, reduces the production and survival of eosi-
penia, pneumonia due to Pneumocystis jirovecii, nophils; however, the mechanism of benralizumab
pneumonitis, pulmonary alveolar hemorrhage (with action in asthma has not been definitively established.
grade 3 thrombocytopenia), pulmonary fibrosis, reac- Pharmacodynamics/Kinetics
tivation of disease (including, but not limited to hep- Half-life Elimination 15 days
atitis B, cytomegalovirus, Mycobacterium tuberculosis, Pregnancy Considerations
herpes zoster), sepsis, septic shock, Stevens-John- Adverse events were not observed in animal reproduc-
son syndrome, toxic epidermal necrolysis, tumor lysis tion studies. IgG monoclonal antibodies, including ben-
syndrome ralizumab, are expected to cross the placenta with
Mechanism of Action Bendamustine is an alkylating higher concentrations in the third trimester.
agent (nitrogen mustard derivative) with a benzimida-
Uncontrolled asthma is associated with adverse events
zole ring (purine analog) which demonstrates only par-
on pregnancy (increased risk of preeclampsia, preterm
tial cross-resistance (in vitro) with other alkylating
birth, low birth weight infants). Asthma should be
agents. It leads to cell death via single and double
closely monitored in pregnant women.
strand DNA cross-linking. Bendamustine is active
against quiescent and dividing cells. The primary cyto- Data collection to monitor pregnancy and infant out-
toxic activity is due to bendamustine (as compared to comes following exposure to benralizumab is ongoing.
metabolites). Healthcare providers are encouraged to enroll exposed
201
BENRALIZUMAB
pregnant females in the MotherToBaby Pregnancy 2009). Antipyresis is produced from inhibition of the
Studies conducted by the Organization of Teratology hypothalamic heat-regulating center.
Information Specialists (OTIS) (877-311-8972 or http:// Pregnancy Considerations
mothertobaby.org). Patients may also enroll them- [US Boxed Warning]: Prolonged use of opioids
selves. during pregnancy can cause neonatal withdrawal
syndrome, which may be life-threatening if not
recognized and treated according to protocols
Benzhydrocodone and developed by neonatology experts. If opioid use is
Acetaminophen required for a prolonged period in a pregnant
(benz hye droe KOE done & a seet a MIN oh fen) woman, advise the patient of the risk of neonatal
opioid withdrawal syndrome and ensure that appro-
Brand Names: US Apadaz
priate treatment will be available.
Pharmacologic Category Analgesic Combination
(Opioid); Analgesic, Opioid Also refer to the individual Acetaminophen and Hydro-
Use codone monographs.
Pain management: Short-term (≤14 days) manage- Product Availability Apadaz: FDA approved February
ment of acute pain severe enough to require an opioid 2018; anticipated availability unknown
analgesic and for which alternative treatments are Controlled Substance C-II
inadequate.
Limitations of use: Reserve for use in patients for whom Benzocaine (BEN zoe kane)
alternative treatment options (eg, nonopioid analge-
sics) are ineffective, not tolerated, or would be other- Related Information
wise inadequate to provide sufficient management Oral Pain on page 1520
of pain. Related Sample Prescriptions
Local Anesthetic/Vasoconstrictor Precautions Ulcerative and Erosive Disorders - Sample Prescrip-
No information available to require special precautions tions on page 47
Effects on Dental Treatment No significant effects or Brand Names: US Aftertest Topical Pain Relief [OTC];
complications reported Anacaine; Anbesol Cold Sore Therapy [OTC] [DSC];
Effects on Bleeding As a single agent, acetamino- Anbesol JR [OTC] [DSC]; Anbesol Maximum Strength
phen does not appear to affect bleeding or platelet [OTC]; Anbesol [OTC]; Baby Anbesol [OTC]; Benz-O-
aggregation. Acetaminophen may prolong the INR Sthetic [OTC]; Bi-Zets/Benzotroches [OTC]; Blistex
and increase bleeding in patients taking warfarin (Cou- Medicated [OTC]; Cepacol INSTAMAX [OTC]; Chig-
madin). For patients taking warfarin, single acetamino- gerex [OTC] [DSC]; Chiggertox [OTC] [DSC]; Dent-O-
phen doses or acetaminophen therapy of short duration Kain/20 [OTC]; Dentapaine [OTC]; Dermoplast [OTC]
should be safe, but if large (>1.3 g/day) doses are [DSC]; Foille [OTC]; HurriCaine One [OTC]; Hurricaine
administered for longer than 10 to 14 days, then the [OTC]; HurriPak Starter Kit [OTC]; Ivy-Rid [OTC]; Kank-
INR should be monitored. A Mouth Pain [OTC]; Ora-film [OTC]; Pinnacaine Otic
Adverse Reactions Also see acetaminophen and [DSC]; Sore Throat Relief [OTC] [DSC]; Topex Topical
hydrocodone. Anesthetic; Trocaine Throat [OTC] [DSC]; Zilactin Baby
>10%: [OTC]
Central nervous system: Drowsiness (19%) Brand Names: Canada Anbesol® Baby; Zilactin
Dermatologic: Pruritus (12%) Baby®; Zilactin-B®
Gastrointestinal: Nausea (22%), vomiting (13%), con- Generic Availability (US) May be product dependent
stipation (12%) Pharmacologic Category Analgesic, Topical; Local
1% to 10%: Anesthetic
Cardiovascular: Hypotension (1% to 5%), presyncope Dental Use Ester-type topical local anesthetic for tem-
(1% to 5%) porary relief of pain associated with toothache, minor
Central nervous system: Dizziness (8%), head- sore throat pain, and canker sore
ache (6%) Use Note: Approved ages and uses for products may
Endocrine & metabolic: Hot flash (1% to 5%) vary; consult product labeling for specific information:
Gastrointestinal: Abdominal distention (1% to 5%), Topical, external:
Dermal irritation: Ointment 5%, spray 5% and 20%:
abdominal pain (1% to 5%), flatulence (1% to 5%)
Temporary relief of pain and itching associated with
Neuromuscular & skeletal: Tremor (1% to 5%), weak-
minor skin irritations, cuts, scrapes, minor burns,
ness (1% to 5%)
sunburn, and insect bites; prevention of infection in
Respiratory: Dyspnea (1% to 5%)
minor cuts, scrapes and burns
<1%, postmarketing, and/or case reports: Agitation,
Poison ivy/sumac: Spray 5% (Ivy-Rid only): Tempo-
chest discomfort, diarrhea, euphoria, eye pruritus, rary relief of pain and itching associated with poison
gastroesophageal reflux disease, hematemesis, hypo- ivy/oak/sumac
esthesia, nightmares, rhinitis, syncope Topical, oral:
Mechanism of Action Mouth and gum irritation:
Benzhydrocodone: Prodrug of hydrocodone; binds to Ointment 20%: Temporary relief of pain associated
opiate receptors in the CNS, altering the perception of with fever blisters and cold sores.
and response to pain; suppresses cough in medullary Gel 10% and 20%, lozenge, spray 5%, liquid 10%
center; produces generalized CNS depression. and 20%: Temporary relief of pain associated with
Acetaminophen: Although not fully elucidated, the anal- toothache, sore gums, sore throat, canker sores,
gesic effects are believed to be due to activation of braces, minor dental procedures, or minor injury of
descending serotonergic inhibitory pathways in the the mouth and gum caused by dentures or ortho-
central nervous system. Interactions with other noci- dontic appliances. Note: Although product is avail-
ceptive systems may be involved as well (Smith able in a gel formulation for relief of pain associated
202
BENZOCAINE
with teething in infants ≥4 months, the FDA, AAP, pain in infants and children <2 years (AAP 2011;
and American Academy of Pediatric Dentistry do AAPD 2012; FDA Safety Announcement 2018).
not recommend use due to safety concerns related Dermal irritation (insect bites, minor cuts, scrapes,
to increased methemoglobinemia risk in infants and minor burns, sunburn): Topical: 20% spray, 5%
children <2 years of age (AAP 2011; FDA 2018). ointment: Children ≥2 years and Adolescents: Apply
Sore throat/mouth, gag reflex suppression: Spray to affected area 3 to 4 times daily as needed.
20%: Topical anesthetic for oral or mucosal areas; Mouth and gum irritation (including fever blisters
temporary relief of occasional minor irritation and and cold sores): Topical:
pain associated with sore mouth and throat; tempo- Oral 10% or 20% gel/liquid: Children ≥2 years and
rary suppression of gag reflex. Adolescents: Apply thin layer to affected area up to
Topical anesthetic: Gel or liquid 20% (Topex only): 4 times daily as needed.
Topical anesthetic for use on oral mucosa prior to Oral 5% spray: Children ≥6 years and Adolescents:
local anesthetic injections, scaling and prophylaxis; Use 1 spray to affected area up to 4 times daily.
to relieve discomfort associated with taking impres- Sore throat/mouth, gag reflex suppression:
sions and intraoral radiographs. Oral: Oral lozenge: Children ≥5 years and Adoles-
Local Anesthetic/Vasoconstrictor Precautions cents: Allow 1 lozenge to dissolve slowly in mouth;
No information available to require special precautions may repeat every 2 hours as needed.
Effects on Dental Treatment A patient history of Topical: Note: Consult product labeling for specific
allergy to ester-type local anesthetics contraindicates dose recommendations.
the use of this product. Oral spray 5%: Children ≥6 years and Adolescents:
Effects on Bleeding No information available to Use 1 spray to affected area or throat up to 4
require special precautions times daily.
Adverse Reactions Frequency not defined. Oral spray 20%: Children ≥2 years and Adoles-
Central nervous system: Localized burning, stinging cents: Spray on affected area or throat up to 4
sensation times daily.
Dermatologic: Contact dermatitis, localized erythema, Renal Impairment: Pediatric There are no dosage
localized rash, urticaria adjustments provided in the manufacturer's labeling.
Hematologic & oncologic: Methemoglobinemia Hepatic Impairment: Pediatric There are no dos-
Hypersensitivity: Hypersensitivity age adjustments provided in the manufacturer's label-
Local: Local pruritus, localized edema, localized ten- ing.
derness
Mechanism of Action Blocks both the initiation and
Dental Usual Dosage Relief of pain (toothache, minor conduction of nerve impulses by decreasing the neuro-
sore throat pain, and canker sore): Children ≥2 years nal membrane's permeability to sodium ions, which
and Adults: Topical (oral): 10% to 20%: Apply thin layer results in inhibition of depolarization with resultant
to affected area up to 4 times daily
blockade of conduction
Dosing
Contraindications
Adult & Geriatric Note: General dosing guidelines
Hypersensitivity to benzocaine, para-aminobenzoic
provided; refer to specific product labeling for dosing
instructions. acid (PABA), or any component of the formulation
Dermal irritation: Topical (external): Spray 5% and OTC labeling: When used for self-medication, do not
20%, ointment 5%: Apply to affected area or use 1 use if you have allergy to local anesthetics (procaine,
spray up to 4 times daily as needed. In cases of bee butacaine, benzocaine, or other "caine" anesthetics).
stings, remove stinger before treatment. Do not use over deep or puncture wounds, infections,
Mouth and gum irritation: Topical (oral): Gel 10% or serious burns, or lacerations.
20%, liquid 10% or 20%, ointment 20%, spray 5%: Warnings/Precautions Methemoglobinemia has been
Apply thin layer to affected area or use 1 spray up to reported following topical use, particularly with higher
4 times daily as needed. concentration (14% to 20%) spray formulations applied
Poison ivy/sumac: Topical (external): Spray 5% (Ivy- to the mouth or mucous membranes. When applied as
Rid only): Spray affected area until wet. a spray to the mouth or throat, multiple sprays (or
Sore throat/mouth, gag reflex suppression: Topical sprays of longer than indicated duration) are not rec-
(oral): ommended. Use caution with breathing problems
Lozenge: Allow 1 lozenge to dissolve slowly in (asthma, bronchitis, emphysema, in smokers),
mouth; may repeat every 2 hours as needed. inflamed/damaged mucosa, heart disease, children <6
Spray 20%: months of age, and hemoglobin or enzyme abnormal-
Benz-O-Sthetic: Spray 2 to 3 times or as needed. ities (glucose-6-phosphate dehydrogenase deficiency,
Repeat if needed for larger areas. hemoglobin-M disease, NADH-methemoglobin reduc-
Hurricaine: Spray on affected area or throat up to 4 tase deficiency, pyruvate-kinase deficiency). Alterna-
times daily. tives to benzocaine sprays, such as topical lidocaine
Topical anesthetic: Topical (oral): Gel or liquid 20% preparations, should be considered for patients at
(Topex only): Apply a small amount to mucosa to higher risk of this reaction. The classical clinical finding
achieve topical anesthesia. of methemoglobinemia is chocolate brown-colored arte-
Renal Impairment: Adult There are no dosage rial blood. However, suspected cases should be con-
adjustments provided in the manufacturer's labeling. firmed by co-oximetry, which yields a direct and
Hepatic Impairment: Adult There are no dosage accurate measure of methemoglobin levels. Standard
adjustments provided in the manufacturer's labeling. pulse oximetry readings or arterial blood gas values are
Pediatric Note: General dosing recommendations not reliable. Clinically significant methemoglobinemia
provided; refer to specific product labeling for dosing requires immediate treatment (Anderson 1988; Cooper
instructions. Due to risk of methemoglobinemia, AAP, 1997; Moore 2004). Due to risk of methemoglobinemia,
FDA, and the American Academy of Pediatric Den- AAP, FDA, and the American Academy of Pediatric
tistry do NOT recommend use for teething and mouth Dentistry do NOT recommend use for teething and
203
BENZOCAINE
mouth pain in infants and children <2 years of age (AAP Drug Interactions
2011; AAPD 2012; FDA 2018). Metabolism/Transport Effects None known.
Some dosage forms may contain benzyl alcohol; large Avoid Concomitant Use There are no known inter-
amounts of benzyl alcohol (≥99 mg/kg/day) have been actions where it is recommended to avoid concomitant
associated with a potentially fatal toxicity ("gasping use.
syndrome") in neonates; the "gasping syndrome" con- Increased Effect/Toxicity
sists of metabolic acidosis, respiratory distress, gasping Benzocaine may increase the levels/effects of: Local
respirations, CNS dysfunction (including convulsions, Anesthetics; Prilocaine; Sodium Nitrite
intracranial hemorrhage), hypotension and cardiovas- The levels/effects of Benzocaine may be increased
cular collapse (AAP ["Inactive" 1997]; CDC 1982); some by: Dapsone (Topical); Methemoglobinemia Associ-
data suggests that benzoate displaces bilirubin from ated Agents; Nitric Oxide
protein binding sites (Ahlfors 2001); avoid or use dos-
Decreased Effect There are no known significant
age forms containing benzyl alcohol with caution in
interactions involving a decrease in effect.
neonates. See manufacturer's labeling. Some dosage
forms may contain propylene glycol; large amounts are
potentially toxic and have been associated hyperosmo-
Onset of Action Anesthetic effect: Spray: 15 to 30
lality, lactic acidosis, seizures and respiratory depres- seconds.
sion; use caution (AAP 1997; Zar 2007). See Dosage Forms: US
manufacturer's labeling. Aerosol, External:
Ivy-Rid [OTC]: 2% (85 g)
When used for self-medication, notify healthcare pro- Aerosol, Mouth/Throat:
vider if condition worsens, or does not improve within 7 Hurricaine [OTC]: 20% (57 g)
days; clears up and occurs again within a few days; or if Topex Topical Anesthetic: 20% (57 g)
accompanied by additional symptoms (eg, swelling, Gel, Mouth/Throat:
rash, headache, nausea, vomiting, or fever). Do not Anbesol [OTC]: 10% (9 g)
use topical products on open wounds; avoid contact Anbesol Maximum Strength [OTC]: 20% (9 g)
with the eyes. Do not use for a prolonged time and/or on Baby Anbesol [OTC]: 7.5% (9 g)
large portions of the body. When topical anesthetics are Benz-O-Sthetic [OTC]: 20% (15 g, 29 g)
used prior to cosmetic or medical procedures, the low-
Dentapaine [OTC]: 20% (11 g)
est amount of anesthetic necessary for pain relief
Hurricaine [OTC]: 20% (5.25 g, 28.4 g, 30 g)
should be applied. High systemic levels and toxic
Zilactin Baby [OTC]: 10% (9.4 g)
effects (eg, methemoglobinemia, irregular heartbeats,
Kit, Mouth/Throat:
respiratory depression, seizures, death) have been
HurriPak Starter Kit [OTC]: 20%
reported in patients who (without supervision of a
trained professional) have applied topical anesthetics Liquid, Mouth/Throat:
in large amounts (or to large areas of the skin), left Anbesol [OTC]: 10% (12 mL)
these products on for prolonged periods of time, or have Anbesol Maximum Strength [OTC]: 20% (12 mL)
used wraps/dressings to cover the skin following appli- Benz-O-Sthetic [OTC]: 20% (56 g)
cation. Dent-O-Kain/20 [OTC]: 20% (9 mL)
Warnings: Additional Pediatric Considerations Hurricaine [OTC]: 20% (30 mL)
There is a significant safety risk of methemoglobinemia Lozenge, Mouth/Throat:
with benzocaine use. The majority of cases of meth- Bi-Zets/Benzotroches [OTC]: 15 mg (10 ea)
emoglobinemia associated with benzocaine use have Cepacol INSTAMAX [OTC]: Benzocaine 15 mg and
been in infants and children <2 years of age for treat- menthol 20 mg (16 ea)
ment of teething and mouth pain; also at greater risk for Ointment, External:
development are patients with asthma, bronchitis, Anacaine: 10% (30 g)
emphysema, mucosal damage, or inflammation at the Blistex Medicated [OTC]: (6.3 g, 10 g)
application site, heart disease, and malnutrition. The Foille [OTC]: 5% (28 g)
FDA has strengthened their warning against using top- Solution, Mouth/Throat:
ical OTC benzocaine for teething pain and are urging Benz-O-Sthetic [OTC]: 20% (30 mL)
manufacturers to stop marketing OTC oral benzocaine Hurricaine [OTC]: 20% (30 mL)
products for treatment of teething in infants and children HurriCaine One [OTC]: 20% (2 ea, 25 ea)
<2 years of age and to add contraindications to use in Kank-A Mouth Pain [OTC]: 20% (9.75 mL)
teething and treatment in infants and children <2 years Stick, External:
(FDA Safety Announcement 2018). The use of OTC Aftertest Topical Pain Relief [OTC]: 10% (4 mL)
topical anesthetics (eg, benzocaine) for teething pain is Strip, Mouth/Throat:
also discouraged by AAP and The American Academy Ora-film [OTC]: 6% (12 ea)
of Pediatric Dentistry (AAP 2011; AAPD 2012). The Swab, Mouth/Throat:
AAP recommends managing teething pain with a chilled Benz-O-Sthetic [OTC]: 20% (2 ea)
(not frozen) teething ring or gently rubbing/massaging Hurricaine [OTC]: 20% (72 ea)
with the caregiver's finger. Dental Health Professional Considerations Health
Some dosage forms may contain propylene glycol; in Canada has issued a reminder to healthcare professio-
neonates large amounts of propylene glycol delivered nals that benzocaine sprays must be used judiciously to
orally, intravenously (eg, >3,000 mg/day), or topically minimize the risk of methemoglobinemia. Almost all
have been associated with potentially fatal toxicities reported cases have been associated with higher con-
which can include metabolic acidosis, seizures, renal centration (14% to 20% benzocaine) spray products
failure, and CNS depression; toxicities have also been used in the mouth and on other mucous membranes.
reported in children and adults including hyperosmolal- Alternatives to benzocaine sprays, such as topical
ity, lactic acidosis, seizures and respiratory depression; lidocaine preparations, should be considered for
use caution (AAP 1997; Shehab 2009). patients at higher risk of this reaction.
204
BEPOTASTINE
psychotic symptoms (exacerbation of preexisting

Benzonatate (ben ZOE na tate) symptoms), toxic psychosis, visual hallucination
Dermatologic: Skin rash
Related Information Gastrointestinal: Constipation, nausea, paralytic ileus,
Perioral Premalignant Lesions and Management of vomiting, xerostomia
Patients Undergoing Cancer Therapy on page 1567 Genitourinary: Dysuria, urinary retention
Brand Names: US Tessalon Perles; Zonatuss [DSC] Ophthalmic: Blurred vision, mydriasis
Pharmacologic Category Antitussive Mechanism of Action Possesses both anticholinergic
Use Cough: Symptomatic relief of cough and antihistaminic effects. In vitro anticholinergic activ-
Local Anesthetic/Vasoconstrictor Precautions ity approximates that of atropine; in vivo it is only about
No information available to require special precautions half as active as atropine. Animal data suggest its
Effects on Dental Treatment No significant effects or antihistaminic activity and duration of action approach
complications reported that of pyrilamine maleate.
Effects on Bleeding No information available to Pharmacodynamics/Kinetics
require special precautions Onset of Action
Adverse Reactions Frequency not defined. IM, IV: Within a few minutes; there is no significant
Cardiovascular: Chest numbness difference between onset of effect after intravenous
Central nervous system: Chills, confusion, dizziness, or intramuscular injection
hallucination, headache, sedation Oral: Within 1 hour
Dermatologic: Pruritus, skin rash
Time to Peak Plasma: Oral: 7 hours (Brocks 1999)
Gastrointestinal: Constipation, gastrointestinal distress,
nausea Pregnancy Considerations Animal reproduction
Hypersensitivity: Hypersensitivity reaction (broncho- studies have not been conducted. Paralytic ileus (which
spasm, laryngospasm, cardiovascular collapse) resolved rapidly) was reported in two newborns
Ophthalmic: Burning sensation of eyes exposed to a combination of benztropine and chlorpro-
Respiratory: Nasal congestion mazine during the second and third trimesters and the
Mechanism of Action Tetracaine congener with anti- last 6 weeks of pregnancy, respectively (Falterman
tussive properties; suppresses cough by topical anes- 1980).
thetic action on the respiratory stretch receptors
Pharmacodynamics/Kinetics Bepotastine (be poe TAS teen)
Onset of Action Therapeutic: 15 to 20 minutes
Duration of Action 3 to 8 hours Brand Names: US Bepreve
Pregnancy Risk Factor C Brand Names: Canada Bepreve
Pregnancy Considerations Animal reproduction Pharmacologic Category Histamine H1 Antagonist;
studies have not been conducted. Information related Histamine H1 Antagonist, Second Generation; Mast
to use in pregnancy is limited (Heinonen 1977). Cell Stabilizer
Use Allergic conjunctivitis: Treatment of itching asso-
Benztropine (BENZ troe peen) ciated with allergic conjunctivitis
Related Information No information available to require special precautions
Dentin Hypersensitivity, Acid Erosion, High Caries Effects on Dental Treatment Key adverse event(s)
Index, Management of Alveolar Osteitis, and Xerosto- related to dental treatment: Taste abnormalities
mia on page 1548 reported in ≤25% of patients
Brand Names: US Cogentin Effects on Bleeding No information available to
Brand Names: Canada Benztropine Omega; Kynesia; require special precautions
PMS-Benztropine Adverse Reactions
Pharmacologic Category Anti-Parkinson Agent, Anti- >10%: Gastrointestinal: Dysgeusia (25%)
cholinergic; Anticholinergic Agent 1% to 10%:
Use Central nervous system: Headache (2% to 5%)
Drug-induced extrapyramidal symptoms (treat- Ophthalmic: Eye irritation (2% to 5%)
ment): Aid in the control of extrapyramidal symptoms Respiratory: Nasopharyngitis (2% to 5%)
(except tardive dyskinesia) due to neuroleptic drugs <1%, postmarketing, and/or case reports: Hypersensi-
(eg, phenothiazines).
tivity reaction, pharyngeal edema, pruritus, skin rash,
Parkinsonism: Adjunctive therapy of all forms of par-
swelling of lips, swollen tongue
kinsonism.
Local Anesthetic/Vasoconstrictor Precautions Mechanism of Action Direct H1-receptor antagonist
and inhibits release of histamine from mast cells
related to dental treatment: Xerostomia and changes in
Onset of Action Within 3 minutes (Macejko 2010)
salivation (normal salivary flow resumes upon discon- Duration of Action Up to 16 hours (Williams 2011)
tinuation), dry throat, and nasal dryness (very preva- Time to Peak Serum: 1 to 2 hours
lent). Pregnancy Considerations Adverse events were
Effects on Bleeding No information available to observed in some animal reproduction studies following
require special precautions oral administration. Plasma concentrations are below
Adverse Reactions Frequency not defined. the limits of detection 24 hours after ophthalmic use. If
Cardiovascular: Tachycardia ophthalmic agents are needed during pregnancy, the
Central nervous system: Confusion, depression, disori- minimum effective dose should be used in combination
entation, heatstroke, hyperthermia, lethargy, memory with punctual occlusion to decrease potential exposure
impairment, nervousness, numbness of fingers, to the fetus (Samples 1988).
205
BERACTANT
Ophthalmic: Conjunctival erythema (2%), blurred vision,

Beractant (ber AKT ant) eye irritation, eye pain, eye pruritus
Mechanism of Action Inhibits both DNA gyrase and
Brand Names: US Survanta topoisomerase IV. DNA gyrase is an essential bacterial
Brand Names: Canada Survanta enzyme required for DNA replication, transcription, and
Pharmacologic Category Lung Surfactant repair. Topoisomerase IV is an essential bacterial
Use Respiratory distress syndrome: Prevention of enzyme required for decatenation during cell division.
respiratory distress syndrome (RDS) in premature neo- Inhibition effect is bactericidal.
nates with birth weight <1,250 g or with evidence of Pharmacodynamics/Kinetics
surfactant deficiency (administer within 15 minutes of Half-life Elimination ~7 hours
birth); treatment of RDS in neonates with x-ray con- Pregnancy Considerations Systemic concentrations
firmation of RDS and requiring mechanical ventilation of besifloxacin following ophthalmic administration are
(administer within 8 hours of birth). low. If ophthalmic agents are needed during pregnancy,
Local Anesthetic/Vasoconstrictor Precautions the minimum effective dose should be used in combi-
No information available to require special precautions nation with punctual occlusion for 3 to 5 minutes after
Effects on Dental Treatment No significant effects or application to decrease potential exposure to the fetus
complications reported (Samples 1988).
require special precautions Beta-Carotene (BAY ta KARE oh teen)
Adverse Reactions Frequency not defined. The fol-
lowing occurred during the dosing procedure: Brand Names: US A-Caro-25 [OTC]; B-Caro-T [OTC];
>10%: Cardiovascular: Bradycardia (transient) Caroguard [OTC]
1% to 10%: Respiratory: Oxygen desaturation Pharmacologic Category Vitamin, Fat Soluble
<1%, postmarketing, and/or case reports: Apnea, Use Dietary supplement: Use as a dietary supplement
emphysema (pulmonary interstitial), hypercapnia, to increase vitamin A when dietary intake is inadequate
hypertension, hypotension, increased susceptibility to Local Anesthetic/Vasoconstrictor Precautions
infection (post-treatment nosocomial sepsis), low No information available to require special precautions
blood CO2, obstruction of endotracheal tube, pallor, Effects on Dental Treatment No significant effects or
pneumothorax (including pneumopericardium), vaso- complications reported
constriction Effects on Bleeding No information available to
Mechanism of Action Replaces deficient or ineffective require special precautions
endogenous lung surfactant in neonates with respira- Adverse Reactions Frequency not defined.
tory distress syndrome (RDS) or in neonates at risk of Central nervous system: Dizziness
developing RDS. Surfactant prevents the alveoli from Dermatologic: Skin discoloration (yellowing of palms,
collapsing during expiration by lowering surface tension hands, or soles of feet, and to a lesser extent the face)
between air and alveolar surfaces. Mechanism of Action The exact mechanism of action
Pharmacodynamics/Kinetics in erythropoietic protoporphyria has not as yet been
Onset of Action Improved oxygenation: Within elucidated; although patient must become carotenemic
minutes before effects are observed, there appears to be more
Pregnancy Considerations Beractant is only indi- than a simple internal light screen responsible for the
cated for use in premature neonates drug's action. A protective effect was achieved when
beta-carotene was added to blood samples. The con-
Besifloxacin (be si FLOX a sin) centrations of solutions used were similar to those
achieved in treated patients. Topically applied beta-
Brand Names: US Besivance carotene is considerably less effective than systemic
Brand Names: Canada Besivance therapy.
Pharmacologic Category Antibiotic, Fluoroquinolone; Pregnancy Considerations Maternal intake of beta-
Antibiotic, Ophthalmic carotene influences cord blood concentrations (Scaife
Use Bacterial conjunctivitis: Treatment of bacterial 2006).
conjunctivitis caused by susceptible isolates of the
following bacteria: Aerococcus viridans, CDC coryne- Betamethasone (Systemic)
form group G, Haemophilus influenzae, Staphylococcus (bay ta METH a sone)
aureus, Staphylococcus epidermidis, Streptococcus
mitis group, Streptococcus oralis, Streptococcus pneu- Related Information
moniae, Corynebacterium pseudodiphtheriticum, Cory- Respiratory Diseases on page 1467
nebacterium striatum, Moraxella lacunata, Moraxella Brand Names: US Celestone Soluspan; Pod-Care
catarrhalis, Pseudomonas aeruginosa, Staphylococcus 100C; ReadySharp Betamethasone
hominis, Staphylococcus lugdunensis, Staphylococcus Brand Names: Canada Betaject; Celestone Soluspan
warneri, Streptococcus salivarius. Generic Availability (US) Yes
Local Anesthetic/Vasoconstrictor Precautions Pharmacologic Category Corticosteroid, Systemic
No information available to require special precautions Dental Use Treatment of a variety of oral diseases of
Effects on Dental Treatment No significant effects or allergic, inflammatory, or autoimmune origin
Effects on Bleeding No information available to Intramuscular:
require special precautions Allergic states: Control of severe or incapacitating
Adverse Reactions Frequency not always defined. allergic conditions intractable to adequate trials of
1% to 2%: conventional treatment in asthma, atopic dermatitis,
Central nervous system: Headache contact dermatitis, drug hypersensitivity reactions,
206
BETAMETHASONE (SYSTEMIC)
perennial or seasonal allergic rhinitis, serum sick- Effects on Dental Treatment No significant effects or
ness, transfusion reactions complications reported
Dermatologic diseases: Bullous dermatitis herpeti- Effects on Bleeding Variable effects on anticoagulant
formis, exfoliative erythroderma, mycosis fungoides, therapy are observed with glucocorticoids such as
pemphigus, severe erythema multiforme (Stevens- betamethasone.
Johnson syndrome)
Adverse Reactions Frequency not defined:
Endocrine disorders: Congenital adrenal hyperpla-
Cardiovascular: Bradycardia, cardiac arrhythmia, cardi-
sia, hypercalcemia associated with cancer, nonsup-
omegaly, circulatory shock, edema, embolism (fat),
purative thyroiditis. Hydrocortisone or cortisone is the
hypertension, hypertrophic cardiomyopathy, myocar-
drug of choice in primary or secondary adrenocort- dial rupture (following recent MI), syncope, tachycar-
ical insufficiency. Synthetic analogs may be used in dia, thromboembolism, thrombophlebitis, vasculitis
conjunction with mineralocorticoids where applica- Central nervous system: Abnormal sensory symptoms,
ble; in infancy mineralocorticoid supplementation is arachnoiditis, depression, emotional lability, euphoria,
of particular importance headache, increased intracranial pressure, insomnia,
Gastrointestinal diseases: To tide the patient over a malaise, meningitis, myasthenia, neuritis, neuropathy,
critical period of the disease in regional enteritis and paraplegia, paresthesia, personality changes, pseudo-
ulcerative colitis tumor cerebri, psychic disorder, seizure, spinal cord
Hematologic disorders: Acquired (autoimmune) compression, vertigo
hemolytic anemia, Diamond-Blackfan anemia, pure Dermatologic: Acne vulgaris, allergic dermatitis, atro-
red cell aplasia, selected cases of secondary throm- phic striae, diaphoresis, ecchymoses, erythema, exfo-
bocytopenia liation of skin, fragile skin, hyperpigmentation,
Neoplastic diseases: Palliative management of leu- hypertrichosis, hypopigmentation, skin atrophy, skin
kemias and lymphomas rash, subcutaneous atrophy, suppression of skin test
Nervous system: Acute exacerbations of multiple reaction, thinning hair, urticaria, xeroderma
sclerosis; cerebral edema associated with primary Endocrine & metabolic: Amenorrhea, calcinosis, cush-
or metastatic brain tumor or craniotomy. Note: Treat- ingoid state, decreased glucose tolerance, decreased
ment guidelines recommend the use of high-dose IV serum potassium, fluid retention, glycosuria, growth
or oral methylprednisolone for acute exacerbations suppression (pediatric), hirsutism, HPA-axis suppres-
of multiple sclerosis (AAN [Scott 2011]; NICE 2014). sion, hypokalemic alkalosis, impaired glucose toler-
Ophthalmic diseases: Sympathetic ophthalmia, tem- ance/prediabetes, insulin resistance (increased
poral arteritis, uveitis and ocular inflammatory con- requirements for insulin or oral hyperglycemic agents),
ditions unresponsive to topical corticosteroids moon face, negative nitrogen balance, protein catab-
Renal diseases: To induce diuresis or remission of olism, sodium retention, weight gain
proteinuria in idiopathic nephrotic syndrome or that Gastrointestinal: Abdominal distention, change in bowel
due to lupus erythematosus habits, hiccups, increased appetite, intestinal perfora-
Respiratory diseases: Berylliosis, fulminating or dis- tion, nausea, pancreatitis, peptic ulcer, ulcerative
seminated pulmonary tuberculosis when used con- esophagitis
currently with appropriate antituberculous Genitourinary: Bladder dysfunction, spermatozoa disor-
chemotherapy, idiopathic eosinophilic pneumonias, der (decreased motility and number)
symptomatic sarcoidosis Hematologic & oncologic: Petechia
Rheumatic disorders: Adjunctive therapy for short- Hepatic: Hepatomegaly, increased liver enzymes
term administration (to tide the patient over an acute Hypersensitivity: Anaphylactoid reaction, anaphylaxis,
episode or exacerbation) in acute gouty arthritis; angioedema
acute rheumatic carditis; ankylosing spondylitis; Infection: Infection (decreased resistance), sterile
psoriatic arthritis; rheumatoid arthritis, including juve- abscess
nile rheumatoid arthritis (selected cases may require Local: Injection site reaction (intra-articular use). post-
low-dose maintenance therapy); treatment of derma- injection flare (intra-articular use)
tomyositis, polymyositis, and systemic lupus eryth- Neuromuscular & skeletal: Amyotrophy, aseptic
ematosus. necrosis of femoral head, aseptic necrosis of humeral
Miscellaneous: Trichinosis with neurologic or myo- head, bone fracture, Charcot arthropathy, lipotrophy,
cardial involvement, tuberculous meningitis with sub- myopathy, osteoporosis, rupture of tendon, steroid
arachnoid block or impending block when used with myopathy
appropriate antituberculous chemotherapy Ophthalmic: Blindness, blurred vision, cataract, exoph-
thalmos, glaucoma, increased intraocular pressure,
Intra-articular or soft tissue administration: papilledema
Adjunctive therapy for short-term administration (to Respiratory: Pulmonary edema
tide the patient over an acute episode or exacerba- Miscellaneous: Wound healing impairment
tion) in acute gouty arthritis, acute and subacute Dosing
bursitis, acute nonspecific tenosynovitis, epicondyli- Adult Note: Dosages expressed as combined amount
tis, rheumatoid arthritis, synovitis of osteoarthritis of betamethasone sodium phosphate and betametha-
Intralesional: sone acetate; 1 mg is equivalent to betamethasone
Treatment of alopecia areata; discoid lupus erythema- sodium phosphate 0.5 mg and betamethasone ace-
tosus; keloids; localized hypertrophic, infiltrated, tate 0.5 mg. Base dosage on severity of disease and
inflammatory lesions of granuloma annulare, lichen patient response.
planus, lichen simplex chronicus (neurodermatitis), Usual dosage range: IM: Initial: 0.25 to 9 mg daily
and psoriatic plaques; necrobiosis lipoidica diabeti- Indication-specific dosing:
corum Antenatal fetal maturation (off-label use): IM:
Local Anesthetic/Vasoconstrictor Precautions 12 mg every 24 hours for a total of 2 doses (ACOG
No information available to require special precautions 171 2016). A single course of betamethasone is
207
recommended for women between 24 and 34 experience (n=70, age range: 2 months to 12
weeks of gestation, including those with ruptured years) prospectively used a betamethasone/triam-
membranes or multiple gestations, who are at risk cinolone combination injection (1.5 to 18 mg beta-
of delivering within 7 days. A single course may be methasone acetate) and showed that 89.23% of
appropriate in some women beginning at 23 weeks lesions with an initial volume <20 cc3 regressed
gestation or late preterm (between 34 0/7 weeks by more than 50%, but only 22.2% of lesions with
and 36 6/7 weeks gestation). A single repeat an initial volume >20 cc3 displayed a good or
course may be considered in some women with excellent response (Chowdri, 1994). Another trial
pregnancies less than 34 weeks gestation at risk for (n=25, age range: 7 weeks to 2 years) used lower
delivery within 7 days and who had a course of doses of 3 to 12 mg (in combination with triamci-
antenatal corticosteroids >14 days prior (ACOG nolone); 16 patients experienced a marked
171 2016; ACOG 713 2017, ACOG 188 2018). response (Kushner, 1985).
Bursitis (other than of foot), tenosynovitis, peri- Renal Impairment: Pediatric There are no dosage
tendinitis: Intrabursal: 3 to 6 mg (0.5 to 1 mL) for adjustments provided in the manufacturer's labeling.
one dose; several injections may be required for Hepatic Impairment: Pediatric There are no dos-
acute exacerbations or chronic conditions; reduced age adjustments provided in the manufacturer's label-
doses may be warranted for repeat injections. ing.
Dermatologic: Intralesional: 1.2 mg/cm2 (0.2 mL/ Mechanism of Action Controls the rate of protein
cm2) for one dose (maximum: 6 mg [1 mL] weekly). synthesis; depresses the migration of polymorphonu-
Foot disorders: Intra-articular: 1.5 mg to 6 mg (0.25 clear leukocytes, fibroblasts; reverses capillary perme-
to 1 mL) per dose at 3 to 7 day intervals. Dose is ability and lysosomal stabilization at the cellular level to
based upon condition: prevent or control inflammation
Bursitis: 1.5 mg to 3 mg (0.25 to 0.5 mL) Contraindications
Tenosynovitis: 3 mg (0.5 mL) Hypersensitivity to any component of the formulation;
Acute gouty arthritis: 3 mg to 6 mg (0.5 to 1 mL) IM administration contraindicated in immune thrombo-
Multiple sclerosis: Note: Treatment guidelines rec- cytopenia (formerly known as idiopathic thrombocyto-
ommend the use of high-dose IV or oral methyl- penic purpura).
prednisolone for acute exacerbations of multiple Canadian labeling: Additional contraindications (not in
sclerosis (AAN [Scott 2011]; NICE 2014). US labeling): Herpes simplex of the eye; systemic
IM: 30 mg daily for 1 week, followed by 12 mg fungal infections; vaccinia; cerebral malaria; use in
every other day for 4 weeks. areas with local infection.
Rheumatoid and osteoarthritis: Intra-articular: Documentation of allergenic cross-reactivity for gluco-
3 mg to 12 mg (0.5 to 2 mL) for one dose. Dose corticoids is limited. However, because of similarities
is based upon the joint size: in chemical structure and/or pharmacologic actions,
Very large (eg, hip): 6 to 12 mg (1 to 2 mL) the possibility of cross-sensitivity cannot be ruled out
Large (eg, knee, ankle, shoulder): 6 mg (1 mL) with certainty.
Medium (eg, elbow, wrist): 3 mg to 6 mg (0.5 to Warnings/Precautions Avoid concurrent use of other
1 mL) corticosteroids.
Small (eg, inter- or metacarpophalangeal, sterno-
clavicular): 1.5 mg to 3 mg (0.25 to 0.5 mL) May cause hypercortisolism or suppression of hypo-
Geriatric Refer to adult dosing. Use the lowest effec- thalamic-pituitary-adrenal (HPA) axis, particularly in
tive dose. younger children or in patients receiving high doses
Renal Impairment: Adult There are no dosage for prolonged periods. HPA axis suppression may lead
adjustments provided in the manufacturer's labeling. to adrenal crisis. Withdrawal and discontinuation of a
Hepatic Impairment: Adult There are no dosage corticosteroid should be done slowly and carefully.
adjustments provided in the manufacturer's labeling. Particular care is required when patients are transferred
from systemic corticosteroids to inhaled products due to
Pediatric Note: Dosages expressed as combined
possible adrenal insufficiency or withdrawal from ste-
amount of betamethasone sodium phosphate and
roids, including an increase in allergic symptoms. Adult
betamethasone acetate; 1 mg is equivalent to beta-
patients receiving >20 mg per day of prednisone (or
methasone sodium phosphate 0.5 mg and betametha-
equivalent) may be most susceptible. Fatalities have
sone acetate 0.5 mg. Dosage should be based on
occurred due to adrenal insufficiency in asthmatic
severity of disease and patient response; use lowest
patients during and after transfer from systemic cortico-
effective dose for shortest period of time to avoid HPA
steroids to aerosol steroids; aerosol steroids do not
axis suppression
provide the systemic steroid needed to treat patients
General dosing, treatment of inflammatory and
having trauma, surgery, or infections. In stressful sit-
allergic conditions: Infants, Children, and Adoles-
uations, HPA axis-suppressed patients should receive
cents: IM: Initial: 0.02 to 0.3 mg/kg/day (0.6 to
adequate supplementation with natural glucocorticoids
9 mg/m2/day) in 3 or 4 divided doses
(hydrocortisone or cortisone) rather than betametha-
Infantile hemangioma, severe: Limited data avail-
sone (due to lack of mineralocorticoid activity).
able: Infants and Children: Intralesional: Dosage
dependent upon size of lesion: Commonly reported: Acute myopathy has been reported with high-dose
6 mg administered as a 6 mg/mL (in combination corticosteroids, usually in patients with neuromuscular
with triamcinolone injection) divided into multiple transmission disorders; may involve ocular and/or res-
injections along the lesion perimeter; reported piratory muscles; monitor creatine kinase; recovery may
range: 1.5 to 18 mg/dose; doses usually adminis- be delayed. Corticosteroid use may cause psychiatric
tered every 8 to 14 weeks; reported range: 6 to 25 disturbances, including depression, euphoria, insomnia,
weeks (Buckmiller, 2008; Chowdri, 1994; Kushner, mood swings, and personality changes. Preexisting
1985; Praseyono, 2011). Dosing based on small psychiatric conditions may be exacerbated by cortico-
trials and case-series, mostly reported in infants steroid use. Prolonged use of corticosteroids may also
and children ≤4 years of age. The largest increase the incidence of secondary infection, mask
208
acute infection (including fungal infections), prolong or Prolonged use in children may affect growth velocity;
exacerbate viral infections, or limit response to killed or growth should be routinely monitored in pediatric
inactivated vaccines. Special pathogens (Amoeba, patients.
Candida, Cryptococcus, Mycobacterium, Nocardia, Warnings: Additional Pediatric Considerations
Pneumocystis, Strongyloides, or Toxoplasma) may be Adrenal suppression with failure to thrive has been
activated or an infection exacerbation may occur (may reported in infants after receiving intralesional cortico-
be fatal). Amebiasis or Strongyloides infections should steroid injections for treatment of hemangioma (Goyal,
be particularly ruled out. Exposure to varicella zoster 2004). May cause osteoporosis (at any age) or inhib-
(chickenpox) should be avoided; corticosteroids should ition of bone growth in pediatric patients. Use with
not be used to treat ocular herpes simplex. Cortico- caution in patients with osteoporosis. In a population-
steroids should not be used for cerebral malaria or viral based study of children, risk of fracture was shown to be
hepatitis. Close observation is required in patients with increased with >4 courses of corticosteroids; underlying
latent tuberculosis and/or TB reactivity; restrict use in clinical condition may also impact bone health and
active TB (only in conjunction with antituberculosis osteoporotic effect of corticosteroids (Leonard, 2007).
treatment). Prolonged treatment with corticosteroids Drug Interactions
has been associated with the development of Kaposi Metabolism/Transport Effects None known.
sarcoma (case reports); if noted, discontinuation of Avoid Concomitant Use
therapy should be considered. High-dose corticoste- Avoid concomitant use of Betamethasone (Systemic)
roids should not be used to manage acute head injury. with any of the following: Aldesleukin; BCG (Intra-
Rare cases of anaphylactoid reactions have been vesical); Cladribine; Desmopressin; Indium 111 Cap-
observed in patients receiving corticosteroids. romab Pendetide; Macimorelin; Mifamurtide;
MiFEPRIStone; Natalizumab; Pimecrolimus; Tacroli-
Use with caution in patients with thyroid disease, hep- mus (Topical)
atic impairment, renal impairment, cardiovascular dis- Increased Effect/Toxicity
ease, diabetes, glaucoma, cataracts, myasthenia Betamethasone (Systemic) may increase the levels/
gravis, patients at risk for osteoporosis, patients at risk effects of: Acetylcholinesterase Inhibitors; Amphoter-
for seizures, or GI diseases (diverticulitis, fresh intesti- icin B; Androgens; Baricitinib; Deferasirox; Desirudin;
nal anastomoses, peptic ulcer, ulcerative colitis) due to Desmopressin; Fingolimod; Leflunomide; Loop Diu-
perforation risk. Use caution following acute MI (cortico- retics; Natalizumab; Nicorandil; Nonsteroidal Anti-
steroids have been associated with myocardial rupture). Inflammatory Agents (COX-2 Selective); Nonsteroidal
Use with caution in patients with HF and/or hyper- Anti-Inflammatory Agents (Nonselective); Quinolones;
tension; long-term use has been associated with fluid Ritodrine; Sargramostim; Siponimod; Thiazide and
retention and electrolyte disturbances. Dietary modifi- Thiazide-Like Diuretics; Tofacitinib; Vaccines (Live);
cations may be necessary. Use with caution in patients Warfarin
with a recent history of myocardial infarction (MI); left
ventricular free wall rupture has been reported after the The levels/effects of Betamethasone (Systemic) may
use of corticosteroids. Use with caution in patients with be increased by: Aprepitant; Cladribine; CYP3A4
renal impairment; fluid and sodium retention and Inhibitors (Strong); Denosumab; DilTIAZem; Estrogen
increased potassium and calcium excretion may occur. Derivatives; Fosaprepitant; Indacaterol; MiFEPRI-
Dietary modifications may be necessary. Not recom- Stone; Neuromuscular-Blocking Agents (Nondepola-
mended for the treatment of optic neuritis; may increase rizing); Ocrelizumab; Pimecrolimus; Roflumilast;
frequency of new episodes. Intra-articular injection may Salicylates; Tacrolimus (Topical); Trastuzumab
result in joint tissue damage. Injection into an infected Decreased Effect
site should be avoided. Injection into a previously Betamethasone (Systemic) may decrease the levels/
infected join is usually not recommended. If infection effects of: Aldesleukin; Antidiabetic Agents; Axicabta-
is suspected, joint fluid examination is recommended. If gene Ciloleucel; BCG (Intravesical); Calcitriol (Sys-
septic arthritis occurs after injection, institute appropri- temic); Coccidioides immitis Skin Test; Corticorelin;
ate antimicrobial therapy. Suspension for injection is for Cosyntropin; Hyaluronidase; Indium 111 Capromab
intramuscular, intra-articular or intralesional use only, do Pendetide; Isoniazid; Macimorelin; Mifamurtide; Nivo-
not administer intravenously. Corticosteroids are not lumab; Pidotimod; Salicylates; Sipuleucel-T; Somatro-
approved for epidural injection. Serious neurologic p i n ; Ta c r o l i m u s ( S y s t e m i c ) ; Te r t o m o t i d e ;
events (eg, spinal cord infarction, paraplegia, quadri- Tisagenlecleucel; Urea Cycle Disorder Agents; Vac-
plegia, cortical blindness, stroke), some resulting in cines (Inactivated); Vaccines (Live)
death, have been reported with epidural injection of The levels/effects of Betamethasone (Systemic) may
corticosteroids, with and without use of fluoroscopy. be decreased by: CYP3A4 Inducers (Strong); Echina-
Intra-articular injected corticosteroids may be systemi- cea; MiFEPRIStone; Mitotane
cally absorbed. May produce systemic as well as local Pharmacodynamics/Kinetics
effects. Appropriate examination of any joint fluid Half-life Elimination 6.5 hours (Peterson 1983)
present is necessary to exclude a septic process. Avoid Time to Peak Serum: IV: 10 to 36 minutes (Peterson
injection into an infected site. Do not inject into unstable 1983)
joints. Intra-articular injection may result in damage to Pregnancy Considerations Betamethasone crosses
joint tissues. Potentially significant drug-drug interac- the placenta (Brownfoot 2013) and is partially metabo-
tions may exist, requiring dose or frequency adjust- lized by placental enzymes to an inactive metabolite
ment, additional monitoring, and/or selection of (Murphy 2007). Some studies have shown an associa-
alternative therapy. Because of the risk of adverse tion between first trimester systemic corticosteroid use
effects, systemic corticosteroids should be used cau- and oral clefts or decreased birth weight; however,
tiously in the elderly in the smallest possible effective information is conflicting and may be influenced by
dose for the shortest duration. Withdraw therapy with maternal dose/indication for use (Lunghi 2010; Park-
gradual tapering of dose. Wyllie 2000; Pradat 2003). Hypoadrenalism may occur
209
in newborns following maternal use of corticosteroids Suspension, Injection:

during pregnancy; monitor. Celestone Soluspan: Betamethasone sodium phos-
phate 3 mg and betamethasone acetate 3 mg per 1
Because antenatal corticosteroid administration may
mL (5 mL)
reduce the incidence of intraventricular hemorrhage,
Generic: Betamethasone sodium phosphate 3 mg and
necrotizing enterocolitis, neonatal mortality, and respi-
betamethasone acetate 3 mg per 1 mL (5 mL)
ratory distress syndrome, the injection is often used for
antenatal fetal lung maturation in patients with preterm
premature rupture of membranes or preterm labor who Betamethasone (Topical) (bay ta METH a sone)
are at risk of preterm delivery. A single course of
betamethasone is recommended for women between Related Sample Prescriptions
24 and 34 weeks gestation who are at risk of delivering Ulcerative and Erosive Disorders - Sample Prescrip-
within 7 days, including those with ruptured membranes tions on page 47
or multiple gestations. A single course of betametha- Brand Names: US AlphaTrex [DSC]; Diprolene; Dipro-
sone may be considered for women beginning at 23 lene AF; Luxiq; Sernivo
weeks gestation, who are at risk of delivering within 7 Brand Names: Canada Betaderm; Beteflam; Betne-
days, in consultation with the family. In addition, a single sol; Celestoderm V; Celestoderm V/2; Diprolene; Dipro-
course of betamethasone may be given to women sone; Luxiq; Prevex B; Rivasone; Rolene; Rosone;
between 34 0/7 weeks and 36 6/7 weeks who are at Valisone Scalp Lotion
risk of preterm delivery within 7 days and who have not Generic Availability (US) May be product dependent
previously received corticosteroids; use of concomitant Pharmacologic Category Corticosteroid, Topical
tocolytics is not currently recommended and adminis- Dental Use Treatment of a variety of oral diseases of
tration of late preterm corticosteroids has not been allergic, inflammatory, or autoimmune origin
evaluated in women with intrauterine infection, multiple Use
gestations, pregestational diabetes, or women who Dermatoses: Relief of inflammatory and pruritic mani-
delivered previously by cesarean section at term. Multi- festations of corticosteroid-responsive dermatoses.
ple repeat courses are not recommended. However, in Dermatoses of the scalp (foam): Relief of inflamma-
women with pregnancies less than 34 weeks gestation tory and pruritic manifestations of corticosteroid-
at risk for delivery within 7 days and who had a course responsive dermatoses of the scalp.
of antenatal corticosteroids >14 days prior, a single Plaque psoriasis (spray; patch [Canadian product]):
repeat course may be considered; use of a repeat Treatment of mild to moderate plaque psoriasis in
course in women with preterm prelabor rupture of patients 18 years and older.
membranes is controversial (ACOG 171 2016; ACOG Local Anesthetic/Vasoconstrictor Precautions
713 2017, ACOG 188 2018). No information available to require special precautions
When systemic corticosteroids are needed in preg- Effects on Dental Treatment No significant effects or
nancy for rheumatic disorders, it is generally recom- complications reported
mended to use the lowest effective dose for the shortest Effects on Bleeding Variable effects on anticoagulant
duration of time, avoiding high doses during the first therapy are observed with glucocorticoids such as
trimester. Intra-articular dosing may also be used during betamethasone.
pregnancy (Götestam Skorpen 2016; Makol 2011; Adverse Reactions
Østensen 2009). >10%: Local: Application site reactions (54%; includes
Breastfeeding Considerations Corticosteroids are burning, stinging, and itching; most reactions were
present in breast milk. mild)
1% to 10%:
The onset of milk secretion after birth may be delayed
Central nervous system: Paresthesia (2%)
and the volume of milk produced may be decreased by
Dermatologic: Acne vulgaris (2%), alopecia (2%), pru-
antenatal betamethasone therapy; this affect was seen
ritus (≤2%)
when delivery occurred 3 to 9 days after the betame-
Ophthalmic: Conjunctivitis (2%)
thasone dose in women between 28 and 34 weeks
Frequency not defined: Endocrine & metabolic: HPA
gestation. Antenatal betamethasone therapy did not
axis suppression
affect milk production when birth occurred <3 days or
<1%, postmarketing, and/or case reports: Bullous der-
>10 days of treatment (Henderson 2008).
matitis, cataract, contact dermatitis, dermatitis, dys-
The manufacturer notes that when used systemically, geusia, erythema, erythematous rash, folliculitis,
maternal use of corticosteroids have the potential to glaucoma, hyperglycemia, hypersensitivity reaction,
cause adverse events in a breastfed infant (eg, growth increased intraocular pressure, localized vesiculation,
suppression, interfere with endogenous corticosteroid retinopathy (central serous), skin discoloration, skin
production) and therefore, recommends that caution be rash, telangiectasia
exercised when administering betamethasone to Dental Usual Dosage Allergic or inflammatory dis-
breastfeeding women. Corticosteroids are generally eases: Topical: Gel: Apply small quantity with cotton
considered compatible with breastfeeding when used swab to affected area 3-4 times/day
in usual doses (Götestam Skorpen 2016; WHO 2002); Dosing
however, monitoring of the breastfeeding infant for Adult Note: Base dosage on severity of disease and
adverse reactions is recommended (WHO 2002). patient response. Use lowest dose possible for short-
Dosage Forms: US est period of time to avoid HPA axis suppression.
Kit, Injection: Therapy should be discontinued when control is
Pod-Care 100C: Betamethasone sodium phosphate achieved.
3 mg and betamethasone acetate 3 mg per 1 mL Corticosteroid-responsive dermatoses: Topical:
ReadySharp Betamethasone: Betamethasone sodium Cream, augmented formulation: Betamethasone
phosphate 3 mg and betamethasone acetate 3 mg dipropionate 0.05%: Apply once or twice daily
per 1 mL (maximum: 50 g weekly).
210
BETAMETHASONE (TOPICAL)
Cream, unaugmented formulation: Gel: Children and Adolescents ≥12 years: Apply a
Betamethasone dipropionate 0.05%: Apply once thin layer to the affected area once or twice daily;
daily; may increase to twice daily if needed rub in gently; maximum dose: 50 g/week; not
Betamethasone valerate 0.1%: Apply 1 to 3 times recommended for use longer than 2 weeks
daily. Note: Once- or twice-daily applications are Lotion: Adolescents: Apply a few drops to the
usually effective. affected area once or twice daily; rub in gently;
Foam: Apply to the scalp twice daily, once in the maximum dose: 50 mL/week; not recommended
morning and once at night. Note: Reassess if no for use for longer than 2 weeks.
improvement after 2 weeks of treatment. Renal Impairment: Pediatric There are no dosage
Gel, augmented formulation: Apply once or twice adjustments provided in the manufacturer's labeling.
daily; rub in gently (maximum: 50 g weekly). Note: Hepatic Impairment: Pediatric There are no dos-
Reassess if no improvement after 2 weeks of age adjustments provided in the manufacturer's label-
treatment. ing.
Lotion, augmented formulation: Betamethasone Mechanism of Action Topical corticosteroids have
dipropionate 0.05%: Apply a few drops once or anti-inflammatory, antipruritic, and vasoconstrictive
twice daily (maximum: 50 mL weekly). Note: Reas- properties. May depress the formation, release, and
sess if no improvement after 2 weeks of treatment. activity of endogenous chemical mediators of inflam-
Lotion, unaugmented formulation: mation (kinins, histamine, liposomal enzymes, prosta-
Betamethasone dipropionate 0.05%: Apply a few glandins) through the induction of phospholipase A2
drops twice daily inhibitory proteins (lipocortins) and sequential inhibition
Betamethasone valerate 0.1%: Apply a few drops of the release of arachidonic acid. Betamethasone has
twice daily; may consider increasing dose for intermediate to very high range potency (dosage-form
resistant cases. Following improvement, may
dependent).
apply once daily.
Contraindications
Ointment, augmented formulation: Betamethasone
Hypersensitivity to betamethasone, other corticoste-
dipropionate 0.05%: Apply once or twice daily
roids, or any component of the formulation
(maximum: 50 g weekly). Note: Reassess if no
Cream, Lotion: Untreated bacterial, tubercular, and
improvement after 2 weeks of treatment.
Ointment, unaugmented formulation: fungal skin infections; viral diseases (eg, herpes sim-
Betamethasone dipropionate 0.05%: Apply once plex, chicken pox, vaccinia)
daily; may increase to twice daily if needed Canadian labeling: Additional contraindications (not in
Betamethasone valerate 0.1%: Apply 1 to 3 times US labeling): Treatment of rosacea, acne vulgaris,
daily. Note: Once- or twice-daily applications are perioral dermatitis, or pruritus without inflammation
usually effective. (foam); skin manifestations relating to tuberculosis or
Plaque psoriasis: Topical: syphilis, eruptions following vaccinations; application
Patch [Canadian product]: Betamethasone valerate: to eyes (foam); <18 years of age (patch). Note:
Apply 1 patch (2.25 mg) to each affected area once Product labels may vary (refer also to product labels).
daily [up to 5 patches (11.25 mg) may be applied Warnings/Precautions Very high potency topical
daily]; maximum duration of therapy: 30 days. products are not for treatment of rosacea, perioral
Spray, unaugmented formulation: Betamethasone dermatitis; not for use on face, groin, or axillae; not for
dipropionate 0.05%: Apply twice daily for up to 4 use in a diapered area. Avoid concurrent use of other
weeks corticosteroids.
Geriatric Refer to adult dosing. Use the lowest effec- May cause hypercortisolism or suppression of hypo-
tive dose. thalamic-pituitary-adrenal (HPA) axis, particularly in
Renal Impairment: Adult There are no dosage younger children or in patients receiving high doses
adjustments provided in the manufacturer's labeling. for prolonged periods. HPA axis suppression may lead
Hepatic Impairment: Adult There are no dosage to adrenal crisis.
adjustments provided in the manufacturer's labeling.
Pediatric Note: Dosage should be based on severity Topical corticosteroids, including betamethasone, may
of disease and patient response; use smallest amount increase the risk of posterior subcapsular cataracts and
for shortest period of time to avoid HPA axis suppres- glaucoma. Monitor for ocular symptoms. Avoid contact
sion. Therapy should be discontinued when control is with eyes.
achieved. Topical corticosteroids may be absorbed percutane-
Dermatoses (corticosteroid-responsive): Topical: ously. Absorption of topical corticosteroids may cause
Betamethasone valerate: manifestations of Cushing syndrome (rare), hypergly-
Cream/ointment: Children and Adolescents: Apply cemia, or glycosuria. Absorption is increased by the use
a thin film to the affected area once to 3 times of occlusive dressings, application to denuded skin,
daily; usually once or twice daily application is application to large surface areas, or prolonged use.
effective. Potentially significant interactions may exist, requiring
Lotion: Children and Adolescents: Apply a few dose or frequency adjustment, additional monitoring,
drops to the affected area twice daily; in some and/or selection of alternative therapy.
cases, more frequent application may be neces-
sary; following improvement reduce to once daily Discontinue if skin irritation or contact dermatitis should
application occur; do not use in patients with decreased skin
Betamethasone dipropionate (augmented formula- circulation. Withdraw therapy with gradual tapering of
tion): dose by reducing the frequency of application or sub-
Cream/ointment: Adolescents: Apply a thin film to stitution of a less potent steroid. Allergic contact derma-
affected area once or twice daily; maximum dose: titis can occur and is usually diagnosed by failure to
50 g/week; evaluate continuation of therapy if no heal rather than clinical exacerbation; discontinue use if
improvement within 2 weeks of treatment. irritation occurs and treat appropriately.
211
BETAMETHASONE (TOPICAL)
For topical use only; avoid contact with eyes. Not for an increased risk of low birth weight infants following
oral, ophthalmic, or intravaginal use. Augmented (eg, maternal use of potent or very potent topical products,
very high potency) product use in patients <13 years of especially in high doses. Use of mild to moderate
age is not recommended. Not for treatment of rosacea, potency topical corticosteroids is preferred in pregnant
perioral dermatitis, or if skin atrophy is present at treat- females, and the use of large amounts or use for
ment site; not for facial, groin, axillary, oral, ophthalmic, prolonged periods of time should be avoided (Chi
or intravaginal use. Children may absorb proportionally 2016; Chi 2017; Murase 2014). Also avoid areas of
larger amounts after topical application and may be high percutaneous absorption (Chi 2017). The risk of
more prone to systemic effects. HPA axis suppression, stretch marks may be increased with use of topical
intracranial hypertension, and Cushing syndrome have corticosteroids (Murase 2014).
been reported in children receiving topical corticoste- Breastfeeding Considerations
roids. Prolonged use may affect growth velocity; growth It is not known if systemic absorption following topical
should be routinely monitored in pediatric patients. Use administration results in detectable quantities of beta-
lowest dose possible for shortest period of time to avoid methasone in breast milk.
HPA axis suppression. Foam contains flammable pro- Systemic corticosteroids are present in breast milk.
pellants. Avoid fire, flame, and smoking during and Although the manufacturer recommends that caution
immediately following administration. Patch [Canadian be used in breastfeeding females, topical corticoste-
product] has not been studied in psoriasis of the face, roids are generally considered acceptable for use
scalp or intertriginous areas; contains methyl and propyl (Butler 2014; WHO 2002).
parahydroxybenzoate, which may cause hypersensitiv- Do not apply topical corticosteroids to breast until
ity (sometimes delayed).
breastfeeding ceases (Leachman 2006); hypertension
Warnings: Additional Pediatric Considerations was noted in a breastfed infant when a high potency
The extent of percutaneous absorption is dependent topical corticosteroid was applied to the nipple (Butler
on several factors, including epidermal integrity (intact 2014; Leachman 2006).
vs abraded skin), formulation, age of the patient, pro-
Dosage Forms: US
longed duration of use, and the use of occlusive dress-
Cream, External:
ings. Percutaneous absorption of topical steroids is
Diprolene AF: 0.05% (15 g, 50 g)
increased in neonates (especially preterm neonates),
infants, and young children. Infants and small children Generic: 0.05% (15 g, 45 g, 50 g); 0.1% (15 g, 45 g)
may be more susceptible to HPA axis suppression, Emulsion, External:
intracranial hypertension, Cushing syndrome, or other Sernivo: 0.05% (120 mL)
systemic toxicities due to larger skin surface area to Foam, External:
body mass ratio. HPA axis suppression was observed Luxiq: 0.12% (50 g, 100 g)
in 32% of infants and children (age range: 3 months to Generic: 0.12% (50 g, 100 g)
12 years) being treated with betamethasone dipropio- Gel, External:
nate cream (0.05%) for atopic dermatitis in an open- Generic: 0.05% (15 g, 50 g)
label trial (n=60); the incidence was greater younger Lotion, External:
patients vs older children (mean reported incidence for Diprolene: 0.05% (30 mL, 60 mL)
age ranges: ≤1 year: 50%; 2 to 8 years: 32% to 38%; 9 Generic: 0.05% (30 mL, 60 mL); 0.1% (60 mL)
to 12 years: 17%). Ointment, External:
Diprolene: 0.05% (15 g, 50 g)
Some dosage forms may contain propylene glycol; in Generic: 0.05% (15 g, 45 g, 50 g); 0.1% (15 g, 45 g)
have been associated with potentially fatal toxicities Betaxolol (Systemic) (be TAKS oh lol)
Related Information
reported in children and adults including hyperosmolal- Cardiovascular Diseases on page 1442
ity, lactic acidosis, seizures and respiratory depression; Pharmacologic Category Antihypertensive; Beta-
use caution (AAP 1997; Shehab 2009). Blocker, Beta-1 Selective
Drug Interactions Use
Metabolism/Transport Effects None known. Hypertension: Management of hypertension. Note:
Avoid Concomitant Use Beta-blockers are not recommended as first-line ther-
Avoid concomitant use of Betamethasone (Topical) apy (ACC/AHA [Whelton 2017]).
with any of the following: Aldesleukin Local Anesthetic/Vasoconstrictor Precautions
Increased Effect/Toxicity No information available to require special precautions
Betamethasone (Topical) may increase the levels/ Effects on Dental Treatment Betaxolol is a cardiose-
effects of: Deferasirox; Ritodrine lective beta-blocker. Local anesthetic with vasoconstric-
Decreased Effect tor can be safely used in patients medicated with
Betamethasone (Topical) may decrease the levels/ betaxolol. Nonselective beta-blockers (ie, propranolol,
effects of: Aldesleukin; Corticorelin; Hyaluronidase nadolol) enhance the pressor response to epinephrine
Pregnancy Risk Factor C or levonordefrin, resulting in hypertension and brady-
Pregnancy Considerations Adverse events have cardia; this has not been reported for betaxolol. Many
been observed with corticosteroids in animal reproduc- nonsteroidal anti-inflammatory drugs, such as ibuprofen
tion studies. Systemic bioavailability of topical cortico- and indomethacin, can reduce the hypotensive effect of
steroids is variable (eg, integrity of skin, use of beta-blockers after 3 or more weeks of therapy with the
occlusion) and may be further influenced by trimester NSAID. Short-term NSAID use (ie, 3 days) requires no
of pregnancy (Chi 2017). In general, the use of topical special precautions in patients taking beta-blockers.
corticosteroids is not associated with a significant risk of Effects on Bleeding No information available to
adverse pregnancy outcomes. However, there may be require special precautions
212
BETRIXABAN
Adverse Reactions maternal hypertension and preeclampsia are also asso-

2% to 10%: ciated with adverse events in the fetus, infant, and
Cardiovascular: Bradycardia (6% to 8%; symptomatic mother (ACOG 2015; Magee 2014). Although beta-
bradycardia: ≤2%; dose-dependent), chest pain (2% blockers may be used when treatment of hypertension
to 7%), cold extremities (2%), palpitations (2%), in pregnancy is indicated, agents other than betaxolol
edema (≤2%; similar to placebo) are preferred (ACOG 2013; Magee 2014; Regitz-Zagro-
Central nervous system: Fatigue (3% to 10%), insom- sek 2011).
nia (1% to 5%), lethargy (3%), paresthesia (2%)
Gastrointestinal: Nausea (2% to 6%), dyspepsia (4% Bethanechol (be THAN e kole)
to 5%), diarrhea (2%)
Hematologic & oncologic: Positive ANA titer (5%) Brand Names: US Urecholine
Neuromuscular & skeletal: Arthralgia (3% to 5%) Brand Names: Canada Duvoid; PHL-Bethanechol;
Respiratory: Dyspnea (2%), pharyngitis (2%) PMS-Bethanechol
<2%, postmarketing, and/or case reports: Abnormal Pharmacologic Category Cholinergic Agonist
dreams, abnormality in thinking, acidosis, alopecia, Use
amnesia, anemia, angina pectoris, anorexia, arthrop- Neurogenic bladder: Treatment of neurogenic atony of
athy, ataxia, atrioventricular block, blepharitis, breast the urinary bladder with retention
fibroadenosis, bronchitis, bronchospasm, cardiac Urinary retention: Treatment of acute postoperative
arrhythmia, cardiac failure, cataract, cerebrovascular and postpartum nonobstructive (functional) urinary
disease, conjunctivitis, constipation, cough, cystitis, retention
deafness, decreased libido, depression, diabetes mel- Local Anesthetic/Vasoconstrictor Precautions
litus, diaphoresis, dysgeusia, dysphagia, dysuria, No information available to require special precautions
emotional lability, epistaxis, erythematous rash, exac- Effects on Dental Treatment This is a cholinergic
erbation of psoriasis, fever, flushing, hallucination, agent similar to pilocarpine; expect to see salivation
hemophthalmos, hypercholesterolemia, hyperglyce- and sweating in patients.
mia, hyperkalemia, hyperlipidemia, hypersensitivity Effects on Bleeding No information available to
reaction, hypertension, hypertrichosis, hyperuricemia, require special precautions
hypoglycemia, hypokalemia, hypotension, impotence, Adverse Reactions Frequency not defined.
increased lactate dehydrogenase, increased serum Cardiovascular: Flushing, hypotension, tachycardia
ALT, increased serum AST, influenza, intermittent Central nervous system: Colic, headache, malaise,
claudication, iritis, labyrinth disease, leukocytosis, seizure
lymphadenopathy, malaise, menstrual disease, Dermatologic: Diaphoresis
muscle cramps, myocardial infarction, nervousness, Gastrointestinal: Abdominal cramps, borborygmi, diar-
neuralgia, neuropathy, numbness, oliguria, peripheral rhea, eructation, nausea, salivation, vomiting
ischemia, Peyronie’s disease, pneumonia, prostatitis, Genitourinary: Urinary urgency
proteinuria, pruritus, purpura, renal insufficiency, rhini- Ophthalmic: Lacrimation, miosis
tis, rigors, scotoma, sinusitis, skin rash, stupor, syn- Respiratory: Asthma, bronchoconstriction
cope, tendonitis, thrombocytopenia, thrombophlebitis, Mechanism of Action Due to stimulation of the para-
thrombosis, tinnitus, tremor, twitching, visual disturb- sympathetic nervous system, bethanechol increases
ance, vomiting, weight gain, weight loss, xerostomia bladder muscle tone causing contractions which initiate
Mechanism of Action Competitively blocks beta1- urination. Bethanechol also stimulates gastric motility,
receptors, with little or no effect on beta2-receptors increases gastric tone and may restore peristalsis.
Pharmacodynamics/Kinetics Pharmacodynamics/Kinetics
Onset of Action 1 to 1.5 hours Onset of Action 30 minutes; Peak effect: ~60 to 90
Half-life Elimination 14 to 22 hours; prolonged in minutes
hepatic disease and/or chronic renal failure. In Duration of Action ~1 hour (with therapeutic doses);
patients with chronic renal failure undergoing dialysis, up to 6 hours with large doses (300 to 400 mg)
the half-life and AUC are approximately doubled. Pregnancy Risk Factor C
Time to Peak 1.5 to 6 hours Pregnancy Considerations Animal reproduction
Pregnancy Risk Factor C studies have not been conducted.
observed in some animal reproduction studies. Betax-
olol crosses the placenta and can be detected in the Betrixaban (be TRIX a ban)
amniotic fluid as well as umbilical cord blood. Meas- Related Information
urable concentrations of betaxolol can also be found in
Antiplatelet and Anticoagulation Considerations in Den-
the newborn blood and urine (Morselli 1990). Following
tistry on page 1454
maternal use of betaxolol, the beta-blocker effects may
Brand Names: US Bevyxxa
persist in the neonate for several days after birth. The
risk of cardiac and pulmonary complications is
lant, Factor Xa Inhibitor; Direct Oral Anticoagulant
increased in the neonate. Bradycardia, hypoglycemia,
(DOAC)
and respiratory distress have been reported and mon-
itoring of the neonate for 3 to 5 days after birth is Use
recommended. Reduced birth weight has also been VTE (prophylaxis): Prophylaxis of VTE in adults hos-
observed following in utero exposure to beta-blockers pitalized for an acute medical illness who are at risk for
as a class. thromboembolic complications due to moderate or
severe restricted mobility and other risk factors for
The maternal half-life and serum concentration of VTE.
betaxolol immediately postpartum are not significantly Limitations of use: Safety and effectiveness have not
different than what is observed in nonpregnant women been established in patients with prosthetic heart
(Boutroy 1990; Morselli 1990). Untreated chronic valves (has not been studied).
213
BETRIXABAN
Local Anesthetic/Vasoconstrictor Precautions Colorectal cancer, metastatic (Avastin, Mvasi): First-

No information available to require special precautions or second-line treatment of metastatic colorectal can-
Effects on Dental Treatment Key adverse event(s) cer (CRC) (in combination with fluorouracil-based
related to dental treatment: Surgical site bleeding may chemotherapy); second-line treatment of metastatic
occur; see Effects on Bleeding CRC (in combination with fluoropyrimidine-irinotecan-
Effects on Bleeding Betrixaban inhibits platelet acti- or fluoropyrimidine-oxaliplatin-based chemotherapy)
vation and fibrin clot formation via direct, selective, and after progression on a first-line treatment containing
reversible inhibition of factor Xa. As with all anticoagu- bevacizumab.
lants, bleeding is the major adverse effect of betrixaban. Limitations of use: Not indicated for the adjuvant treat-
Hemorrhage may occur at virtually any site; risk is ment of colon cancer.
dependent on multiple variables including the intensity Glioblastoma, recurrent (Avastin): Treatment of
of anticoagulation and patient susceptibility. Medical recurrent glioblastoma
Glioblastoma, progressive (Mvasi): Treatment of
consult is suggested.
glioblastoma (as a single agent) in patients with pro-
Adverse Reactions gressive disease
1% to 10%: Non-small cell lung cancer, nonsquamous (Avastin,
Cardiovascular: Hypertension (2%) Mvasi): First-line treatment of unresectable, locally
Central nervous system: Headache (2%) advanced, recurrent or metastatic nonsquamous
Endocrine & metabolic: Hypokalemia (3%) non-small cell lung cancer (NSCLC) (in combination
Gastrointestinal: Constipation (3%), diarrhea (2%), with carboplatin and paclitaxel).
nausea (2%) Ovarian (epithelial), fallopian tube, or primary peri-
Genitourinary: Urinary tract infection (3%), hematu- toneal cancer (Avastin):
ria (2%) Stage III or IV disease, following initial surgical resec-
Hematologic & oncologic: Hemorrhage (2%; clinically tion: Treatment of stage III or IV epithelial ovarian,
relevant non-major bleeding) fallopian tube, or primary peritoneal cancer following
Respiratory: Epistaxis (2%) initial surgical resection (in combination with carbo-
<1%, postmarketing, and/or case reports: Hypersensi- platin and paclitaxel, followed by single-agent bev-
tivity reaction, major hemorrhage (including gastro- acizumab).
intestinal bleeding, intracranial hemorrhage, and Platinum-resistant recurrent: Treatment of platinum-
intraocular bleeding) resistant recurrent epithelial ovarian, fallopian tube,
Mechanism of Action Inhibits fibrin clot formation via or primary peritoneal cancer (in combination with
direct and selective inhibition of factor Xa (FXa). FXa, paclitaxel, doxorubicin [liposomal], or topotecan) in
as part of the prothrombinase complex consisting also patients who received no more than 2 prior chemo-
of factor Va, calcium ions, and phospholipid, catalyzes therapy regimens.
the conversion of prothrombin to thrombin. Thrombin Platinum-sensitive recurrent: Treatment of platinum-
both activates platelets and catalyzes the conversion of sensitive recurrent epithelial ovarian, fallopian tube,
fibrinogen to fibrin. or primary peritoneal cancer (in combination with
Pharmacodynamics/Kinetics carboplatin and paclitaxel or with carboplatin and
Onset of Action Peak effect: 3 to 4 hours gemcitabine and then followed by single-agent bev-
Duration of Action ≥72 hours acizumab).
Half-life Elimination 19 to 27 hours Renal cell carcinoma, metastatic (Avastin, Mvasi):
Time to Peak 3 to 4 hours Treatment of metastatic renal cell carcinoma (RCC) (in
combination with interferon alfa).
Pregnancy Considerations Adverse fetal events
were not observed in animal reproduction studies.
Use during pregnancy may increase the risk hemor-
rhage during labor or delivery. Data are insufficient to
evaluate the safety of oral factor Xa inhibitors during
flow resumes upon discontinuation), stomatitis, taste
pregnancy; use during pregnancy should be avoided
disorder, and gingival bleeding.
(Guyatt 2012).
Dental Health Professional Considerations Rou- Cases of osteonecrosis of the jaw (ONJ) have been
tine coagulation testing (INR) is not required, or neces- associated with bevacizumab exposure. ONJ presents
sary, for Direct-Acting Oral Anticoagulants (DOAC). clinically as exposed necrotic bone of at least 8 weeks
duration with or without the presence of pain, infection,
or previous trauma in a patient who has not received
Bevacizumab (be vuh SIZ uh mab) radiation to the jaw. Since ONJ is also associated with
bisphosphonate exposure and bisphosphonates are
Related Information
known to have antiangiogenic properties, inhibition of
Osteonecrosis of the Jaw on page 1486
angiogenesis may play a role in ONJ associated with
Brand Names: US Avastin these two classes of drugs. Patients developing ONJ
Brand Names: Canada Avastin while on bevacizumab therapy should receive care by
Pharmacologic Category Antineoplastic Agent, an oral surgeon. See Dental Health Professional Con-
Monoclonal Antibody; Antineoplastic Agent, Vascular siderations.
Endothelial Growth Factor (VEGF) Inhibitor; Vascular Effects on Bleeding Minor gum bleeding has been
Endothelial Growth Factor (VEGF) Inhibitor reported in 2% to 4% of patients. Thrombocytopenia
Use has been reported. A medical consult is suggested.
Cervical cancer, persistent/recurrent/metastatic Adverse Reactions Percentages reported as mono-
(Avastin [bevacizumab], Mvasi [bevacizumab- therapy and as part of combination chemotherapy regi-
awwb; biosimilar]): Treatment of persistent, recur- mens. Some studies only reported hematologic
rent, or metastatic cervical cancer (in combination with toxicities grades ≥4 and nonhematologic toxicities
paclitaxel and either cisplatin or topotecan). grades ≥3.
214
BEVACIZUMAB
>10%: Hematologic & oncologic: Febrile neutropenia (5%),

Cardiovascular: Hypertension (19% to 42%), venous neutropenic infection (grades 3/4: 5%), hemorrhage
thromboembolism (secondary: 21%; with oral anti- (CNS; 5%)
coagulants), peripheral edema (15%), hypotension Hepatic: Increased serum AST (15%)
(7% to 15%), venous thromboembolism (8% to Infection: Abscess (tooth, 2%)
14%), arterial thrombosis (6%) Neuromuscular & skeletal: Weakness (grades 3/4:
Central nervous system: Fatigue (33% to 82%), pain 10%), neck pain (9%)
(8% to 62%), headache (22% to 49%), dizziness Ophthalmic: Blurred vision (2%)
(13% to 26%), insomnia (21%), taste disorder (14% Otic: Tinnitus (2%), deafness (1%)
to 21%), peripheral sensory neuropathy (17% to Respiratory: Rhinorrhea (10%), nasal congestion
18%), anxiety (17%), myasthenia (13%) (8%), pneumonitis (grades 3/4: 5%)
Dermatologic: Alopecia (6% to 32%), exfoliative der- Miscellaneous: Fistula (gastrointestinal-vaginal; 8%),
matitis (23%), palmar-plantar erythrodysesthesia fistula (anal; 6%), infusion related reaction (<3%),
(11%), xeroderma (7%) fistula (≤2%)
Endocrine & metabolic: Ovarian failure (34%), hyper- <1%, postmarketing, and/or case reports: Anaphylaxis,
glycemia (26% to 31%), hypomagnesemia (24% to anastomotic ulcer, angina pectoris, antibody develop-
27%), weight loss (15% to 21%), hyponatremia (17% ment (anti-bevacizumab and neutralizing), bladder
to 19%), hypoalbuminemia (11% to 16%), hypocal- fistula, bronchopleural fistula, cerebral infarction, con-
cemia (12%) junctival hemorrhage, endophthalmitis (infectious and
Gastrointestinal: Nausea (72%), abdominal pain (33% sterile), eye discomfort, eye pain, fistula of bile duct,
to 61%), vomiting (33% to 52%), anorexia (35% to fulminant necrotizing fasciitis, gallbladder perforation,
43%), constipation (40%), diarrhea (21% to 39%), gastrointestinal ulcer, hemolytic anemia (microangio-
decreased appetite (34% to 35%), stomatitis (15% to pathic; when used in combination with sunitinib),
33%), gastrointestinal hemorrhage (19% to 24%), hemoptysis, hemorrhagic stroke, hypersensitivity,
dyspepsia (17% to 24%), mucosal inflammation hypertensive crisis, hypertensive encephalopathy,
(13% to 15%) increased intraocular pressure, inflammation of ante-
Genitourinary: Proteinuria (4% to 36%; median onset: rior segment of eye (toxic anterior segment syndrome)
5.6 months; median time to resolution: 6.1 months), (Sato 2010), intestinal necrosis, intraocular inflamma-
urinary tract infection (22%), pelvic pain (14%) tion (iritis, vitritis), mesenteric thrombosis, myocardial
Hematologic & oncologic: Thrombocytopenia (5% to infarction, nasal septum perforation, nephrotic syn-
58%; grade 3/4: 40%), hemorrhage (40%; grades drome, ocular hyperemia, osteonecrosis of the jaw,
3/4: ≤7%), leukopenia (grades 3/4: 37%), pulmonary pancytopenia, permanent vision loss, polyserositis,
hemorrhage (4% to 31%), neutropenia (12%; grades pulmonary hypertension, rectal fistula, renal failure,
≥3: 8% to 27%, grade 4: 27%), bruise (17%), lym- renal fistula, renal thrombotic microangiopathy, retinal
phocytopenia (12%; grades 3/4: 6%) detachment, retinal hemorrhage, reversible posterior
Infection: Infection (55%; serious: 7% to 14%; pneu- leukoencephalopathy syndrome, sepsis, tracheoeso-
monia, catheter infection, or wound infection) phageal fistula, transient ischemic attacks, vaginal
Neuromuscular & skeletal: Arthralgia (28% to 45%), fistula, visual disturbance, vitreous hemorrhage, vitre-
myalgia (19% to 29%), limb pain (25%), back pain ous opacity
(12% to 21%), dysarthria (8% to 14%) Mechanism of Action Bevacizumab is a recombinant,
Renal: Increased serum creatinine (13% to 16%) humanized monoclonal antibody which binds to, and
Respiratory: Epistaxis (17% to 55%), upper respiratory neutralizes, vascular endothelial growth factor (VEGF),
tract infection (40% to 47%), cough (26% to 30%), preventing its association with endothelial receptors,
dyspnea (25% to 30%), allergic rhinitis (17%), oro- Flt-1 and KDR. VEGF binding initiates angiogenesis
pharyngeal pain (16%), sinusitis (7% to 15%), nasal (endothelial proliferation and the formation of new blood
sign & symptoms (mucosal disorder: 14%), rhinitis vessels). The inhibition of microvascular growth is
(3% to >10%) believed to retard the growth of all tissues (including
Miscellaneous: Postoperative wound complication metastatic tissue).
(including dehiscence, 1% to 15%) Pharmacodynamics/Kinetics
1% to 10%: Half-life Elimination
Cardiovascular: Thrombosis (8% to 10%), deep vein IV:
thrombosis (6% to 9%), chest pain (8%), intra- Pediatric patients (age: 1 to 21 years): Median: 11.8
abdominal thrombosis (venous, grades 3/4: 3%), days (range: 4.4 to 14.6 days) (Glade Bender 2008)
syncope (grades 3/4: 3%), left ventricular dysfunction Adults: ~20 days (range: 11 to 50 days)
(grades 3/4: 1%), pulmonary embolism (1%) Intravitreal: ~5 to 10 days (Bakri 2007; Krohne 2008)
Central nervous system: Voice disorder (5% to 13%) Pregnancy Considerations Based on findings in
Dermatologic: Nail disease (10%), dermal ulcer (6%), animal reproduction studies and on the mechanism of
cellulitis (grades 3/4: 3%), acne vulgaris (1%) action, bevacizumab may cause fetal harm if adminis-
Endocrine & metabolic: Dehydration (grades 3/4: 4% tered to a pregnant woman. Information from postmar-
to 10%), hyperkalemia (9%), hypokalemia (grades keting reports following exposure in pregnancy is
3/4: 7%) limited. Women of reproductive potential should use
Gastrointestinal: Hemorrhoids (8%), xerostomia (4% effective contraception during therapy and for 6 months
to 7%), gingival hemorrhage (minor, 2% to 7%), following the last bevacizumab dose. Bevacizumab
rectal pain (6%), colitis (1% to 6%), intestinal treatment may also increase the risk of ovarian failure
obstruction (grades 3/4: 4%), gastrointestinal perfo- and impair fertility; long term effects on fertility are not
ration (≤3%), gastroesophageal reflux disease (2%), known.
gingivitis (2%), oral mucosa ulcer (2%), gastrointes- Product Availability Mvasi (bevacizumab-awwb):
tinal fistula (≤2%), gastritis (1%), gingival pain (1%) FDA approved September 2017; anticipated availability
Genitourinary: Vaginal hemorrhage (4%) is currently unknown. Mvasi has been approved as a
215
BEVACIZUMAB
biosimilar, not as an interchangeable product. Consult Gastrointestinal: Colitis (<10%), hematochezia (3%),
the prescribing information for additional information. hemorrhoidal bleeding (1%)
Dental Health Professional Considerations Three Hematologic & oncologic: Rectal hemorrhage (4%)
case reports describe the development of ONJ in asso- Hypersensitivity: Hypersensitivity (<10%)
ciation with bevacizumab therapy. All three cases were Neuromuscular & skeletal: Panniculitis (<10%)
cancer patients treated with bevacizumab 10 mg/kg Ophthalmic: Uveitis (4%)
every 2 weeks and 15 mg/kg every 3 weeks (Estilo Frequency not defined:
2009; Greuter 2008). Another report showed that a Cardiovascular: Left ventricular dysfunction
combination of bisphosphonates and antiangiogenic Central nervous system: Headache
factors (primarily bevacizumab) induces ONJ more <1%, postmarketing, and/or case reports: Interstitial
frequently than bisphosphonates alone. Of the 25 pulmonary disease, pneumonitis, retinal vein occlu-
patients receiving concurrent treatment with bisphosph- sion, rhabdomyolysis
onates and the antiangiogenic drug bevacizumab, four Mechanism of Action Binimetinib reversibly inhibits
developed ONJ (16%). Of the 91 patients receiving mitogen-activated extracellular kinase (MEK) 1 and 2
bisphosphonates without antiangiogenic factors, one activation and kinase activity. MEK proteins are
developed ONJ (1.1%), a significant statistical differ- upstream regulators of the extracellular signal-related
ence (Christodoulou 2009). kinase (ERK) pathway. Binimetinib inhibits ERK phos-
phorylation and viability and MEK-dependent phosphor-
ylation of the protein kinase B-raf (BRAF) mutant cell
Binimetinib (bin i ME ti nib) lines. The combination of binimetinib and encorafenib
allows for greater antitumor activity in BRAF V600
Brand Names: US Mektovi mutant cell lines; in animal studies, the combination
Pharmacologic Category Antineoplastic Agent, MEK also delayed the emergence of resistance in BRAF
Inhibitor V600E mutant cells compared to either drug alone.
Use Melanoma, unresectable or metastatic: Treat- Pharmacodynamics/Kinetics
ment of unresectable or metastatic melanoma with a Half-life Elimination 3.5 hours
BRAF V600E or V600K mutation (in combination with Time to Peak 1.6 hours
encorafenib) as detected by an approved test. Pregnancy Considerations
Local Anesthetic/Vasoconstrictor Precautions Based on its mechanism of action and on findings in
No information available to require special precautions animal reproduction studies, binimetinib may cause
Effects on Dental Treatment Key adverse event(s) fetal harm if administered during pregnancy.
related to dental treatment: Hypertension reported
(>10%); consider monitoring blood pressure prior to Verify pregnancy status in females of reproductive
using local anesthetic with a vasoconstrictor potential prior to initiating binimetinib therapy. Females
Effects on Bleeding Frequent hemorrhagic events of reproductive potential should use a highly effective
reported which were gastrointestinal in nature, although contraceptive during therapy and for at least 30 days
none involving the oral cavity after the final binimetinib dose.
Adverse Reactions Incidences of adverse reactions Product Availability Mektovi: FDA approved June
were defined during combination therapy with encora- 2018; anticipated availability is late June 2018. Consult
fenib. the prescribing information for additional information.
>10%: Prescribing and Access Restrictions Binimetinib is
Cardiovascular: Peripheral edema (13%), hyperten- available through a network of select specialty pharma-
sion (11%) cies. Refer to https://www.braftovimektovi.com/hcp/ for
Central nervous system: Fatigue (43%), dizzi- more information.
ness (15%)
Dermatologic: Skin rash (22%) Bismuth Subcitrate, Metronidazole,
transferase (45%), hyponatremia (18%)
and Tetracycline
(BIZ muth sub CIT rate, me troe NI da zole, & tet ra SYE kleen)
Gastrointestinal: Nausea (41%), diarrhea (36%), vom-
iting (30%), abdominal pain (28%), constipa- Brand Names: US Pylera
tion (22%) Pharmacologic Category Antibiotic, Miscellaneous;
Hematologic & oncologic: Anemia (36%, grades 3/4: Antibiotic, Tetracycline Derivative; Antidiarrheal
4%), hemorrhage (19%; grades 3/4:3%), leukopenia Use Duodenal ulcer associated with Helicobacter
(13%), lymphocytopenia (13%, grades 3/4: 2%), pylori infection: In combination with omeprazole for
neutropenia (13%, grades 3/4: 3%) the treatment of patients with H. pylori infection and
Hepatic: Increased serum alanine aminotransferase duodenal ulcer disease (active or history of within the
(29%), increased serum aspartate aminotransferase past 5 years) to eradicate H. pylori.
(27%), increased serum alkaline phosphatase (21%) Local Anesthetic/Vasoconstrictor Precautions
Neuromuscular & skeletal: Increased creatine phos- No information available to require special precautions
phokinase in blood specimen (58%) Effects on Dental Treatment Tetracyclines are not
Ophthalmic: Visual impairment (20%), retinal pigment recommended for use during pregnancy since they can
changes (≤20%, retinal pigment epithelial dystro- cause enamel hypoplasia and permanent teeth discol-
phy), retinopathy (≤20%, serous including 8% retinal oration; long-term use associated with oral candidiasis;
detachment and 6% macular edema) taste perversion has been reported.
Renal: Increased serum creatinine (93%) Effects on Bleeding No information available to
Miscellaneous: Fever (18%) require special precautions
1% to 10%: Adverse Reactions Also see individual agents.
Cardiovascular: Decreased left ventricular ejection Adverse reactions are associated with concomitant
fraction (7%), venous thromboembolism (6%), pul- administration of omeprazole.
monary embolism (3%) >10%: Gastrointestinal: Abnormal stools (16%)
216
BISOPROLOL
1% to 10%: after 3 or more weeks of therapy with the NSAID. Short-

Central nervous system: Headache (5%), dizzi- term NSAID use (ie, 3 days) requires no special pre-
ness (3%) cautions in patients taking beta-blockers.
Dermatologic: Maculopapular rash (1%) Effects on Bleeding No information available to
Gastrointestinal: Nausea (8%), diarrhea (7%), require special precautions
abdominal pain (5%), dysgeusia (4%), dyspepsia Adverse Reactions
(3%), constipation (1%), xerostomia (1%) 1% to 10%:
Genitourinary: Vaginitis (3%), urine abnormality (1%) Cardiovascular: Chest pain (1%)
Hepatic: Increased serum ALT (1%), increased serum Central nervous system: Fatigue (7%), hypoesthe-
AST (1%) sia (1%)
Neuromuscular & skeletal: Weakness (3%) Gastrointestinal: Diarrhea (3%), vomiting (1%)
Miscellaneous: Laboratory test abnormality (2%) Hepatic: Increased serum alanine aminotransferase
<1%, postmarketing, and/or case reports: Abdominal (≤4%), increased serum aspartate aminotransferase
distention, anxiety, back pain, candidiasis, chest dis- (≤4%)
comfort, chest pain, drowsiness, duodenal ulcer, eruc- Respiratory: Upper respiratory tract infection (5%),
tation, fatigue, flatulence, gastritis, gastroenteritis, dyspnea (1%)
increased appetite, increased creatine phosphoki- Frequency not defined:
nase, malaise, myalgia, skin rash, tachycardia, tongue Cardiovascular: Cardiac arrhythmia, cardiac failure,
discoloration (darkening), visual disturbance, vomit- claudication, cold extremities, edema, flushing,
ing, weight gain hypersensitivity angiitis, hypotension, orthostatic
Mechanism of Action hypotension, palpitations
Bismuth: Has both antisecretory and antimicrobial Central nervous system: Anxiety, depression, dizzi-
action; may provide some anti-inflammatory action ness, drowsiness, headache, hyperesthesia, insom-
as well. nia, lack of concentration, malaise, memory
Metronidazole: After diffusing into the organism, inter- impairment, paresthesia, restlessness, sensation of
acts with DNA to cause a loss of helical DNA structure eye pressure, twitching, vertigo, vivid dream
and strand breakage resulting in inhibition of protein Dermatologic: Acne vulgaris, alopecia, diaphoresis,
synthesis and cell death in susceptible organisms. eczema, pruritus, skin irritation, skin rash
Tetracycline: Inhibits bacterial protein synthesis by bind- Endocrine & metabolic: Decreased libido, gout,
ing with the 30S and possibly the 50S ribosomal increased serum glucose, increased serum phos-
subunit(s) of susceptible bacteria; may also cause phate, increased serum potassium, increased serum
alterations in the cytoplasmic membrane. triglycerides, increased uric acid, weight gain
Bismuth, metronidazole, and tetracycline individually Gastrointestinal: Abdominal pain, constipation, dys-
have demonstrated in vitro activity against most sus- geusia, dyspepsia, epigastric pain, gastric pain, gas-
ceptible strains of H. pylori isolated from patients with tritis, nausea, peptic ulcer, xerostomia
duodenal ulcers. Genitourinary: Cystitis, impotence
Pregnancy Considerations This combination is con- Hematologic & oncologic: Decreased white blood cell
traindicated in women who are pregnant. Metronidazole count, positive ANA titer, purpuric rash, thrombocy-
and tetracycline both cross the human placenta and topenia
may have adverse effects to the fetus. See individual Neuromuscular & skeletal: Back pain, muscle cramps,
agents. myalgia, neck pain, tremor
Ophthalmic: Abnormal lacrimation, eye pain, visual
disturbance
Otic: Otalgia, tinnitus
Bisoprolol (bis OH proe lol) Renal: increased blood urea nitrogen, increased
serum creatinine, polyuria, renal colic
Related Information Respiratory: Asthma, bronchitis, bronchospasm,
Cardiovascular Diseases on page 1442 cough, dyspnea on exertion, pharyngitis, rhinitis,
Brand Names: US Zebeta [DSC] sinusitis
Brand Names: Canada Apo-Bisoprolol; Ava-Bisopro- <1%, postmarketing, and/or case reports: Angioedema,
lol; Mylan-Bisoprolol; Novo-Bisoprolol; PHL-Bisoprolol; arthralgia, asthenia, auditory impairment, bradycardia,
PMS-Bisoprolol; PRO-Bisoprolol; Sandoz-Bisoprolol; dermatitis, exfoliative dermatitis, Peyronie disease,
Teva-Bisoprolol psoriasis, sleep disturbance, syncope, unsteadiness
Pharmacologic Category Antihypertensive; Beta- Mechanism of Action Selective inhibitor of beta1-
Blocker, Beta-1 Selective adrenergic receptors; competitively blocks beta1-recep-
Use Hypertension: Management of hypertension. tors, with little or no effect on beta2-receptors at doses
Note: Beta-blockers are not recommended as first-line ≤20 mg
therapy (ACC/AHA [Whelton 2017]). Pharmacodynamics/Kinetics
Local Anesthetic/Vasoconstrictor Precautions Onset of Action 1 to 2 hours
No information available to require special precautions Half-life Elimination Normal renal function: 9 to 12
Effects on Dental Treatment Bisoprolol is a cardio- hours; CrCl <40 mL/minute: 27 to 36 hours; Hepatic
selective beta-blocker. Local anesthetic with vasocon- cirrhosis: 8 to 22 hours
strictor can be safely used in patients medicated with Time to Peak 2 to 4 hours
bisoprolol. Nonselective beta-blockers (ie, propranolol, Pregnancy Risk Factor C
nadolol) enhance the pressor response to epinephrine, Pregnancy Considerations Adverse events were
resulting in hypertension and bradycardia; this has not observed in animal reproduction studies. Adverse
been reported for bisoprolol. Many nonsteroidal anti- events, such as fetal/neonatal bradycardia, hypoglyce-
inflammatory drugs, such as ibuprofen and indometha- mia, and reduced birth weight have been observed
cin, can reduce the hypotensive effect of beta-blockers following in utero exposure to beta-blockers as a class.
217
BISOPROLOL
Adequate facilities for monitoring infants at birth are Hematologic & oncologic: Major hemorrhage (Protocol
generally recommended. defined: 2% to 4%; heparin 4% to 9%; TIMI defined:
0.6%; heparin 0.9%; transfusion required: 1% to 2%;
Untreated chronic maternal hypertension and pree-
heparin 2% to 6% [Lincoff, 2003])
clampsia are also associated with adverse events in
Local: Pain at injection site (≤8%)
the fetus, infant, and mother (ACOG 2015; Magee
2014). Although beta-blockers may be used when treat- Miscellaneous: Fever (5%)
ment of hypertension or heart failure in pregnancy is <1%, postmarketing, and/or case reports: Cardiac tam-
indicated, agents other than bisoprolol are preferred ponade, cerebral ischemia, confusion, facial paralysis,
( A C O G 2 0 1 3 ; E S C [ R e g i t z - Z a g r o s e k 2 0 11 ] ; hemorrhage, hypersensitivity reaction (including ana-
Magee 2014). phylaxis), increased INR, increased susceptibility to
infection, intracranial hemorrhage, oliguria, pulmonary
edema, pulmonary hemorrhage, renal failure, retro-
Bivalirudin (bye VAL i roo din) peritoneal hemorrhage, sepsis, syncope, thrombocy-
topenia, vascular disease, venous thrombosis (during
Related Information
PCI, including intracoronary brachytherapy), ventricu-
lar fibrillation
Brand Names: US Angiomax
Mechanism of Action Bivalirudin acts as a specific
Brand Names: Canada Angiomax and reversible direct thrombin inhibitor; it binds to the
Pharmacologic Category Anticoagulant; Anticoagu- catalytic and anionic exosite of both circulating and clot-
lant, Direct Thrombin Inhibitor bound thrombin. Catalytic binding site occupation func-
Use Percutaneous coronary intervention: Anticoagu- tionally inhibits coagulant effects by preventing throm-
lant for use in patients undergoing percutaneous coro- bin-mediated cleavage of fibrinogen to fibrin monomers,
nary intervention (PCI) including patients with heparin- and activation of factors V, VIII, and XIII. Shows linear
induced thrombocytopenia (HIT) and heparin-induced
dose- and concentration-dependent prolongation of
thrombocytopenia/thrombosis syndrome (HIT/TS)
ACT, aPTT, PT, and TT.
Local Anesthetic/Vasoconstrictor Precautions Pharmacodynamics/Kinetics
No information available to require special precautions Onset of Action Immediate
Duration of Action Coagulation times return to base-
related to dental treatment: Bleeding is the major
line ~1 hour following discontinuation of infusion
adverse effect of bivalirudin. Additional adverse effects
are often related to idiosyncratic reactions, the fre- Half-life Elimination
quency is difficult to estimate. Adverse reactions Normal renal function and mild renal impairment: 25
reported were generally less than those seen with minutes
heparin. See Effects on Bleeding. Moderate renal impairment: 34 minutes
Effects on Bleeding As with all anticoagulants, bleed- Severe renal impairment: 57 minutes
ing is a potential adverse effect of bivalirudin during Dialysis: 3.5 hours
dental surgery; risk is dependent on multiple variables, Pregnancy Considerations Bivalirudin is used in
including the intensity of anticoagulation and patient conjunction with aspirin, which may lead to maternal
susceptibility. Medical consult is suggested. It is unlikely or fetal adverse effects, especially during the third
that ambulatory patients presenting for dental treatment trimester. Use of parenteral direct thrombin inhibitors
will be taking intravenous anticoagulant therapy such as in pregnancy should be limited to those women who
bivalirudin. have severe allergic reactions to heparin, including
Adverse Reactions As with all anticoagulants, bleed- heparin-induced thrombocytopenia, and who cannot
ing is the major adverse effect of bivalirudin. Hemor- receive danaparoid (Guyatt 2012).
rhage may occur at virtually any site. Risk is dependent
on multiple variables, including the intensity of anti- Bleomycin (blee oh MYE sin)
coagulation, concurrent use of a glycoprotein IIb/IIIa
inhibitor, and patient susceptibility. Additional adverse Brand Names: Canada Blenoxane; Bleomycin Injec-
effects are often related to idiosyncratic reactions, and tion, USP
the frequency is difficult to estimate. Adverse reactions Pharmacologic Category Antineoplastic Agent, Anti-
reported were generally less than those seen with biotic
heparin. Use
>10%: Head and neck cancers: Treatment of squamous cell
Cardiovascular: Hypotension (≤12%) carcinomas of the head and neck
Central nervous system: Pain (≤15%), head-
Hodgkin lymphoma: Treatment of Hodgkin lymphoma
ache (≤12%)
Malignant pleural effusion: Sclerosing agent for
Gastrointestinal: Nausea (≤15%)
malignant pleural effusion
Hematologic & oncologic: Minor hemorrhage (Protocol
Testicular cancer: Treatment of testicular cancer
defined: 14%; heparin 26%; TIMI defined: 1%; hep-
arin 3% [Lincoff, 2003]) Local Anesthetic/Vasoconstrictor Precautions
Neuromuscular & skeletal: Back pain (9% to 42%) No information available to require special precautions
1% to 10%: Effects on Dental Treatment Key adverse event(s)
Cardiovascular: Hypertension (6%), bradycardia (5%), related to dental treatment: Stomatitis and mucositis.
angina pectoris (≤5%), thrombosis (1%; <4 hours, in Effects on Bleeding No information available to
patients with STEMI undergoing primary PCI) require special precautions
Central nervous system: Insomnia (7%), anxiety (6%), Adverse Reactions Frequency not always defined.
nervousness (5%) The pathogenesis of respiratory adverse effects is not
Gastrointestinal: Vomiting (≤6%), abdominal pain certain, but may be due to damage of pulmonary,
(5%), dyspepsia (5%) vascular, or connective tissue. Response to steroid
Genitourinary: Pelvic pain (6%), urinary retention (4%) therapy is variable and somewhat controversial.
218
BORTEZOMIB
>10%:
Cardiovascular: Phlebitis Bortezomib (bore TEZ oh mib)
Central nervous system: Tumor pain
Dermatologic: Hyperpigmentation (50%), atrophic Brand Names: US Velcade
striae (≤50%), erythema (≤50%), exfoliation of the Brand Names: Canada Velcade
skin (≤50%; particularly on the palmar and plantar Pharmacologic Category Antineoplastic Agent, Pro-
surfaces of the hands and feet), hyperkeratosis teasome Inhibitor
(≤50%), localized vesiculation (≤50%), skin rash Use
(≤50%), skin sclerosis (≤50%), alopecia (may be Mantle cell lymphoma: Treatment of mantle cell lym-
dose-related and reversible with discontinuation), phoma.
nailbed changes (may be dose-related and reversi- Multiple myeloma: Treatment of multiple myeloma.
ble with discontinuation) Local Anesthetic/Vasoconstrictor Precautions
Endocrine & metabolic: Weight loss No information available to require special precautions
Gastrointestinal: Stomatitis (≤30%), mucositis (≤30%), Effects on Dental Treatment Key adverse event(s)
anorexia related to dental treatment: Abnormal taste and stoma-
Miscellaneous: Febrile reaction (25% to 50%; acute) titis.
1% to 10%: Effects on Bleeding Dose-related thrombocytopenia
Dermatologic: Onycholysis, pruritus, thickening of skin (~35%; nadir: day 11; recovery: by day 21) is most
Hypersensitivity: Anaphylactoid reaction (including common hematological event with platelet counts usu-
chills, confusion, fever, hypotension, wheezing; ally returning to baseline following active therapy each
cycle. A medical consult is suggested.
onset may be immediate or delayed for several
hours; includes idiosyncratic reaction in 1% of lym-
Adverse Reactions Incidences reported are associ-
ated with monotherapy. Additional adverse reactions
phoma patients)
reported with mono- or combination therapy; frequency
Neuromuscular & skeletal: Scleroderma (diffuse)
not defined.
Respiratory: Tachypnea (≤5% to 10%), rales (≤5% to
Cardiovascular: Hypotension (8% to 9%), cardiac dis-
10%), interstitial pneumonitis (acute or chronic: ≤5%
ease (treatment emergent; 8%), acute pulmonary
to 10%), pulmonary fibrosis (≤5% to 10%), hypo- edema (≤1%), cardiac failure (≤1%), cardiogenic
xia (1%) shock (≤1%), pulmonary edema (≤1%), aggravated
<1%, postmarketing, and/or case reports: Angioedema, atrial fibrillation, angina pectoris, atrial flutter, atrioven-
bone marrow depression (rare), cerebrovascular acci- tricular block, bradycardia, cerebrovascular accident,
dent, cerebral arteritis, chest pain, coronary artery deep vein thrombosis, edema, embolism (peripheral),
disease, hepatotoxicity, hyperpigmentation (flagel- facial edema, hemorrhagic stroke, hypertension,
late), ischemic heart disease, malaise, myocardial ischemic heart disease, myocardial infarction, pericar-
infarction, nausea, nephrotoxicity, pericarditis, Ray- dial effusion, pericarditis, peripheral edema, phlebitis,
naud’s phenomenon, scleroderma (scleroderma-like portal vein thrombosis, pulmonary embolism, septic
skin changes), Stevens-Johnson syndrome, throm- shock, sinoatrial arrest, subdural hematoma, torsades
botic thrombocytopenic purpura, toxic epidermal nec- de pointes, transient ischemic attacks, ventricular
rolysis, vomiting tachycardia
Mechanism of Action Bleomycin inhibits synthesis of Central nervous system: Peripheral neuropathy (IV:
DNA; binds to DNA leading to single- and double-strand 35% to 54%; SubQ: 37%; grade ≥2: 24% to 39%;
breaks; also inhibits (to a lesser degree) RNA and grade ≥3: SubQ: 5% to 6%; IV: 7% to 15%; grade 4:
protein synthesis <1%), fatigue (7% to 52%), neuralgia (23%), head-
Pharmacodynamics/Kinetics ache (10% to 19%), paresthesia (7% to 19%), dizzi-
Half-life Elimination Terminal: IV: 2 hours ness (10% to 18%; excludes vertigo), agitation,
Time to Peak Serum: IM, SubQ, Intrapleural: 30 to 60 anxiety, ataxia, brain disease, cerebral hemorrhage,
minutes chills, coma, confusion, cranial nerve palsy, dysarthria,
Pregnancy Risk Factor D dysautonomia, dysesthesia, insomnia, malaise, men-
Pregnancy Considerations Adverse effects were tal status changes, motor dysfunction, paralysis, psy-
chosis, seizure, spinal cord compression, suicidal
observed in animal reproduction studies. According to
ideation, vertigo
the manufacturer, women of childbearing potential
Dermatologic: Skin rash (12% to 23%), pruritus, urti-
should avoid becoming pregnant during bleomycin
caria
treatment. The European Society for Medical Oncology
Endocrine & metabolic: Dehydration (2%), amyloid
has published guidelines for diagnosis, treatment, and
heart disease, hyperglycemia (diabetic patients),
follow-up of cancer during pregnancy; the guidelines hyperkalemia, hypernatremia, hyperuricemia, hypo-
recommend referral to a facility with expertise in cancer calcemia, hypoglycemia (diabetic patients), hypokale-
during pregnancy and encourage a multidisciplinary mia, hyponatremia, weight loss
team (obstetrician, neonatologist, oncology team). In Gastrointestinal: Diarrhea (19% to 52%), nausea (14%
general, if chemotherapy is indicated, it should be to 52%), constipation (24% to 34%), vomiting (9% to
avoided in the first trimester and there should be a 3- 29%), anorexia (14% to 21%), abdominal pain (11%),
week time period between the last chemotherapy dose decreased appetite (11%), cholestasis, duodenitis
and anticipated delivery, and chemotherapy should not (hemorrhagic), dysphagia, fecal impaction, gastritis
be administered beyond week 33 of gestation (Pecca- (hemorrhagic), gastroenteritis, gastroesophageal
tori 2013). When multiagent therapy is needed to treat reflux disease, hematemesis, intestinal obstruction,
Hodgkin lymphoma during pregnancy, bleomycin (as a intestinal perforation, melena, oral candidiasis, pan-
component of the ABVD [doxorubicin, bleomycin, vin- creatitis, paralytic ileus, peritonitis, stomatitis
blastine, and dacarbazine] regimen) may be used, Genitourinary: Bladder spasm, hematuria, hemorrhagic
starting with the second trimester (Follows 2014; Pec- cystitis, urinary incontinence, urinary retention, urinary
catori 2013). tract infection
219
BORTEZOMIB
Hematologic & oncologic: Thrombocytopenia (16% to therapy; women of reproductive potential should avoid
52%; grade 3: 5% to 24%; grade 4: 3% to 7%; nadir: becoming pregnant during bortezomib treatment.
Day 11; recovery: By day 21), neutropenia (5% to Females and males of reproductive potential should
27%; grade 3: 8% to 18%; grade 4: 2% to 4%; nadir: use effective contraception during and for at least 2
Day 11; recovery: By day 21), anemia (12% to 23%; months following bortezomib treatment (refer to specific
grade 3: 4% to 6%; grade 4: <1%). leukopenia (18% to product labeling for details). Bortezomib may potentially
20%; grade 3: 5%; grade 4: ≤1%), hemorrhage affect male or female fertility (based on the mechanism
(≥grade 3: 2%), disseminated intravascular coagula- of action).
tion, febrile neutropenia, lymphocytopenia, oral
mucosal petechiae
Hepatic: Ascites, hepatic failure, hepatic hemorrhage,
Bosentan (boe SEN tan)
hepatitis, hyperbilirubinemia Brand Names: US Tracleer
Hypersensitivity: Anaphylaxis, angioedema, hypersen- Brand Names: Canada Tracleer
sitivity reaction, hypersensitivity angiitis
Pharmacologic Category Endothelin Receptor
Infection: Herpes zoster (reactivation; 6% to 11%),
Antagonist; Vasodilator
herpes simplex infection (1% to 3%), herpes zoster
Use Pulmonary arterial hypertension: Treatment of
(1% to 2%), aspergillosis, bacteremia, listeriosis, tox-
pulmonary artery hypertension (PAH) (WHO Group I)
oplasmosis
in adults with WHO-FC II, III, or IV symptoms to improve
Local: Injection site reaction (mostly redness; SubQ:
exercise ability and to decrease clinical deterioration;
6%), irritation at injection site (IV 5%), catheter
treatment of PAH (WHO Group 1) in pediatric patients
infection
≥3 years with idiopathic or congenital PAH to improve
Neuromuscular & skeletal: Weakness (7% to 16%),
arthralgia, back pain, bone fracture, limb pain, myal- pulmonary vascular resistance (PVR), resulting in an
gia, ostealgia improvement in exercise ability.
Ophthalmic: Blurred vision, conjunctival infection, con- Note: According to treatment guidelines from the Fifth
junctival irritation, diplopia World Symposium on Pulmonary Hypertension
Otic: Auditory impairment (WSPH), only a small number of PAH patients with
Renal: Bilateral hydronephrosis, nephrolithiasis, prolif- WHO-FC IV symptoms (ie, severely ill patients) were
erative glomerulonephritis, renal failure included in clinical trials, therefore, most experts con-
Respiratory: Dyspnea (11%), pneumonia (1% to 3%), sider bosentan second-line therapy in these patients
adult respiratory distress syndrome, aspiration pneu- (WSPH [Gailè 2013]).
monia, atelectasis, bronchitis, chronic obstructive pul- Local Anesthetic/Vasoconstrictor Precautions
monary disease (exacerbation), cough, epistaxis, No information available to require special precautions
hemoptysis, hypoxia, laryngeal edema, nasopharyng- Effects on Dental Treatment Key adverse event(s)
itis, pleural effusion, pneumonitis, pulmonary hyper- related to dental treatment: Endothelin antagonists
tension, pulmonary infiltrates (including diffuse), have caused bleeding gums; there have been no
respiratory tract infection, sinusitis specific reports for bosentan
Miscellaneous: Fever (8% to 23%) Effects on Bleeding No information available to
<1%, postmarketing, and/or case reports: Acute ische- require special precautions
mic stroke, amyloidosis, autonomic neuropathy, blind- Adverse Reactions
ness, cardiac tamponade, chalazion (Fraunfelder >10%:
2016), deafness (bilateral), decreased left ventricular Cardiovascular: Edema (≤11%)
ejection fraction, dysgeusia, dyspepsia, hemolytic-ure- Central nervous system: Headache (15%)
mic syndrome, herpes meningoencephalitis, Hepatic: Increased serum ALT (≥3 times ULN: ≤12%;
increased gamma-glutamyl transferase, increased 8 times ULN: ≤2%; dose-related), increased serum
serum alkaline phosphatase, increased serum trans- AST (≥3 times ULN: ≤12%; 8 times ULN: ≤2%; dose-
aminases, interstitial pneumonitis, intestinal obstruc- related)
tion, ischemic colitis, ocular herpes simplex, optic Respiratory: Respiratory tract infection (22%)
neuritis, optic neuropathy, progressive multifocal leu- 1% to 10%:
koencephalopathy, prolonged Q-T interval on ECG, Cardiovascular: Chest pain (5%), syncope (5%), flush-
pulmonary disease, respiratory insufficiency, reversi- ing (4%), hypotension (4%), palpitations (4%)
ble posterior leukoencephalopathy syndrome, sepsis, Endocrine & metabolic: Fluid retention (≤2%)
SIADH, Stevens-Johnson syndrome, subarachnoid Hematologic & oncologic: Anemia (3%)
hemorrhage, Sweet syndrome, syncope, tachycardia, Neuromuscular & skeletal: Arthralgia (4%)
toxic epidermal necrolysis, tumor lysis syndrome Respiratory: Sinusitis (4%)
Mechanism of Action Bortezomib inhibits protea- <1%, postmarketing, and/or case reports: Anaphylaxis,
somes, enzyme complexes which regulate protein angioedema, DRESS syndrome, hepatic cirrhosis
homeostasis within the cell. Specifically, it reversibly (prolonged therapy), hepatic failure (rare), hypersen-
inhibits chymotrypsin-like activity at the 26S protea- sitivity reaction, jaundice, leukopenia, nasal conges-
some, leading to activation of signaling cascades, cell- tion, neutropenia, peripheral edema, severe anemia,
cycle arrest, and apoptosis. skin rash, thrombocytopenia
Pharmacodynamics/Kinetics Mechanism of Action Endothelian receptor antago-
Half-life Elimination Single dose: IV: 9 to 15 hours; nist that blocks endothelin receptors on endothelium
Multiple dosing: 1 mg/m2: 40 to 193 hours; 1.3 mg/m2: and vascular smooth muscle (stimulation of these
76 to 108 hour receptors is associated with vasoconstriction). Bosen-
Pregnancy Considerations Based on the mecha- tan blocks both ETA and ETB receptors, with a slightly
nism of action and on findings in animal reproduction higher affinity for the A subtype.
studies, bortezomib may cause fetal harm if adminis- Pharmacodynamics/Kinetics
tered during pregnancy. Verify pregnancy status in Half-life Elimination ~5 hours; prolonged with heart
women of reproductive potential prior to initiating failure, possibly with PAH
220
BRIVARACETAM
Time to Peak Plasma: 3 to 5 hours grades 3/4: 3% to 5%), abnormal phosphorus levels
Pregnancy Considerations [US Boxed Warning]: (decreased; 15% to 23%; grades 3/4: <1%), pro-
Bosentan is likely to cause major birth defects if longed partial thromboplastin time (20% to 22%;
used by pregnant women based on animal data. grades 3/4: ≤2%)
Therefore, pregnancy must be excluded before the Hepatic: Increased serum alkaline phosphatase (15%
start of treatment with bosentan. Throughout treat- to 29%)
ment and for 1 month after stopping bosentan, Neuromuscular & skeletal: Increased creatine phos-
women of childbearing potential must use 2 reliable phokinase (27% to 48%), muscle spasm (12% to
methods of contraception unless the patient has an 17%), back pain (10% to 15%), myalgia (9% to
intrauterine device (IUD) or tubal sterilization in 15%), arthralgia (14%), limb pain (4% to 11%)
which case no other contraception is needed. Hor- Respiratory: Cough (18% to 34%), dyspnea (21%
monal contraceptives, including oral, injectable, to 27%)
transdermal, and implantable contraceptives, Miscellaneous: Fever (6% to 14%)
should not be used as the sole means of contra- 1% to 10%:
ception because these may not be effective in Cardiovascular: Bradycardia (6% to 8%)
patients receiving bosentan. Obtain monthly preg- Ophthalmic: Visual disturbance (7% to 10%; including
nancy tests. When a hormonal or barrier contraceptive blurred vision, diplopia, and reduced visual acuity)
is used, one additional method of contraception is still Respiratory: Interstitial pneumonitis (≤9%), pneumo-
needed if a male partner has had a vasectomy. When nitis (≤9%), hypoxia (≤3%), pneumonia (5% to 10%)
initiating treatment for women of reproductive potential, Mechanism of Action Brigatinib is a broad spectrum
a negative pregnancy test should be documented within multikinase inhibitor with activity against anaplastic
the first 5 days of a normal menstrual period and ≥11 lymphoma kinase (ALK), ROS1, insulin-like growth
days after the last unprotected intercourse. A missed factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR
menses or suspected pregnancy should be reported to deletion and point mutations. ALK autophosphorylation
a healthcare provider and prompt immediate pregnancy and ALK-mediated phosphorylation of downstream sig-
testing. Sperm counts may be reduced in men during naling proteins STAT3, AKT, ERK1/2, and S6 are inhib-
treatment. Women with pulmonary arterial hypertension ited by brigatinib. In vitro, brigatinib also inhibited
(PAH) are encouraged to avoid pregnancy (McLaughlin proliferation of cell lines expressing EML4-ALK and
2009; Taichman 2014). NPM-ALK fusion proteins. Brigatinib has activity against
cells expressing EML4-ALK and 17 mutant forms asso-
ciated with ALK inhibitor resistance, as well as EGFR-
Brigatinib (bri GA ti nib) Del (E746-A750), ROS1-L2026M, FLT3-F691L, and
FLT3-D835Y. Clinically, brigatinib showed anti-tumor
Brand Names: US Alunbrig activity against EML4-ALK mutant forms (including
Brand Names: Canada Alunbrig G1202R and L1196M) which were identified in NSCLC
Pharmacologic Category Antineoplastic Agent, Ana- cells in patients who progressed on crizotinib.
plastic Lymphoma Kinase Inhibitor; Antineoplastic Pharmacodynamics/Kinetics
Agent, Tyrosine Kinase Inhibitor Half-life Elimination 25 hours
Use Non-small cell lung cancer, metastatic: Treat- Time to Peak 1 to 4 hours
ment of anaplastic lymphoma kinase (ALK)-positive Pregnancy Considerations
metastatic non-small cell lung cancer (NSCLC) in Based on the mechanism of action and adverse events
patients who have progressed on or are intolerant to observed in animal reproduction studies, brigatinib may
crizotinib be expected to cause fetal harm if used during preg-
Local Anesthetic/Vasoconstrictor Precautions nancy.
Effects on Dental Treatment Key adverse event(s) Evaluate pregnancy status prior to therapy. Women of
related to dental treatment: Hypertension has been reproductive potential should use an effective nonhor-
reported in approximately 10% to 20% of patients monal contraceptive during therapy and for at least 4
receiving brigatinib. Monitoring of blood pressure prior months after the last brigatinib dose. Males with female
to dental treatment is advised. partners of reproductive potential should use effective
Effects on Bleeding No information available to contraception during therapy and for at least 3 months
require special precautions after the last dose.
Adverse Reactions
>10%: Brivaracetam (briv a RA se tam)
Cardiovascular: Hypertension (11% to 21%)
Central nervous system: Fatigue (29% to 36%), head- Brand Names: US Briviact
ache (27% to 28%), peripheral neuropathy (13%, Brand Names: Canada Brivlera
grades 3/4: ≤2%), insomnia (7% to 11%) Pharmacologic Category Anticonvulsant, Miscella-
Dermatologic: Skin rash (15% to 24%) neous
Endocrine & metabolic: Increased serum AST (38% to Use Partial-onset seizures: Treatment of partial-onset
65%), hyperglycemia (38% to 49%; including exac- seizures in patients with epilepsy as monotherapy or
erbations), increased serum ALT (34% to 40%), adjunctive therapy.
increased amylase (27% to 39%) Local Anesthetic/Vasoconstrictor Precautions
Gastrointestinal: Increased serum lipase (21% to No information available to require special precautions
45%), nausea (33% to 40%), diarrhea (19% to Effects on Dental Treatment Key adverse event(s)
38%), vomiting (23% to 24%), decreased appetite related to dental treatment: Incidence of sedation and
(15% to 22%), constipation (15% to 19%), abdominal equilibrium disturbances in patients taking brivaracetam
pain (10% to 17%) reported; monitor for symptoms, particularly for equili-
Hematologic & oncologic: Anemia (23% to 40%; brium problems, as patient arises from dental chair, and
grades 3/4: <1%), lymphocytopenia (19% to 27%; assist as necessary.
221
BRIVARACETAM
Effects on Bleeding No information available to Cardiovascular: Angina pectoris, chest tightness, circu-
require special precautions latory shock, extrasystoles, hypotension, increased
Adverse Reactions blood pressure, palpitations, tachycardia
>10%: Central nervous system: Anxiety, ataxia, central nerv-
Central nervous system: Drowsiness (≤27%), fatigue ous system stimulation, chills, confusion, dizziness,
(≤27%), hypersomnia (≤27%), lethargy (≤27%), drowsiness, euphoria, excitement, fatigue, headache,
malaise (≤27%), sedation (≤27%), abnormal gait hysteria, insomnia, irritability, nervousness, neuritis,
(≤16%), ataxia (≤16%), dizziness (≤16%), equili- paresthesia, restlessness, sedation, seizure, tension,
brium disturbance (≤16%), vertigo (≤16%), psychiat- vertigo
ric disturbance (13%; includes psychotic and Dermatologic: Diaphoresis, skin photosensitivity, skin
nonpsychotic) rash, urticaria
Neuromuscular & skeletal: Asthenia (≤27%) Gastrointestinal: Abdominal cramps, anorexia, consti-
Ophthalmic: Nystagmus (≤16%) pation, diarrhea, epigastric distress, heartburn, nau-
1% to 10%: sea, vomiting, xerostomia
Central nervous system: Euphoria (IV: ≥3%), infusion Genitourinary: Dysuria, early menses, urinary retention
site pain (IV: ≥3%), intoxicated feeling (IV: ≥3%), Hematologic & oncologic: Agranulocytosis, hemolytic
irritability (3%) anemia, hypoplastic anemia, thrombocytopenia
Gastrointestinal: Nausea (≤5%), vomiting (≤5%), dys- Hypersensitivity: Anaphylactic shock
geusia (IV: ≥3%), constipation (2%) Neuromuscular & skeletal: Tremor, weakness
Hematologic & oncologic: Decreased white blood cell Ophthalmic: Blurred vision, diplopia, mydriasis
count (2%) Otic: Acute labyrinthitis, tinnitus
Frequency not defined: Renal: Polyuria
Central nervous system: Suicidal ideation Respiratory: Dry nose, dry throat, nasal congestion,
Hypersensitivity: Hypersensitivity reaction thickening of bronchial secretions, wheezing
<1%, postmarketing, and/or case reports: Angioedema, Mechanism of Action Competes with histamine for
bronchospasm, decreased neutrophils H1-receptor sites on effector cells
Mechanism of Action The precise mechanism by Pharmacodynamics/Kinetics
which brivaracetam exerts its antiepileptic activity is Half-life Elimination Children: ~12 hours (Simons,
unknown. Brivaracetam displays a high and selective 1999); Adults: ~25 hours (Simons, 1982)
affinity for synaptic vesicle protein 2A (SV2A) in the Time to Peak Serum: Children: 3-3.5 hours (Simons,
brain, which may contribute to the antiepileptic effect. 1999); Adults: 2-4 hours (Simons, 1982)
Pharmacodynamics/Kinetics Pregnancy Considerations Maternal first-generation
Half-life Elimination ~9 hours antihistamine use has generally not resulted in an
Time to Peak Oral: 1 hour (fasting, range: 0.25 to 3 increased risk of birth defects (Babalola, 2013; Murase,
hours). 2014); however, information specific to bromphenir-
Pregnancy Considerations amine is limited (Heinonen, 1977; Seto, 1993). Antihist-
Adverse events have been observed in animal repro- amines may be used for the treatment of rhinitis,
duction studies. urticaria, systemic pruritus or atopic dermatitis in preg-
nant women (although agents other than bromphenir-
Females exposed to brivaracetam during pregnancy amine or second generation antihistamines may be
are encouraged to enroll themselves into the North preferred) (Babalola, 2013; Murase, 2014; Wallace,
American Antiepileptic Drug (NAAED) Pregnancy 2008; Zuberbier, 2014). Antihistamines are not recom-
Registry by calling 1-888-233-2334. Additional informa- mended for treatment of pruritus associated with intra-
tion is available at http://www.- hepatic cholestasis in pregnancy (Ambros-Rudolph,
aedpregnancyregistry.org. 2011; Kremer, 2011).
Controlled Substance C-V
Budesonide (Systemic) (byoo DES oh nide)
Brompheniramine (brome fen IR a meen)
Brand Names: US Entocort EC; Uceris
Brand Names: US J-Tan PD [OTC] [DSC]; Respa-BR Brand Names: Canada Cortiment; Entocort
[DSC] Pharmacologic Category Corticosteroid, Systemic
Pharmacologic Category Alkylamine Derivative; His- Use
tamine H1 Antagonist; Histamine H1 Antagonist, First Crohn disease, mild to moderate (capsules): Treat-
Generation ment of active Crohn disease (mild to moderate)
Use Upper respiratory allergies: Temporary relief of involving the ileum and/or the ascending colon in
sneezing; itchy, watery eyes; itchy nose or throat; and patients ≥8 years of age; maintenance of clinical
runny nose caused by hay fever (allergic rhinitis) or remission (for up to 3 months) of Crohn disease (mild
other upper respiratory allergies. to moderate) involving the ileum and/or the ascending
Local Anesthetic/Vasoconstrictor Precautions colon in adults
No information available to require special precautions Ulcerative colitis (tablets): Induction of remission in
Effects on Dental Treatment Key adverse event(s) patients with active ulcerative colitis (mild to mod-
related to dental treatment: Xerostomia (normal salivary erate)
flow resumes upon discontinuation). Chronic use of Local Anesthetic/Vasoconstrictor Precautions
antihistamines will inhibit salivary flow, particularly in No information available to require special precautions
elderly patients; this may contribute to periodontal dis- Effects on Dental Treatment Key adverse event(s)
ease and oral discomfort. related to dental treatment: Xerostomia (normal salivary
Effects on Bleeding No information available to flow resumes upon discontinuation), dry throat, abnor-
require special precautions mal taste, and herpes simplex. Localized infections with
Adverse Reactions Frequency not defined. Candida albicans or Aspergillus niger have occurred
222
BUDESONIDE (NASAL)
frequently in the mouth and pharynx with repetitive use mediators of inflammation (eg, kinins, prostaglandins).
of oral inhaler of corticosteroids. These infections may Oral budesonide formulations allow for targeted, pH-
require treatment with appropriate antifungal therapy or dependent budesonide release in the treatment of IBD
discontinuance of treatment with corticosteroid inhaler. (eg, Crohn disease, ulcerative colitis). The controlled
Effects on Bleeding Variable effects on anticoagulant release capsule contains enteric coated granules that
therapy are observed with glucocorticoids such as dissolve at a pH ≥5.5, delivering budesonide to the
budesonide (systemic, oral inhalation). ileum and ascending colon. The multimatrix enteric
Adverse Reactions coated tablet dissolves at a pH ≥7, delivering budeso-
>10%: nide to the entire colon (Abdalla 2016; Iborra 2014).
Central nervous system: Headache (15% to 21%) Pharmacodynamics/Kinetics
Dermatologic: Acne vulgaris (15%) Half-life Elimination IV:
Endocrine & metabolic: Decreased cortisol (foam Children ≥9 years and Adolescents ≤14 years: 1.9
17%; tablets 2% to 4%), bruise (15%), moon hours
face (11%) Adults: 2 to 3.6 hours
Gastrointestinal: Nausea (2% to 11%) Time to Peak Capsule: Children ≥9 years and Ado-
Respiratory: Respiratory tract infection (11%) lescents ≤14 years: Median: 5 hours; Adults: 0.5 to 10
1% to 10%: hours; Tablet (extended release): 13.3 ± 5.9 hours
Cardiovascular: Chest pain (<5%), edema (<5%), Pregnancy Considerations Some studies have
facial edema (<5%), flushing (<5%), hypertension shown an association between first trimester systemic
(<5%), palpitations (<5%), tachycardia (<5%) corticosteroid use and oral clefts (Park-Wyllie 2000;
Central nervous system: Dizziness (<5% to 7%), Pradat 2003). Systemic corticosteroids may also influ-
fatigue (3% to 5%), agitation (<5%), amnesia ence fetal growth (decreased birth weight); however,
(<5%), confusion (<5%), drowsiness (<5%), insom- information is conflicting (Lunghi 2010). Hypoadrenal-
nia (<5%), malaise (<5%), nervousness (<5%), par- ism may occur in newborns following maternal use of
esthesia (<5%), sleep disorder (<5%), vertigo (<5%) corticosteroids in pregnancy (monitor). When systemic
Dermatologic: Alopecia (<5%), dermatitis (<5%), der- corticosteroids are needed in pregnancy, it is generally
matological disease (<5%), diaphoresis (<5%), recommended to use the lowest effective dose for the
eczema (<5%) shortest duration of time, avoiding high doses during
Endocrine & metabolic: Hirsutism (≤5%), hypokalemia the first trimester (Leachman 2006; Lunghi 2010).
(1% to <5%), intermenstrual bleeding (<5%), men- Budesonide may be used for the induction of remission
strual disease (<5%), weight gain (<5%), adrenocort- in pregnant women with inflammatory bowel disease
ical insufficiency (foam 4%; capsules >1%), (Habal 2012; Nguyen 2016).
redistribution of body fat (1%)
Gastrointestinal: Diarrhea (10%), dyspepsia (6%),
anal disease (<5%), enteritis (<5%), epigastric pain Budesonide (Nasal) (byoo DES oh nide)
(<5%), exacerbation of Crohn's disease (<5%), gas-
Brand Names: US Rhinocort Allergy [OTC]; Rhinocort
trointestinal fistula (<5%), glossitis (<5%), hemor-
Aqua [DSC]
rhoids (<5%), increased appetite (<5%), intestinal
Brand Names: Canada Rhinocort Aqua; Rhinocort
obstruction (<5%), oral candidiasis (<5%), upper
Turbuhaler
abdominal pain (3% to 4%), flatulence (3%), abdomi-
nal distention (2%), constipation (2%) Pharmacologic Category Corticosteroid, Nasal
Genitourinary: Urinary tract infection (2% to <5%), Use
dysuria (<5%), nocturia (<5%), urinary frequency US labeling:
(<5%), hematuria (≥1%), pyuria (≥1%) Rx: Allergic rhinitis: Management of symptoms of
Hematologic & oncologic: C-reactive protein increased seasonal or perennial allergic rhinitis in adults and
(1% to <5%), leukocytosis (1% to <5%), purpura children ≥6 years.
(<5%), abnormal neutrophils (≥1%), anemia (≥1%), OTC: Upper respiratory symptoms: Relief of symp-
increased erythrocyte sedimentation rate (≥1%) toms of hay fever or other upper respiratory allergies
Hepatic: Increased serum alkaline phosphatase (≥1%) (eg, nasal congestion, runny nose, itchy nose,
Hypersensitivity: Tongue edema (<5%) sneezing) in adults and children ≥6 years.
Infection: Viral infection (6%), abscess (<5%) Canadian labeling:
Neuromuscular & skeletal: Ankle edema (7%), arthral- Nasal polyps: Treatment of nasal polyps; prevention
gia (5%), arthritis (≤5%), hyperkinesia (<5%), muscle of nasal polyps after polypectomy.
cramps (<5%), myalgia (<5%), tremor (<5%), weak- Rhinitis: Management of symptoms of seasonal aller-
ness (<5%) gic, perennial, and vasomotor rhinitis unresponsive
Ophthalmic: Eye disease (<5%), visual disturb- to conventional therapy.
ance (<5%) Local Anesthetic/Vasoconstrictor Precautions
Otic: Otic infection (<5%) No information available to require special precautions
Respiratory: Sinusitis (8%), bronchitis (<5%), dyspnea Effects on Dental Treatment No significant effects or
(<5%), flu-like symptoms (<5%), pharyngeal disease complications reported
(<5%), rhinitis (<5%) Effects on Bleeding No information available to
Miscellaneous: Fever (<5%) require special precautions
<1%, postmarketing, and/or case reports: Allergic der- Adverse Reactions
matitis, anaphylaxis, emotional lability, hyperglycemia, 1% to 10%: Respiratory: Epistaxis (8%), pharyngitis
maculopapular rash, pancreatitis, peripheral edema, (4%), bronchospasm (2%), cough (2%), nasal mucosa
pruritus, pseudotumor cerebri, rectal bleeding, irritation (2%)
skin rash <1%, postmarketing, and/or case reports: Anosmia,
Mechanism of Action Budesonide, a glucocorticoid cataract, crusting of nose, dizziness, fatigue, glau-
with high topical potency and limited systemic effects, coma, growth suppression, headache, hypersensitivity
depresses the activity of endogenous chemical reaction, increased intraocular pressure, mucous
223
BUDESONIDE (NASAL)
membrane ulceration, nasal septum perforation, nau- 1% to 10%:

sea, pharyngeal disease (irritation, itchy throat, throat Cardiovascular: Syncope (powder: 1% to 3%), chest
pain), wheezing pain (suspension: 1% to <3%)
Mechanism of Action Controls the rate of protein Central nervous system: Headache (powder: ≥3%;
synthesis; depresses the migration of polymorphonu- suspension: <1%), pain (powder: ≥3%), hypertonia
clear leukocytes, fibroblasts; reverses capillary perme- (powder: 1% to 3%), insomnia (powder: 1% to 3%),
ability and lysosomal stabilization at the cellular level to voice disorder (powder: 1% to 3%), emotional lability
prevent or control inflammation. Has potent glucocorti- (suspension: 1% to <3%), fatigue (suspension: 1%
coid activity and weak mineralocorticoid activity. to <3%)
Pharmacodynamics/Kinetics Dermatologic: Skin rash (suspension: 4%; powder:
Onset of Action Rhinocort Aqua: Within 10 hours; <1%), contact dermatitis (suspension: 1% to <3%),
Peak effect: Up to 2 weeks eczema (suspension: 1% to <3%), pruritus (suspen-
Half-life Elimination 2 to 3 hours sion: 1% to <3%), pustular rash (suspension: 1%
Time to Peak Plasma: Nasal: 30 minutes to <3%)
Pregnancy Risk Factor B Endocrine & metabolic: Weight gain (1% to 3%)
Pregnancy Considerations Adverse events have Gastrointestinal: Dyspepsia (≥5%), nausea (2% to
been observed with corticosteroids in animal reproduc- ≥5%), gastroenteritis (suspension: 5%), diarrhea
tion studies. Hypoadrenalism may occur in newborns (suspension: 4%), vomiting (1% to 4%), abdominal
following maternal use of corticosteroids in pregnancy; pain (1% to 3%), dysgeusia (powder: 1% to 3%),
monitor. Studies of pregnant women using intranasal xerostomia (powder: 1% to 3%), anorexia (suspen-
budesonide have not demonstrated an increased risk of sion: 1% to <3%), viral gastroenteritis (powder: 2%),
oral candidiasis (powder: 1%)
abnormalities. Intranasal corticosteroids are recom-
Hematologic & oncologic: Ecchymosis (powder: 1% to
mended for the treatment of rhinitis during pregnancy;
3%), cervical lymphadenopathy (suspension: 1% to
the lowest effective dose should be used (NAEPP,
<3%), purpura (suspension: 1% to <3%)
2005; Wallace, 2008); budesonide is preferred (Wal-
Hypersensitivity: Hypersensitivity reaction (1%
lace, 2008).
to <3%)
Infection: Candidiasis (suspension: 4% to 5%), viral
Budesonide (Oral Inhalation) infection (suspension: 4% to 5%), infection (1% to
(byoo DES oh nide) 3%), herpes simplex infection (suspension: 1%
to <3%)
Brand Names: US Pulmicort; Pulmicort Flexhaler
Neuromuscular & skeletal: Arthralgia (≥5%), weak-
Brand Names: Canada Pulmicort Nebuamp; Pulmi- ness (≥5%), back pain (powder: ≥3%), bone fracture
cort Turbuhaler
(1% to 3%), myalgia (1% to 3%), neck pain (powder:
Pharmacologic Category Corticosteroid, Inhalant 1% to 3%), hyperkinesia (suspension: 1% to <3%)
(Oral) Ophthalmic: Conjunctivitis (suspension: 4%), eye
Use infection (suspension: 1% to <3%)
Asthma: Maintenance and prophylactic treatment of Otic: Otic infection (suspension: 5%), otalgia (suspen-
asthma in patients ≥6 years of age (dry powder sion: 1% to <3%), otitis externa (suspension: 1%
inhaler) or 12 months to 8 years of age (nebulization to <3%)
suspension). Respiratory: Nasopharyngitis (powder: 9%), cough
Limitations of use: Not for relief of acute bronchospasm. (5% to 9%), epistaxis (suspension: 2% to 4%),
Guideline recommendations: A low-dose inhaled corti- respiratory tract infection (powder: ≥3%), sinusitis
costeroid (in addition to an as-needed short acting (powder: ≥3%; suspension: <1%), nasal congestion
beta2-agonist) is the initial preferred long-term control (powder: 3%), pharyngitis (powder: 3%; suspension:
medication for children, adolescents, and adult <1%), flu-like symptoms (suspension: 1% to <3%),
patients with persistent asthma who are candidates stridor (suspension: 1% to <3%), allergic rhinitis
for treatment according to a step-wise treatment (powder: 2%), viral upper respiratory tract infection
approach (GINA 2018; NAEPP 2007). (powder: 2%)
Local Anesthetic/Vasoconstrictor Precautions Miscellaneous: Fever (≥3%)
No information available to require special precautions Postmarketing and/or case reports: Adrenocortical
Effects on Dental Treatment Key adverse event(s) insufficiency, aggressive behavior, anxiety, avascular
related to dental treatment: Xerostomia (normal salivary necrosis of femoral head, bronchitis, bruise, cataract,
flow resumes upon discontinuation), dry throat, abnor- depression, glaucoma, growth suppression, hypercor-
mal taste, and herpes simplex. Localized infections with ticoidism, increased intraocular pressure, irritability,
Candida albicans or Aspergillus niger have occurred nervousness, osteoporosis, pain, psychosis, restless-
frequently in the mouth and pharynx with repetitive use ness, skin irritation (facial), throat irritation, wheezing
of oral inhaler of corticosteroids. These infections may Mechanism of Action Controls the rate of protein
require treatment with appropriate antifungal therapy or synthesis; depresses the migration of polymorphonu-
discontinuance of treatment with corticosteroid inhaler. clear leukocytes, fibroblasts; reverses capillary perme-
Effects on Bleeding Variable effects on anticoagulant ability and lysosomal stabilization at the cellular level to
therapy are observed with glucocorticoids such as prevent or control inflammation. Has potent glucocorti-
budesonide (systemic, oral inhalation). coid activity and weak mineralocorticoid activity.
Frequencies are for both formulations unless otherwise Onset of Action Nebulization: 2 to 8 days; Inhalation:
indicated. 24 hours
>10%: Peak effect: Nebulization: 4 to 6 weeks; Inhalation: 1
Otic: Otitis media (suspension: 12%; powder: 1%) to 2 weeks
Respiratory: Respiratory infection (suspension: 38%; Half-life Elimination
powder: ≥3%), rhinitis (5% to 12%) Children 4 to 6 years: 2.3 hours (after nebulization)
224
BUDESONIDE AND FORMOTEROL
Children and Adolescents 10 to 14 years: 1.5 hours Pregnancy Considerations Adverse events were
Adults: 2 to 3.6 hours observed in some animal reproduction studies. Hypoa-
Time to Peak drenalism may occur in newborns following maternal
Nebulization: Pulmicort Respules: Children: 20 use of corticosteroids in pregnancy; monitor. Oral bude-
minutes sonide has been used for the induction of remission in
Oral inhalation: Pulmicort Flexhaler: pregnant women with inflammatory bowel disease
Children and Adolescents: 15 to 30 minutes (Habal, 2012).
Adults: 10 minutes
Pregnancy Risk Factor B
Budesonide and Formoterol
(byoo DES oh nide & for MOH te rol)
Studies of pregnant women using inhaled budesonide
have not demonstrated an increased risk of congenital Related Information
abnormalities. Budesonide (Oral Inhalation) on page 224
Uncontrolled asthma is associated with adverse events Formoterol on page 627
on pregnancy (increased risk of perinatal mortality, pre- Brand Names: US Symbicort
eclampsia, preterm birth, low birth weight infants). Brand Names: Canada Symbicort
Poorly controlled asthma or asthma exacerbations Pharmacologic Category Beta2 Agonist; Beta2-Adre-
may have a greater fetal/maternal risk than what is nergic Agonist, Long-Acting; Corticosteroid, Inhalant
associated with appropriately used asthma medica- (Oral)
tions. Inhaled corticosteroids are recommended for Use
the treatment of asthma during pregnancy; budesonide Asthma: Treatment of asthma in patients ≥6 years.
is preferred (ACOG 2008; GINA 2018; Namazy 2016). Chronic obstructive pulmonary disease: Mainte-
nance treatment of airflow obstruction in patients with
Budesonide (Topical) (byoo DES oh nide)
chronic obstructive pulmonary disease (COPD),
including chronic bronchitis and/or emphysema; to
Brand Names: US Uceris reduce COPD exacerbations.
Brand Names: Canada Entocort Enema Limitations of use: Budesonide/formoterol is not indi-
Pharmacologic Category Corticosteroid, Rectal cated for the relief of acute bronchospasm.
Ulcerative colitis: Remission induction in patients with No information available to require special precautions
active mild to moderate distal ulcerative colitis extend- Effects on Dental Treatment Key adverse event(s)
ing up to 40 cm from the anal verge related to dental treatment: Formoterol: Xerostomia
Entocort Enema [Canadian product]: Management of (normal salivary flow resumes upon discontinuation).
distal ulcerative colitis (rectum, sigmoid, and descend- Localized infections with Candida albicans or Aspergil-
ing colon) lus niger have occurred frequently in the mouth and
Local Anesthetic/Vasoconstrictor Precautions pharynx with repetitive use of oral inhaler of cortico-
No information available to require special precautions steroids. These infections may require treatment with
Effects on Dental Treatment No significant effects or appropriate antifungal therapy or discontinuance of
complications reported treatment with corticosteroid inhaler.
require special precautions require special precautions
Adverse Reactions Frequency not always defined. Adverse Reactions Reported incidences are for ado-
>10%: Endocrine & metabolic: Decreased plasma cor- lescents and adults unless specified otherwise. Also
tisol (17%) see individual agents.
1% to 10%: >10%:
Endocrine & metabolic: Adrenocortical insufficiency Central nervous system: Headache (7% to 11%; chil-
(4%), hpa-axis suppression, hypercortisolism dren: ≥3%)
Gastrointestinal: Nausea (2%) Respiratory: Nasopharyngitis (7% to 11%), upper res-
<1%, postmarketing, and/or case reports: Acne vulga- piratory tract infection (4% to 11%; children: ≥3%)
ris, adrenal cortex hypofunction, agitation, allergic 1% to 10%:
dermatitis, anaphylaxis, anxiety, depression, diarrhea, Gastrointestinal: Abdominal distress (1% to 7%), oral
dizziness, drowsiness, dysphoria, emotional lability, candidiasis (1% to 6%), vomiting (1% to 3%)
exacerbation of diabetes mellitus, fever, flatulence, Infection: Influenza (2% to 3%)
hyperacidity (peptic ulcer), hyperglycemia, hyperten- Neuromuscular & skeletal: Back pain (2% to 3%)
sion, insomnia, maculopapular rash, pancreatitis, Respiratory: Pharyngolaryngeal pain (6% to 9%), pul-
peripheral edema, pruritus, pseudotumor cerebri, skin monary infection (7% to 8%), lower respiratory tract
rash, sleep disorder, urticaria infection (3% to 8%), sinusitis (4% to 6%), bronchitis
Mechanism of Action Controls the rate of protein (5%), nasal congestion (3%), pharyngitis (children:
synthesis; depresses the migration of polymorphonu- ≥3%), rhinitis (children: ≥3%)
clear leukocytes, fibroblasts; reverses capillary perme- <1%, postmarketing, and/or case reports: Agitation,
ability and lysosomal stabilization at the cellular level to anaphylaxis, angina pectoris, angioedema, atrial
prevent or control inflammation. Has potent glucocorti- arrhythmia, behavioral changes, bronchospasm,
coid activity and weak mineralocorticoid activity. bruise, cataract, cough, decreased linear skeletal
Pharmacodynamics/Kinetics growth rate (pediatric patients), depression, dermati-
Half-life Elimination Rectal enema [Canadian prod- tis, dizziness, extrasystoles, glaucoma, hypercorti-
uct]: 2 to 3 hours coidism signs and symptoms, hyperglycemia,
Time to Peak Rectal enema [Canadian product]: 1.5 hypersensitivity reaction, hypertension, hypokalemia,
hours hypotension, immunosuppression, increased intraoc-
Pregnancy Risk Factor C ular pressure, insomnia, muscle cramps, nausea,
225
BUDESONIDE AND FORMOTEROL
nervousness, palpitations, pruritus, restlessness, skin water, sodium, chloride, magnesium, phosphate, and
rash, tachycardia, throat irritation, tremor, urticaria, calcium; it does not appear to act on the distal tubule
ventricular arrhythmia, voice disorder Pharmacodynamics/Kinetics
Mechanism of Action Onset of Action Oral, IM: 0.5 to 1 hour; IV: 2 to 3
Formoterol: Relaxes bronchial smooth muscle by selec- minutes
tive action on beta2 receptors with little effect on heart Peak effect: Oral: 1 to 2 hours; IV: 15 to 30 minutes
rate; formoterol has a long-acting effect. Duration of Action Oral: 4 to 6 hours; IV: 2 to 3 hours
Budesonide: A corticosteroid which controls the rate of Half-life Elimination
protein synthesis, depresses the migration of polymor- Premature and full term neonates: 6 hours (range up
phonuclear leukocytes/fibroblasts, and reverses capil- to 15 hours)
lary permeability and lysosomal stabilization at the Infants <2 months: 2.5 hours
cellular level to prevent or control inflammation. Infants 2 to 6 months: 1.5 hours
Pregnancy Considerations Adverse events were Adults: 1 to 1.5 hours
observed in animal reproduction studies using this Pregnancy Considerations Adverse events have
combination. Refer to individual agents. been observed in some animal reproduction studies.
Bumetanide (byoo MET a nide) Bupivacaine (byoo PIV a kane)
Related Information Related Information

Cardiovascular Diseases on page 1442 Oral Pain on page 1520
Brand Names: US Bumex Brand Names: US Bupivacaine Spinal; Marcaine; Mar-
Brand Names: Canada Burinex caine Preservative Free; Marcaine Spinal; P-Care M;
Pharmacologic Category Antihypertensive; Diuretic, ReadySharp Bupivacaine [DSC]; Sensorcaine; Sensor-
Loop caine-MPF; Sensorcaine-MPF Spinal [DSC]
Use Edema, heart failure: Management of edema Brand Names: Canada Marcaine; Sensorcaine
secondary to heart failure or hepatic or renal disease Pharmacologic Category Local Anesthetic
(including nephrotic syndrome) Use Local or regional anesthesia; spinal anesthesia
Local Anesthetic/Vasoconstrictor Precautions (0.75% in dextrose 8.25% injection); diagnostic and
No information available to require special precautions therapeutic procedures; obstetrical procedures (only
Effects on Dental Treatment No significant effects or 0.25% and 0.5% concentrations)
complications reported 0.25%: Local infiltration, peripheral nerve block, sym-
Effects on Bleeding No information available to pathetic block, caudal or epidural block
require special precautions 0.5%: Peripheral nerve block, caudal and epidural
Adverse Reactions block
>10%: 0.75% (not for obstetrical anesthesia): Retrobulbar
Endocrine & metabolic: Hyperuricemia (18%), hypo- block, epidural block. Note: Reserve for surgical
chloremia (15%), hypokalemia (15%) procedures where a high degree of muscle relaxa-
Genitourinary: Azotemia (11%) tion and prolonged effect are necessary
1% to 10%: Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Dizziness (1%) No information available to require special precautions
Endocrine & metabolic: Hyponatremia (9%), hyper- Effects on Dental Treatment No significant effects or
glycemia (7%), phosphorus change (5%), variations complications reported
in bicarbonate (3%), abnormal serum calcium (2%), Effects on Bleeding No information available to
abnormal lactate dehydrogenase (1%) require special precautions
Neuromuscular & skeletal: Muscle cramps (1%) Adverse Reactions Frequency not defined. Reactions
Renal: Increased serum creatinine (7%) listed are based on reports for other agents in this same
Respiratory: Variations in CO2 content (4%) pharmacologic class and may not be specifically
<1%, postmarketing, and/or case reports: Abdominal reported for bupivacaine.
pain, abnormal alkaline phosphatase, abnormal bilir- Cardiovascular: Bradycardia, cardiac insufficiency, cir-
ubin levels, abnormal hematocrit, abnormal hemoglo- culatory shock, heart block, hypotension, ventricular
bin level, abnormal transaminase, arthritic pain, arrhythmia
asterixis, auditory impairment, blood cholesterol Central nervous system: Anxiety, arachnoiditis, central
abnormal, brain disease (in patients with preexisting nervous system depression, central nervous system
liver disease), change in creatinine clearance, change stimulation, chills, cranial nerve palsy, dizziness,
in prothrombin time, change in WBC count, chest pain, headache, localized numbness (perineal), meningism,
dehydration, diaphoresis, diarrhea, dyspepsia, ECG paralysis, paraplegia, paresthesia, persistent anesthe-
changes, erectile dysfunction, fatigue, glycosuria, sia, restlessness, seizure, shivering
headache, hyperventilation, hypotension, musculos- Gastrointestinal: Fecal incontinence, loss of anal
keletal pain, nausea, nipple tenderness, orthostatic sphincter control, nausea, vomiting
hypotension, otalgia, ototoxicity, premature ejacula- Genitourinary: Prolonged labor, sexual disorder (loss of
tion, proteinuria, pruritus, renal failure, skin rash, Ste- function), urinary incontinence, urinary retention
vens-Johnson syndrome, thrombocytopenia, toxic Hematologic & oncologic: Methemoglobinemia
epidermal necrolysis, urticaria, vertigo, vomiting, Hypersensitivity: Hypersensitivity reaction
weakness, xerostomia Infection: Septic meningitis
Mechanism of Action Inhibits reabsorption of sodium Neuromuscular & skeletal: Asthenia, back pain, lower
and chloride in the ascending loop of Henle and prox- extremity weakness, tremor
imal renal tubule, interfering with the chloride-binding Ophthalmic: Blurred vision, miosis
cotransport system, thus causing increased excretion of Otic: Tinnitus
226
BUPIVACAINE AND EPINEPHRINE
Respiratory: Apnea, hypoventilation (usually associated perceived by many patients as a stressful procedure in
with unintentional subarachnoid injection during high dentistry. Common symptoms to this stress are diapho-
spinal anesthesia), respiratory paralysis resis, palpitations, and hyperventilation. Patients may
Mechanism of Action Blocks both the initiation and exhibit hypersensitivity to bisulfites contained in local
conduction of nerve impulses by decreasing the neuro- anesthetic solution to prevent oxidation of epinephrine.
nal membrane's permeability to sodium ions, which In general, patients reacting to bisulfites have a history
results in inhibition of depolarization with resultant of asthma and their airways are hyper-reactive to
blockade of conduction asthmatic syndrome.
Onset of Action Anesthesia (route and dose depend- Degree of adverse effects in the CNS and cardiovas-
ent): cular system is directly related to the blood levels of
Epidural: Up to 17 minutes to spread to T6 dermatome bupivacaine: Bradycardia, hypersensitivity reactions
(Scott 1980) (rare; may be manifest as dermatologic reactions and
Infiltration: Fast (Barash 2009); Dental injection: 2 to edema at injection site), asthmatic syndromes.
10 minutes
Spinal: Within 1 minute; maximum dermatome level High blood levels: Anxiety, restlessness, disorientation,
achieved within 15 minutes in most cases confusion, dizziness, tremors, seizures, CNS depres-
Duration of Action Route and dose dependent: sion (resulting in somnolence, unconsciousness and
Epidural: 2 to 7.7 hours (Barash 2009) possible respiratory arrest), nausea, and vomiting.
Infiltration: 2 to 8 hours (Barash 2009); Dental injec- Effects on Bleeding No information available to
tion: Up to 7 hours require special precautions
Spinal: 1.5 to 2.5 hours (Tsai 2007) Adverse Reactions See individual agents.
Half-life Elimination Age dependent: Neonates: 8.1 Dental Usual Dosage
hours; Adults: 2.7 hours Infiltration and nerve block in maxillary and mandibular
Time to Peak Plasma: Caudal, epidural, or peripheral area: Children >12 years and Adults: 9 mg (1.8 mL) of
nerve block: 30 to 45 minutes bupivacaine as a 0.5% solution with epinephrine
Pregnancy Considerations Adverse events were 1:200,000 per injection site. A second dose may be
observed in animal reproduction studies. Bupivacaine administered if necessary to produce adequate anes-
crosses the placenta. Bupivacaine is approved for use thesia after allowing up to 10 minutes for onset. Up to
at term in obstetrical anesthesia or analgesia. [U.S. a maximum of 90 mg of bupivacaine hydrochloride per
Boxed Warning]: The 0.75% is not recommended dental appointment. The effective anesthetic dose
for obstetrical anesthesia. Bupivacaine 0.75% solu- varies with procedure, intensity of anesthesia needed,
tions have been associated with cardiac arrest following duration of anesthesia required, and physical condi-
epidural anesthesia in obstetrical patients and use of tion of the patient; always use the lowest effective
this concentration is not recommended for this purpose. dose along with careful aspiration.
Use in obstetrical paracervical block anesthesia is con-
traindicated. The following numbers of dental carpules (1.8 mL)
provide the indicated amounts of bupivacaine hydro-
chloride 0.5% and vasoconstrictor (epinephrine
Bupivacaine and Epinephrine 1:200,000). See table.
(byoo PIV a kane & ep i NEF rin)
Related Information mg
# of Cartridges mg Bupivacaine Vasoconstrictor
Bupivacaine on page 226 (1.8 mL) (0.5%) (Epinephrine
EPINEPHrine (Systemic) on page 495 1:200,000)
Oral Pain on page 1520 1 9 0.009
Brand Names: US Marcaine with Epinephrine; Sen- 2 18 0.018
sorcaine with Epinephrine; Sensorcaine-MPF with Epi- 3 27 0.027
nephrine; Vivacaine
4 36 0.036
Brand Names: Canada Sensorcaine with Epinephrine
5 45 0.045
Pharmacologic Category Local Anesthetic 6 54 0.054
Dental Use Local anesthesia 7 63 0.063
Use Anesthesia/analgesia: Local or regional anesthe- 8 72 0.072
sia or analgesia for surgery, dental and oral procedures,
diagnostic and therapeutic procedures, and obstetrical 9 81 0.081
procedure 10 90 0.090
0.25%: Local infiltration, peripheral nerve block, sym-
pathetic block, lumbar epidural, or caudal Note: Adult and children doses of bupivacaine hydro-
0.5%: Peripheral nerve block, lumbar epidural, caudal, chloride with epinephrine cited from USP Dispensing
epidural test dose, or dental blocks Information (USP DI), 17th ed, The United States
0.75% (not for obstetrical anesthesia): Retrobulbar Pharmacopeial Convention, Inc, Rockville, MD,
block or lumbar epidural; Note: Reserve for surgical 1997, 134.
procedures where a high degree of muscle relaxa- Dosing
tion and prolonged effect are necessary. Adult & Geriatric Dose varies with procedure, depth
Local Anesthetic/Vasoconstrictor Precautions of anesthesia, vascularity of tissues, duration of anes-
No information available to require special precautions thesia, and condition of patient. Do not use solutions
Effects on Dental Treatment It is common to mis- containing preservatives for caudal or epidural block.
interpret psychogenic responses to local anesthetic Doses may be repeated up to once every 3 hours
injection as an allergic reaction. Intraoral injections are (maximum: 400 mg/day of bupivacaine).
227
BUPIVACAINE AND EPINEPHRINE
Caudal and lumbar epidural block test dose (pres- component of the formulation; obstetrical paracervical
ervative free): 2 to 3 mL of 0.5% (maximum: 15 mg/ block anesthesia
dose of bupivacaine or 15 mcg/dose of epinephrine) Warnings/Precautions Some commercially available
Caudal block (preservative free): 15 to 30 mL of formulations contain sodium metabisulfite, which may
0.25% or 0.5% (maximum: 75 mg/dose of 0.25% cause allergic-type reactions. Do not use solutions
bupivacaine or 150 mg/dose of 0.5% bupivacaine) containing preservatives for caudal or epidural block.
Epidural block (other than caudal block, preserva- Intravascular injections should be avoided. Local anes-
tive free): 10 to 20 mL of 0.25% or 0.5% (maximum: thetics have been associated with rare occurrences of
50 mg/dose of 0.25% bupivacaine or 100 mg/dose of sudden respiratory arrest. Convulsions due to systemic
0.5% bupivacaine). Administer in 3 to 5 mL incre- toxicity leading to cardiac arrest have also been
ments, allowing sufficient time to detect toxic mani- reported, presumably following unintentional intravas-
f e s ta t i o n s o f i n a d v e r t e n t I V o r i n t r a t h e c a l cular injection. [US Boxed Warning]: The 0.75% is not
administration. recommended for obstetrical anesthesia. A test
Surgical procedures requiring a high degree of dose is recommended prior to epidural administration
muscle relaxation and prolonged effects only: 10 and all reinforcing doses with continuous catheter tech-
to 20 mL of 0.75%; Note: Not to be used in nique. Use caution with cardiovascular dysfunction,
obstetrical cases (maximum: 150 mg/dose of bupi- hepatic impairment, or patients with compromised blood
vacaine) supply. Bupivacaine-containing products have been
Local anesthesia: Infiltration: 0.25% infiltrated locally associated with rare occurrences of arrhythmias, car-
(maximum: 400 mg/day of bupivacaine) diac arrest, and death. Use caution in debilitated, eld-
Peripheral nerve block: 5 mL of 0.25% or 0.5% erly, or acutely ill patients; dose reduction may be
(maximum: 400 mg/day of bupivacaine) required. Dental practitioners and/or clinicians using
Retrobulbar anesthesia: 2 to 4 mL of 0.75% (max- local anesthetic agents should be well trained in diag-
imum: 30 mg/dose of bupivacaine) nosis and management of emergencies that may arise
Sympathetic nerve block: 20 to 50 mL of 0.25% from the use of these agents. Resuscitative equipment,
(maximum: 125 mg/dose of bupivacaine) oxygen, and other resuscitative drugs should be avail-
Dental block: 1.8 mL (9 mg) of bupivacaine as a able for immediate use. Not recommended for use in
0.5% solution with epinephrine 1:200,000 per injec- children <12 years of age.
tion site. A second dose may be administered if Methemoglobinemia has been reported with local anes-
necessary to produce adequate anesthesia after thetics; clinically significant methemoglobinemia
allowing up to 10 minutes for onset. Up to a max- requires immediate treatment along with discontinua-
imum of 90 mg of bupivacaine per dental appoint- tion of the anesthetic and other oxidizing agents. Onset
ment. The effective anesthetic dose varies with may be immediate or delayed (hours) after anesthetic
procedure, intensity of anesthesia needed, duration exposure. Patients with glucose-6-phosphate dehydro-
of anesthesia required, and physical condition of the genase deficiency, congenital or idiopathic methemo-
patient; always use the lowest effective dose along globinemia, cardiac or pulmonary compromise,
with careful aspiration. exposure to oxidizing agents or their metabolites, or
Renal Impairment: Adult There are no dosage infants <6 months of age are more susceptible and
adjustments provided in the manufacturer’s labeling; should be closely monitored for signs and symptoms
use with caution. of methemoglobinemia (eg, cyanosis, headache, rapid
Hepatic Impairment: Adult There are no dosage pulse, shortness of breath, lightheadedness, fatigue).
adjustments provided in the manufacturer’s labeling;
Continuous intra-articular infusion of local anesthetics
use with caution.
after arthroscopic or other surgical procedures is not an
Pediatric approved use; chondrolysis (primarily shoulder joint)
Children >12 years and Adolescents: Refer to adult has occurred following infusion, with some requiring
dosing. arthroplasty or shoulder replacement.
Renal Impairment: Pediatric There are no dosage Drug Interactions
adjustments provided in manufacturer’s labeling; use Metabolism/Transport Effects Refer to individual
with caution. components.
Hepatic Impairment: Pediatric There are no dos- Avoid Concomitant Use
age adjustments provided in manufacturer’s labeling; Avoid concomitant use of Bupivacaine and Epinephr-
use with caution. ine with any of the following: Blonanserin; Bromper-
Mechanism of Action Local anesthetics bind selec- idol; Ergot Derivatives; Lurasidone
tively to the intracellular surface of sodium channels to Increased Effect/Toxicity
block influx of sodium into the axon. As a result, Bupivacaine and Epinephrine may increase the levels/
depolarization necessary for action potential propaga- effects of: Amifostine; Antipsychotic Agents (Second
tion and subsequent nerve function is prevented. The Generation [Atypical]); Bupivacaine (Liposomal); Dox-
block at the sodium channel is reversible. When drug ofylline; Hypotension-Associated Agents; Levodopa-
diffuses away from the axon, sodium channel function is Containing Products; Lurasidone; Neuromuscular-
restored and nerve propagation returns. Blocking Agents; Nitroprusside; Pholcodine; Solriam-
Epinephrine prolongs the duration of the anesthetic fetol; Sympathomimetics
actions of bupivacaine by causing vasoconstriction The levels/effects of Bupivacaine and Epinephrine
(alpha-adrenergic receptor agonist) of the vasculature may be increased by: Alfuzosin; AtoMOXetine; Barbi-
surrounding the nerve axons. This prevents the diffu- turates; Beta-Blockers; Beta-Blockers (Nonselective);
sion of bupivacaine away from the nerves resulting in a Blood Pressure Lowering Agents; Brimonidine (Top-
longer retention in the axon ical); Cannabinoid-Containing Products; Chloropro-
Contraindications Hypersensitivity to bupivacaine, c a i n e ; C o c a i n e (To p i c a l ) ; CO M T In h i b i to r s ;
epinephrine, amide-type local anesthetics, or any Diazoxide; Ergot Derivatives; Guanethidine; Herbs
228
BUPIVACAINE (LIPOSOMAL)
(Hypotensive Properties); Hyaluronidase; Inhalational Adverse Reactions

Anesthetics; Linezolid; Lormetazepam; Methemoglo- >10%:
binemia Associated Agents; Molsidomine; Monoamine Central nervous system: Motor dysfunction (12%
Oxidase Inhibitors; Naftopidil; Nicergoline; Nicorandil; to 21%)
Obinutuzumab; Pentoxifylline; Phosphodiesterase 5 Gastrointestinal: Nausea (<40%), vomiting (28%),
Inhibitors; Prostacyclin Analogues; Quinagolide; Sero- constipation (2% to 22%)
tonin/Norepinephrine Reuptake Inhibitors; Tedizolid; Miscellaneous: Fever (2% to 23%)
Tricyclic Antidepressants 1% to 10%:
Decreased Effect Cardiovascular: Hypertension (<10%; includes proce-
Bupivacaine and Epinephrine may decrease the lev- dural hypertension), hypotension (7%), procedural
els/effects of: Antidiabetic Agents; Benzylpenicilloyl hypotension (4%), tachycardia (4%), peripheral
Polylysine; Technetium Tc 99m Tilmanocept edema (2% to 3%), sinus tachycardia (2% to 3%),
atrial fibrillation (<2%), bradycardia (<2%), bundle
The levels/effects of Bupivacaine and Epinephrine branch block (<2%), cardiac arrhythmia (<2%), deep
may be decreased by: Alpha1-Blockers; Benperidol; vein thrombosis (<2%), edema (<2%), first degree
Beta-Blockers (Beta1 Selective); Beta-Blockers (with atrioventricular block (<2%), oxygen saturation
Alpha-Blocking Properties); Blonanserin; Bromperidol; decreased (<2%), orthostatic hypotension (<2%),
CloZAPine; Promethazine; Spironolactone palpitations (<2%), presyncope (<2%), prolonged
Pregnancy Risk Factor C QT interval on ECG (<2%), sinus bradycardia
Pregnancy Considerations See individual agents. (<2%), supraventricular extrasystole (<2%), syncope
Dosage Forms: US (2%), ventricular premature contractions (<2%), ven-
Injection, solution [preservative free]: Bupivacaine tricular tachycardia (<2%)
0.25% and epinephrine 1:200,000 (10 mL, 30 mL); Central nervous system: Insomnia (2% to <10%),
bupivacaine 0.5% and epinephrine 1:200,000 (10 mL, procedural pain (2% to <10%), headache (4% to
30 mL) 8%), dizziness (≤6%; includes postural dizziness),
confusion (5%), fatigue (5%), drowsiness (2% to
Marcaine® with Epinephrine: Bupivacaine 0.25% and
5%), hypoesthesia (2% to 4%), anxiety (3%), sensa-
epinephrine 1:200,000 (10 mL, 30 mL); bupivacaine
tion of cold (3%), falling (2% to 3%), feeling hot (2%),
0.5% and epinephrine 1:200,000 (10 mL, 30 mL)
mobility disorder (decreased: 2%), sensation disor-
Sensorcaine® MPF with Epinephrine: Bupivacaine
der (sensory loss: 2%), agitation (<2%), chills (<2%),
0.25% and epinephrine 1:200,000 (10 mL, 30 mL); delirium (<2%), depression (<2%), hyperthermia
bupivacaine 0.5% and epinephrine 1:200,000 (10 (<2%), myasthenia (<2%), pain (<2%), paresthesia
mL, 30 mL); bupivacaine 0.75% and epinephrine (<2%), restlessness (<2%), sedation (<2%), leth-
1:200,000 (30 mL) argy (1%)
Injection, solution: Bupivacaine 0.25% and epinephr- Dermatologic: Hyperhidrosis (5%), pruritus (3%), cel-
ine 1:200,000 (50 mL); bupivacaine 0.5% and epi- lulitis (<2%), diaphoresis (<2%), erythema (<2%),
nephrine 1:200,000 (50 mL) increased wound secretion (<2%), pallor (<2%), pru-
Marcaine® with Epinephrine, Sensorcaine® with Epi- ritic rash (<2%), skin blister (<2%), skin rash (<2%),
nephrine: Bupivacaine 0.25% and epinephrine urticaria (<2%)
1:200,000 (50 mL); bupivacaine 0.5% and epinephr- Gastrointestinal: Dysgeusia (7%), oral hypoesthesia
ine 1:200,000 (50 mL) (3% to 4%), hiccups (1% to 2%)
Injection, solution [for dental use]: Genitourinary: Urinary retention (8%), dysuria (<2%),
Marcaine® with Epinephrine, Vivacaine™: Bupiva- urinary incontinence (<2%)
caine 0.5% and epinephrine 1:200,000 (1.8 mL) Hematologic & oncologic: Acute posthemorrhagic
Dental Health Professional Considerations A anemia (2% to <10%; postoperative), anemia (6%),
2010 report, reviewed adverse events submitted volun- bruise (≤2%), hematoma (<2%), leukocytosis (<2%),
tarily over a 10-year period involving the dental local postoperative hematoma (≤2%)
anesthetics articaine, bupivacaine, lidocaine, mepiva- Hepatic: Increased liver enzymes (4%), increased
caine, and prilocaine in the United States. Bupivacaine serum aspartate aminotransferase (3%), increased
reported incidence: One case per 124,286,050 car- serum alanine aminotransferase (1%)
tridges sold. The reported incidence of paresthesia Hypersensitivity: Fixed drug eruption (<2%), hyper-
was one case for 13,800,970 cartridges of all local sensitivity reaction (<2%)
anesthetics sold in the U.S. (Garisto, 2010). Infection: Fungal infection (2%)
Local: Localized edema (incision site: <2%)
Neuromuscular & skeletal: Back pain (<10%), muscle
Bupivacaine (Liposomal) spasm (<10%), muscle twitching (8%), arthralgia
(byoo PIV a kane lye po SO mal) (<2%), asthenia (<2%), joint swelling (<2%), laryng-
Brand Names: US Exparel ospasm (<2%), musculoskeletal pain (<2%), neck
pain (<2%), tremor (<2%)
Pharmacologic Category Local Anesthetic
Ophthalmic: Blurred vision (<2%), decreased visual
Use Analgesia, postsurgical: Single-dose infiltration in acuity (<2%)
adults to produce postsurgical local analgesia and as Otic: Auditory impairment (<2%), tinnitus (<2%)
an interscalene brachial plexus nerve block to produce Renal: Increased serum creatinine (2%)
postsurgical regional analgesia. Respiratory: Hypoxia (1% to 2%), apnea (<2%), ate-
Local Anesthetic/Vasoconstrictor Precautions lectasis (<2%), cough (<2%), dyspnea (<2%), pulmo-
No information available to require special precautions nary infiltrates (<2%), pneumonia (<2%), pulmonary
Effects on Dental Treatment No significant effects or infection (<2%), respiratory depression (<2%), respi-
complications reported ratory failure (<2%)
Effects on Bleeding No information available to Miscellaneous: Procedural complications (postproce-
require special precautions dural swelling: 2%), dehiscence (<2%)
229
BUPIVACAINE (LIPOSOMAL)
<1%, postmarketing, and/or case reports: Paralysis, Effects on Bleeding No information available to
seizure require special precautions
Mechanism of Action Blocks both the initiation and Adverse Reactions
conduction of nerve impulses by decreasing the neuro- Buccal film:
nal membrane's permeability to sodium ions, which 1% to 10%:
results in inhibition of depolarization with resultant Cardiovascular: Hypertension (1% to <5%), periph-
blockade of conduction. eral edema (1% to <5%)
Pharmacodynamics/Kinetics Central nervous system: Fatigue (≥5%), headache
Onset of Action Rapid (Hu 2013) (4% to ≥5%), dizziness (2% to ≥5%), drowsiness
Duration of Action Local: Up to 72 hours (Hu 2013); (1% to ≥5%), anxiety (1% to <5%), depression (1%
Systemic: Plasma levels can persist for 96 hours after to <5%), falling (1% to <5%), insomnia (1% to
local administration and 120 hours after interscalene <5%), opioid withdrawal syndrome (1% to <5%)
brachial plexus nerve block. Dermatologic: Hyperhidrosis (1% to <5%), pruritus
Half-life Elimination 13 to 34 hours (Hu 2013) (1% to <5%), skin rash (1% to <5%)
Time to Peak Within 1 hour (initial peak); 12 to 36 Endocrine & metabolic: Hot flash (1% to <5%)
hours (second peak) (Hu 2013) Gastrointestinal: Nausea (9% to 10%), diarrhea
(≥5%), xerostomia (≥5%), vomiting (4% to ≥5%),
constipation (3% to ≥5%), abdominal pain (1% to
been observed in animal reproduction studies. Bupiva-
<5%), decreased appetite (1% to <5%), gastro-
caine crosses the placenta. Not recommended for use
enteritis (1% to <5%)
in pregnancy. Use in obstetrical paracervical block
Genitourinary: Urinary tract infection (1% to <5%)
anesthesia is contraindicated; may cause fetal brady-
Hematologic & oncologic: Anemia (1% to <5%),
cardia and death.
bruise (1% to <5%)
Neuromuscular & skeletal: Back pain (1% to <5%),
Buprenorphine (byoo pre NOR feen) muscle spasm (1% to <5%)
Respiratory: Upper respiratory tract infection (≥5%),
Brand Names: US Belbuca; Buprenex; Butrans; Pro- bronchitis (1% to <5%), nasopharyngitis (1% to
buphine Implant Kit; Sublocade <5%), oropharyngeal pain (1% to <5%), paranasal
Brand Names: Canada Belbuca; Butrans; Probuphine sinus congestion (1% to <5%), sinusitis (1%
Generic Availability (US) May be product dependent to <5%)
Pharmacologic Category Analgesic, Opioid; Analge- Miscellaneous: Fever (1% to <5%)
sic, Opioid Partial Agonist Implant:
Use >10%:
Opioid dependence: Central nervous system: Headache (13%)
Extended-release injection: Treatment of moderate to Local: Local pain (13%; at implant site), local pruritus
severe opioid use disorder in patients who have (12%; at implant site)
initiated treatment with 8 to 24 mg of a transmucosal 1% to 10%:
buprenorphine-containing product, followed by dose Cardiovascular: Chest pain (1%)
adjustment for a minimum of 7 days. Central nervous system: Depression (6%), dizziness
Subdermal implant: Maintenance treatment of opioid (4%), pain (4%), drowsiness (3%), fatigue (3%),
dependence in patients who have achieved and chills (2%), migraine (2%), paresthesia (1%), seda-
sustained prolonged clinical stability on low to mod- tion (1%), sensation of cold (1%)
erate doses (≤8 mg/day) of a transmucosal bupre- Dermatologic: Localized erythema (10%; at implant
norphine-containing product for 3 months or longer site), skin rash (2%), excoriation (1% to 2%; includ-
ing scratch), skin lesion (1%)
with no need for supplemental dosing or adjustments
Gastrointestinal: Constipation (6%), nausea (6%),
Sublingual tablet: Treatment of opioid dependence
vomiting (6%), toothache (5%), upper abdominal
Limitations of use: Buprenorphine should be used as
pain (3%), flatulence (1%)
part of a complete treatment program to include coun-
Hematologic & oncologic: Local hemorrhage (7%; at
seling and psychosocial support.
implant site)
Pain management:
Local: Localized edema (5%; at implant site), local
Buccal film, transdermal patch: Management of pain
swelling (1%)
severe enough to require around-the-clock, long- Neuromuscular & skeletal: Back pain (6%), limb pain
term opioid treatment and for which alternative treat- (3%), asthenia (2%)
ment options are inadequate Respiratory: Oropharyngeal pain (5%), cough (3%),
Immediate-release injection: Management of pain dyspnea (1%)
severe enough to require an opioid analgesic and Miscellaneous: Fever (3%), laceration (3%)
for which treatments are inadequate Injection:
Limitations of use: Reserve buprenorphine for use in >10%: Central nervous system: Sedation (≤66%)
patients for whom alternative treatment options (eg, 1% to 10%:
nonopioid analgesics, opioid combination products, Cardiovascular: Hypotension (1% to 5%)
immediate-release opioids) are ineffective, not toler- Central nervous system: Vertigo (5% to 10%), dizzi-
ated, or would be otherwise inadequate to provide ness (2% to 10%), headache (1% to 9%), fatigue
sufficient management of pain. Buprenorphine buccal (4% to 6%), drowsiness (2% to 5%)
film and transdermal patch are not indicated as an as Dermatologic: Injection site pruritus (6% to 10%),
needed analgesic. diaphoresis (1% to 5%)
Local Anesthetic/Vasoconstrictor Precautions Endocrine & metabolic: Increased gamma-glutamyl
No information available to require special precautions transferase (3% to 4%)
Effects on Dental Treatment No significant effects or Gastrointestinal: Nausea (5% to 10%), constipation
complications reported (8% to 9%), vomiting (1% to 9%)
230
BUPRENORPHINE
Hepatic: Increased serum aspartate aminotransfer- accident, changes in respiration, chest pain, chills,
ase (3% to 5%), increased serum alanine amino- cholecystitis, coma, confusion, conjunctivitis, contact
transferase (1% to 5%) dermatitis, coronary artery disease, cough, cyanosis,
Local: Pain at injection site (5% to 6%), erythema at decreased libido, decreased mental acuity,
injection site (3% to 4%), bruising at injection site decreased plasma testosterone, dehydration, deper-
(1%), induration at injection site (1%), swelling at sonalization, depressed mood, depression, diarrhea,
injection site (≤1%) diplopia, disorientation, disturbance in attention,
Neuromuscular & skeletal: Increased creatine phos- diverticulitis of the gastrointestinal tract, drug
phokinase (3% to 5%) dependence (physical dependence), dysarthria, dys-
Ophthalmic: Miosis (1% to 5%) geusia, dyspepsia, dysphagia, dysphoria, dyspnea,
Respiratory: Hypoventilation (1% to 5%) emotional lability, euphoria, exacerbation of asthma,
Sublingual tablet: excoriation, facial edema, flatulence, flushing, gall-
>10%: bladder disease (intracholedochal pressure), glos-
Central nervous system: Headache (29%), insom- salgia, glossitis, hallucination, hepatic
nia (21%) encephalopathy, hepatic failure, hepatic necrosis,
Dermatologic: Diaphoresis (13%) hepatitis (including cytolytic), hepatorenal syndrome,
Gastrointestinal: Nausea (14%), abdominal hiccups, hot flash, hypersensitivity reaction, hyper-
pain (12%) ventilation, hypoesthesia, hypogonadism (Brennan
Infection: Infection (12%) 2013; Debono 2011), hypotension, hypoventilation,
1% to 10%: Gastrointestinal: Constipation (8%), vomit- increased blood pressure, increased serum alanine
ing (8%) aminotransferase, increased serum aspartate ami-
Transdermal patch: notransferase, increased serum transaminases,
>10%: injection site reaction, intestinal obstruction, jaun-
Central nervous system: Dizziness (2% to 15%), dice, laceration, lethargy, local discomfort, localized
headache (3% to 14%), drowsiness (2% to 13%) warm feeling, loss of consciousness, malaise, mem-
Gastrointestinal: Nausea (6% to 21%), constipation ory impairment, mental status changes, migraine,
(3% to 13%) miosis, musculoskeletal pain, myasthenia, nasal
Local: Application-site pruritus (5% to 15%) congestion, neck pain, nervousness, nightmares,
1% to 10%: noncardiac chest pain, opioid withdrawal syndrome,
Cardiovascular: Chest pain (<5%), hypertension oral hypoesthesia, oral mucosa erythema, orthostatic
(<5%), peripheral edema (1% to <5%) hypotension, osteoarthritis, pallor, palpitations, pneu-
Central nervous system: Fatigue (≤5%), insomnia monia, prolonged Q-T interval on ECG, pruritus,
(<5%), anxiety (1% to <5%), depression (1% to psychosis, respiratory depression, respiratory dis-
<5%), falling (1% to <5%), hypoesthesia (1% to tress, respiratory failure, restlessness, rhinitis, rhinor-
<5%), migraine (1% to <5%), pain (1% to <5%), rhea, sedation, seizure, sensation of cold, sexual
paresthesia (1% to <5%) disorder, skin rash, slurred speech, stomatitis, syn-
Dermatologic: Pruritus (1% to 5%), hyperhidrosis cope, tachycardia, tinnitus, tooth abscess, tooth-
(1% to <5%), skin rash (1% to <5%) ache, transient ischemic attacks, tremor, urinary
Gastrointestinal: Vomiting (≤9%), xerostomia (≥5% to hesitancy, urinary incontinence, urinary retention,
6%), anorexia (1% to <5%), diarrhea (1% to <5%), urticaria, vasodilatation, vertigo, visual disturbance,
dyspepsia (1% to <5%), upper abdominal pain (1% weight loss, Wenckebach period on ECG, wheezing,
to <5%), stomach discomfort (2%) xeroderma, xerophthalmia, xerostomia
Genitourinary: Urinary tract infection (1% to <5%) Dosing
Infection: Influenza (1% to <5%) Adult
Local: Application site erythema (5% to 10%), appli- Note: Buprenorphine 8 mg sublingual tablet = bupre-
cation site rash (5% to 8%), application site irritation norphine/naloxone 8 mg/2 mg sublingual film =
(1% to 6%) buprenorphine/naloxone 4.2 mg/0.7 mg buccal film
Neuromuscular & skeletal: Arthralgia (1% to <5%), = buprenorphine/naloxone 5.7 mg/1.4 mg sublingual
asthenia (1% to <5%), back pain (1% to <5%), joint tablet.
swelling (1% to <5%), limb pain (1% to <5%), Acute pain (moderate to severe): Note: Long-term
muscle spasm (1% to <5%), musculoskeletal pain use is not recommended. The following recom-
(1% to <5%), myalgia (1% to <5%), neck pain (1% mendations are guidelines and do not represent the
to <5%), tremor (1% to <5%) maximum doses that may be required in all patients.
Respiratory: Bronchitis (1% to <5%), cough (1% to Doses should be titrated to pain relief/prevention.
<5%), dyspnea (1% to <5%), nasopharyngitis (1% Immediate-release injection:
to <5%), pharyngolaryngeal pain (1% to <5%), IM: Initial: 0.3 mg every 6 to 8 hours as needed;
sinusitis (1% to <5%), upper respiratory tract infec- initial dose (up to 0.3 mg) may be repeated once
tion (1% to <5%) in 30 to 60 minutes after the initial dose if needed
Miscellaneous: Fever (1% to <5%) Slow IV: Initial: 0.3 mg every 6 to 8 hours as
<1%, postmarketing, and/or case reports: Abdominal needed; initial dose (up to 0.3 mg) may be
distention, abdominal distress, abdominal pain, repeated once in 30 to 60 minutes after the initial
abnormal dreams, abnormal gait, abnormal hepatic dose if needed
function tests, accidental injury, acute sinusitis, agi-
tation, amblyopia, anaphylactic shock, angina pecto- Chronic pain (moderate to severe):
ris, angioedema, apathy, apnea, application site Buccal film: Note: Buprenorphine buccal film doses of
burning, application site dermatitis, application site 600, 750, and 900 mcg are only for use following
discharge, application site reaction, application site titration from lower doses (maximum dose: 900 mcg
vesicles, asthenia, ataxia, atrial fibrillation, blurred every 12 hours).
vision, bone fracture, bradycardia, bronchospasm, Opioid-naive patients and opioid-non-tolerant
cellulitis, cellulitis at injection site, cerebrovascular patients: Initial: 75 mcg once daily or, if tolerated,
231
BUPRENORPHINE
every 12 hours for at least 4 days, then increase to provide adequate analgesia; consider the use of
150 mcg every 12 hours. an alternate analgesic.
Opioid-experienced patients (conversion from other Dose titration (opioid-naive or opioid-experienced
opioids to buprenorphine): Discontinue all other patients): May increase dose in 5 mcg/hour, 7.5
around-the-clock opioids when buprenorphine is mcg/hour, or 10 mcg/hour increments (using no more
initiated. Taper patient's current opioid to no more than two patches), based on patient's supplemental
than 30 mg oral morphine sulfate equivalents daily short-acting analgesic requirements, with a minimum
before initiating buprenorphine. Following analgesic titration interval of 72 hours (maximum dose: 20 mcg/
taper, base the initial buprenorphine dose on the hour applied once every 7 days; risk for QTc prolon-
patient's daily opioid dose prior to taper. Patients gation increases with doses >20 mcg/hour patch).
may require additional short-acting analgesics dur- Discontinuation of therapy: Taper dose gradually
ing the taper period. every 7 days to prevent withdrawal in the physically
Patients who were receiving daily dose of <30 mg dependent patient; consider initiating immediate-
of oral morphine equivalents: Initial: 75 mcg once release opioids, if needed.
daily or every 12 hours
Opioid withdrawal in heroin-dependent hospital-
Patients who were receiving daily dose of 30 to
ized patients (off-label use): Immediate-release
89 mg of oral morphine equivalents: Initial: 150
injection: IV infusion: 0.3 to 0.9 mg (diluted in 50 to
mcg every 12 hours
100 mL of NS) over 20 to 30 minutes every 6 to 12
Patients who were receiving daily dose of 90 to
hours (Welsh 2002)
160 mg of oral morphine equivalents: Initial: 300
mcg every 12 hours Opioid dependence:
Patients who were receiving daily dose of >160 mg Extended-release injection: SubQ: Initial: 300 mg
of oral morphine equivalents: Buprenorphine buc- monthly for the first 2 months, after treatment has
cal film may not provide adequate analgesia; been inducted and adjusted with 8 to 24 mg of a
consider the use of an alternate analgesic. transmucosal buprenorphine-containing product for
Conversion from methadone: Close monitoring is a minimum of 7 days. Maintenance: 100 mg monthly,
required when converting methadone to another increasing to 300 mg monthly for patients who toler-
opioid. Ratio between methadone and other ate the 100 mg dose but do not demonstrate a
opioid agonists varies widely according to pre- satisfactory clinical response (as evidenced by self-
vious dose exposure. Methadone has a long reported illicit opioid use or urine drug screens pos-
half-life and can accumulate in the plasma. itive for illicit opioid use). Note: Administer doses at
Dose titration (opioid-naive or opioid-experienced least 26 days apart.
patients): Individually titrate in increments of 150 Subdermal implant: Insert 4 implants subdermally in
mcg every 12 hours, no more frequently than every the inner side of the upper arm. Remove no later
4 days, to a dose that provides adequate analgesia than 6 months after the date of insertion; if continued
and minimizes adverse reactions (maximum dose: treatment is desired, insert 4 new implants subder-
900 mcg every 12 hours; doses up to 450 mcg mally in the inner side of the contralateral arm. After
every 12 hours were studied in opioid naive one insertion in each arm, discontinue treatment with
patients). Patients may require additional short-act- subdermal implants.
ing analgesics during titration. Converting back to sublingual tablet: On day of
Discontinuation of therapy: Use a gradual downward implant removal, resume buprenorphine treatment
titration of the dose to prevent withdrawal; do not at previous sublingual dose.
abruptly discontinue. Sublingual tablet: Note: The combination product,
Patients with oral mucositis: Reduce the starting buprenorphine and naloxone, is preferred therapy
dose and titration incremental dose by 50%. over buprenorphine monotherapy for induction treat-
Transdermal patch: ment (and stabilization/maintenance treatment) for
Opioid-naive patients: Initial: 5 mcg/hour applied short-acting opioid dependence (US Department of
once every 7 days Health and Human Services 2005).
Opioid-experienced patients (conversion from other Induction: 2 to 4 mg; if no signs of precipitated with-
opioids to buprenorphine): Discontinue all other drawal after 60 to 90 minutes, may increase in
around-the-clock opioid drugs when buprenorphine increments of 2 to 4 mg. Once initial dose is
therapy is initiated. Short-acting analgesics as tolerated, may increase to a dose that is clinically
needed may be continued until analgesia with effective and provides 24 hours of stabilization.
transdermal buprenorphine is attained. There is a Buprenorphine treatment initiation should begin
potential for buprenorphine to precipitate with- after mild to moderate opioid withdrawal signs
drawal in patients already receiving opioids. appear (to avoid precipitated withdrawal), which is
Patients who were receiving daily dose of <30 mg of generally at least 6 to 12 hours after last use of
oral morphine equivalents: Initial: 5 mcg/hour short-acting opioids (eg, heroin, oxycodone) and 24
applied once every 7 days to 72 hours after last use of long-acting opioids
Patients who were receiving daily dose of 30 to (methadone) (Kampman [ASAM 2015]).
80 mg of oral morphine equivalents: Taper the After induction and titration, daily dose usually
current around-the-clock opioid for up to 7 days to ≥8 mg/day. In patients continuing to use opioids,
≤30 mg/day of oral morphine or equivalent before consider increasing the dose by 4 to 8 mg to a daily
initiating therapy. Initial: 10 mcg/hour applied once dose of ≥12 to 16 mg/day (Kampman
every 7 days [ASAM 2015]).
Patients who were receiving daily dose of >80 mg of Manufacturer's labeling: Dosing in the prescribing
oral morphine equivalents: Buprenorphine trans- information may not reflect current clinical practice.
dermal patch, even at the maximum dose of 20 Induction: Day 1: 8 mg; Day 2 and subsequent
mcg/hour applied once every 7 days, may not induction days: Induction usually accomplished
232
BUPRENORPHINE
over 3 to 4 days. Dosing on the first day may be Severe impairment: Consider reducing initial and
given in 2 to 4 mg increments. titration incremental dose by 50%; monitor for signs
Maintenance: Target dose: 16 mg/day; doses and symptoms of toxicity or overdose.
higher than 24 mg/day have not been demon- Transdermal patch:
strated to provide any clinical advantage. Mild or moderate impairment: There are no dosage
Perineural anesthesia (off-label use): Immediate- adjustments provided in the manufacturer's label-
release perineural injection: 200 to 300 mcg added ing; however, need for dosage adjustment is
to local anesthetic (eg, bupivacaine, mepivacaine, unlikely as systemic exposure following IV bupre-
tetracaine) with or without epinephrine and adminis- norphine in these patients was similar to that
tered as a single injection (Kosel 2015; observed in healthy subjects.
Krishnan 2016). Severe impairment: There are no dosage adjust-
Geriatric ments provided in the manufacturer's labeling
Acute pain (moderate to severe): Immediate- (has not been studied); consider alternative therapy
release injection: IM, slow IV: Refer to adult dosing; with more flexibility for dosing adjustments.
use with caution. Pediatric
Chronic pain (moderate to severe): Buccal film, Acute pain (moderate to severe): Dose should be
transdermal patch: No specific dosage adjustments titrated to appropriate effect. The following recom-
required; use caution and titrate slowly due to poten- mendations are guidelines and do not represent the
tial for increased risk of adverse events. maximum doses that may be required in all patients.
Opioid dependence: Extended-release injection, Children 2 to 12 years: IM, slow IV injection: Initial:
subdermal implant: No specific dosage adjustments Opioid-naive: 2 to 6 mcg/kg/dose every 4 to 6
required; use caution due to potential for increased hours (APS 2016); Note: Not all children have
risk of adverse events and inability to adjust dosage. faster clearance rates than adults; some children
Renal Impairment: Adult There are no dosage may require dosing intervals of every 6 to 8 hours;
adjustments provided in the manufacturer's labeling observe clinical effects to establish the proper dos-
(has not been adequately studied); use with caution. ing interval.
In pharmacokinetic studies, renal impairment (includ- Adolescents: IM, slow IV injection: Initial: Opioid-
ing administration pre- or post-hemodialysis) was not naive: 0.3 mg every 6 to 8 hours as needed; initial
associated with increased buprenorphine plasma con- dose may be repeated once in 30 to 60 minutes if
centrations. clinically needed
Hepatic Impairment: Adult Chronic pain (moderate to severe): Adolescents
Buccal film: ≥18 years: Transdermal patch:
Mild impairment (Child-Pugh class A): No dosage Opioid-naive patients: Initial: 5 mcg/hour applied
adjustment necessary. once every 7 days
Moderate impairment (Child-Pugh class B): No dos- Opioid-experienced patients (conversion from other
age adjustment necessary; use caution and monitor opioids to buprenorphine patch): Discontinue all
for signs and symptoms of toxicity or overdose. other around-the-clock opioid drugs when bupre-
Severe impairment (Child-Pugh class C): Reduce norphine therapy is initiated. Short-acting analge-
starting dose and reduce titration dose by 50% sics as needed may be continued until analgesia
(ie, from 150 mcg to 75 mcg). with transdermal buprenorphine is attained. There
Extended-release injection (SubQ): is a potential for buprenorphine to precipitate with-
Mild impairment: There are no dosage adjustments drawal in patients already receiving opioids.
provided in the manufacturer's labeling. Patients who were receiving daily dose of <30 mg
Moderate to severe impairment: Use is not recom- of oral morphine equivalents: Initial: 5 mcg/hour
mended. If signs and symptoms of hepatic impair- applied once every 7 days
ment occur within 2 weeks of injection, removal of Patients who were receiving daily dose of 30 to
depot may be required. Monitor for signs and 80 mg of oral morphine equivalents: Taper the
symptoms of toxicity or overdose. current around-the-clock opioid for up to 7 days
Immediate-release injection (IM, IV): to ≤30 mg/day of oral morphine or equivalent
Mild or moderate impairment: There are no dosage before initiating therapy. Initial: 10 mcg/hour
adjustments provided in the manufacturer's label- applied once every 7 days.
ing; however, need for dosage adjustment is Patients who were receiving daily dose of >80 mg
unlikely as systemic exposure following IV bupre- of oral morphine equivalents: Buprenorphine
norphine in these patients was similar to healthy transdermal patch, even at the maximum dose
subjects. of 20 mcg/hour applied once every 7 days, may
Severe impairment: There are no dosage adjust- not provide adequate analgesia; consider the use
ments provided in the manufacturer's labeling; of an alternate analgesic.
use with caution. Dose titration (opioid-naive or opioid-experienced
Subdermal implant: patients): May increase dose in 5 mcg/hour, 7.5
Mild impairment: There are no dosage adjustments mcg/hour, or 10 mcg/hour increments (using no
provided in the manufacturer's labeling (has not more than two 5 mcg/hour patches); titrate no more
been studied). frequently than every 72 hours; maximum dose: 20
Moderate or severe impairment: Use is not recom- mcg/hour applied once every 7 days due to risk of
mended. QTc prolongation associated with higher doses.
Sublingual: Discontinuation of therapy: Taper dose gradually
Mild impairment: No dosage adjustment necessary. every 7 days to prevent withdrawal in the physically
Moderate impairment: No dosage adjustment neces- dependent patient; consider initiating immediate-
sary; use caution and monitor for signs and symp- release opioids, if needed for signs and symptoms
toms of toxicity or overdose. of withdrawal.
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BUPRENORPHINE
Opioid dependence: Note: Do not start induction Hepatic Impairment: Pediatric

with buprenorphine until objective and clear signs Injection (immediate release): Children ≥2 years and
of withdrawal are apparent (otherwise withdrawal Adolescents: Use caution due to extensive hepatic
may be precipitated). metabolism; dosage adjustments may be necessary.
Sublingual tablet: Note: The combination product, Subdermal implant: Adolescents ≥16 years:
buprenorphine and naloxone, is preferred therapy Mild impairment: There are no dosage adjustments
over buprenorphine monotherapy for induction provided in the manufacturer's labeling (has not
treatment (and stabilization/maintenance treat- been studied).
ment) for short-acting opioid dependence (US Moderate or severe impairment: Use is not recom-
Department of Health and Human Services 2005) mended.
American Society of Addiction Medicine Guidelines Mechanism of Action Buprenorphine exerts its anal-
(Kampman [ASAM 2015]): Limited data available: gesic effect via high-affinity binding to mu opiate recep-
Adolescents: Sublingual tablet: tors in the CNS; displays partial mu agonist and weak
Note: Buprenorphine treatment initiation should kappa antagonist activity. Due to it being a partial mu
begin after mild to moderate opioid withdrawal agonist, its analgesic effects plateau at higher doses
signs appear (to avoid precipitated withdrawal), and it then behaves like an antagonist. The extended-
which is generally at least 6 to 12 hours after last release formulation is injected subcutaneously as a
use of short-acting opioids (eg, heroin, oxyco- liquid; subsequent precipitation following injection
done) and 24 to 72 hours after last use of long- results in a solid depot which will gradually release
acting opioids (methadone). buprenorphine via diffusion and biodegradation of the
Induction: Initial: 2 to 4 mg; if no signs of precipi- depot.
tated withdrawal after 60 to 90 minutes, may Contraindications
increase in increments of 2 to 4 mg. Once initial Hypersensitivity (eg, anaphylaxis) to buprenorphine or
dose is tolerated, may increase to a dose that is any component of the formulation
clinically effective and provides 24 hours of Buccal film, immediate-release injection, transdermal
stabilization. patch: Additional contraindications: Significant respi-
After induction and titration, daily dose usually ratory depression; acute or severe asthma in an
≥8 mg/day are necessary. In patients continuing unmonitored setting or in the absence of resuscitative
to use opioids, consider increasing the dose by 4 equipment; GI obstruction, including paralytic ileus
to 8 mg to a daily dose of ≥12 to 16 mg/day. (known or suspected)
Maximum daily dose 24 mg/day. Documentation of allergenic cross-reactivity for opioids
Manufacturer's labeling: Adolescents ≥16 years: is limited. However, because of similarities in chemical
Induction: Day 1: 8 mg/day divided in 2 to 4 mg structure and/or pharmacologic actions, the possibility
increments; day 2 and subsequent induction of cross-sensitivity cannot be ruled out with certainty.
days dose dependent upon patient response.
In 1 study, patients received 8 mg on day 1, Canadian labeling: Additional contraindications (not in
followed by 16 mg on day 2; induction usually US labeling): Acute respiratory depression; hypercap-
accomplished over 3 to 4 days. Treatment nia; cor pulmonale; acute alcoholism or alcohol
should begin only when objective and clear signs dependence; delirium tremens; convulsive disorders;
of moderate opioid withdrawal appear, and not severe CNS depression; increased cerebrospinal or
less than 4 hours after last use of heroin or other intracranial pressure; head injury; severe hepatic
short-acting opioids or not less than 24 hours insufficiency
after last use of methadone or other long-acting Buccal film, transdermal patch: Additional contraindi-
opioids. Titrating dose to clinical effectiveness cations: Hypersensitivity to other opioids; suspected
should be done as rapidly as possible to prevent surgical abdomen (eg, acute appendicitis or pan-
undue withdrawal symptoms and patient drop- creatitis); mild, intermittent or short duration pain that
out during the induction period. can otherwise be managed; management of acute
Maintenance: Target dose: 16 mg/day; reported pain, including use in outpatient or day surgeries;
range: 4 to 24 mg/day; doses higher than management of perioperative pain relief, or in other
24 mg/day have not been demonstrated to pro- situations characterized by rapidly varying analgesic
vide any clinical advantage; patients should be requirements; obstructive airway (other than
switched to the buprenorphine/naloxone combi- asthma); status asthmaticus; concurrent use or use
nation product for maintenance and unsuper- within 14 days of MAOIs; myasthenia gravis; opioid-
vised therapy dependent patients and for opioid withdrawal treat-
Subdermal implant: Adolescents ≥16 years: Insert 4 ment; pregnancy or during labor and delivery; breast-
implants subdermally in the inner side of the upper feeding; known or suspected oral mucositis (buccal
arm. Remove no later than 6 months after the date film only)
of insertion; if continued treatment is desired, insert Subdermal implant: Additional contraindications:
4 new implants subdermally in the inner side of the Severe respiratory insufficiency, opioid-naive
contralateral arm. After 1 insertion in each arm, patients, known or suspected GI obstruction or any
discontinue treatment with subdermal implants. condition affecting bowel transit, congenital long QT
To convert back to sublingual tablet: On day of prolongation or QTc prolongation at baseline, uncor-
implant removal, resume buprenorphine treatment rected hypokalemia, hypomagnesemia, hypocal-
at previous sublingual dose cemia
Renal Impairment: Pediatric There are no dosage Warnings/Precautions An opioid-containing analge-
adjustments provided in manufacturer's labeling (has sic regimen should be tailored to each patient's needs
not been studied); use with caution. In pharmacoki- and based upon the type of pain being treated (acute
netic studies, renal impairment (including administra- versus chronic), the route of administration, degree of
tion pre- or posthemodialysis) was not associated with tolerance for opioids (naive versus chronic user), age,
increased buprenorphine plasma concentrations. weight, and medical condition. The optimal analgesic
234
BUPRENORPHINE
dose varies widely among patients. Doses should be may be more sensitive to adverse effects (eg, life-
titrated to pain relief/prevention. When switching threatening respiratory depression). In chronic pain,
patients from buprenorphine to naltrexone, do not ini- monitor opioid use closely in this age group due to an
tiate naltrexone until 7 to 14 days after buprenorphine increased potential for risks, including certain risks such
discontinuation. No time delay is required when switch- as falls/fracture, cognitive impairment, and constipation
ing patients from buprenorphine to methadone (Kamp- (Dowell [CDC 2016]). Consider the use of alternative
man [ASAM 2015]). nonopioid analgesics in these patients. Also use with
caution in debilitated or cachectic patients; there is a
[US Boxed Warning]: To ensure that the benefits of greater potential for life-threatening respiratory depres-
opioid analgesics outweigh the risks of addiction, sion, even at therapeutic dosages. Consider the use of
abuse, and misuse, a REMS is required. Drug com- alternative nonopioid analgesics in these patients.
panies with approved opioid analgesic products
must make REMS-compliant education programs Hypersensitivity reactions, including bronchospasm,
available to health care providers. Health care pro- angioneurotic edema, and anaphylactic shock, have
viders are encouraged to complete a REMS-com- been reported. The most common symptoms include
pliant education program; counsel patients and/or rash, hives, and pruritus.
their caregivers, with every prescription, on safe Hepatitis has been reported; hepatic events ranged
use, serious risks, storage, and disposal of these from transient, asymptomatic transaminase elevations
products; emphasize to patients and their care- to hepatic failure; in many cases, patients had preexist-
givers the importance of reading the Medication ing hepatic impairment. Monitor liver function tests in
Guide every time it is provided by their pharmacist; patients at increased risk for hepatotoxicity (eg, history
and consider other tools to improve patient, house- of alcohol abuse, preexisting hepatic dysfunction, IV
hold, and community safety. drug abusers) prior to and during therapy. Remove
buprenorphine subdermal implant if signs and symp-
May cause CNS depression, which may impair physical toms of buprenorphine toxicity develop concurrent with
or mental abilities; patients must be cautioned about hepatic impairment. If signs and symptoms of toxicity or
performing tasks that require mental alertness (eg, overdose occur within 2 weeks of extended-release
operating machinery, driving). [US Boxed Warning]: injection, removal of the depot may be required. Use
Serious, life-threatening, or fatal respiratory buccal film and sublingual tablet with caution in patients
depression may occur. Monitor closely for respira- with moderate hepatic impairment; dosage adjustment
tory depression, especially during initiation or dose recommended in severe hepatic impairment. Use
escalation. Misuse or abuse by chewing, swallow- immediate-release injection with caution in patients with
ing, snorting, or injecting buprenorphine extracted severe impairment. Subdermal implants should not be
from the buccal film or transdermal system will used in patients with preexisting moderate to severe
result in the uncontrolled delivery of buprenorphine hepatic impairment. Transdermal patch should not be
and pose a significant risk of overdose and death. used in patients with severe hepatic impairment; con-
Misuse by self-injection of buprenorphine or the consider alternative therapy with more flexibility for dosing
comitant use of buprenorphine and benzodiazepines adjustments. Patients with preexisting moderate or
(or other CNS depressants, including alcohol) may severe hepatic impairment are not candidates for the
result in coma or death. Carbon dioxide retention from extended-release injection. If moderate or severe
opioid-induced respiratory depression can exacerbate impairment develops during treatment with the
the sedating effects of opioids. If the extended release extended-release injection, continue with caution and
injection is discontinued due to respiratory depression, monitor for toxicity for several months.
monitor the patient for ongoing respiratory depression
Avoid use in patients with CNS depression or coma as
for several months due to its extended release charac-
these patients are susceptible to intracranial effects of
teristics. Use with caution in patients with compromised
CO2 retention. Use with extreme caution in patients with
respiratory function (eg, chronic obstructive pulmonary
head injury, intracranial lesions, or elevated intracranial
disease, cor pulmonale, decreased respiratory reserve,
pressure (ICP); exaggerated elevation of ICP may
hypoxia, hypercapnia, or preexisting respiratory depres-
occur. Buprenorphine can produce miosis and changes
sion). Accidental exposure to even one dose, especially
in the level of consciousness that may interfere with
in children, can result in a fatal overdose. Use with
patient evaluation. May cause severe hypotension,
caution and monitor for respiratory depression in
including orthostatic hypotension and syncope; use with
patients with significant chronic obstructive pulmonary
caution in patients with hypovolemia, cardiovascular
disease or cor pulmonale and those with a substantially
disease (including acute MI), or drugs that may exag-
decreased respiratory reserve, hypoxia, hypercapnia,
gerate hypotensive effects (including phenothiazines or
or preexisting respiratory depression, particularly when
general anesthetics). Monitor for symptoms of hypoten-
initiating and titrating therapy; critical respiratory
sion following initiation or dose titration. Avoid use in
depression may occur, even at therapeutic dosages.
patients with circulatory shock. May obscure diagnosis
Consider the use of alternative nonopioid analgesics in
or clinical course of patients with acute abdominal
these patients. Use opioids with caution for chronic pain
conditions. Use with caution in patients with a history
and titrate dosage cautiously in patients with risk factors of ileus or bowel obstruction; buccal film, immediate-
for sleep-disordered breathing, including HF and obe- release injection, and transdermal patch are contra-
sity. Avoid opioids in patients with moderate to severe indicated in patients with known or suspected GI
sleep-disordered breathing (Dowell [CDC 2016]). When obstruction, including paralytic ileus. Use with caution
using buprenorphine for treatment of opioid depend- in patients with biliary tract dysfunction, including acute
ence, treat acute pain with nonopioid analgesics when- pancreatitis; may cause constriction of sphincter of
ever possible. If treatment with a high-affinity full opioid Oddi. Use with caution in patients with a history of
analgesic is required, monitor closely for respiratory seizure disorders; may cause or exacerbate preexisting
depression, as high doses may be necessary to seizures. Use with caution in patients with adrenal
achieve pain relief. Use with caution in elderly patients; insufficiency, including Addison disease. Long-term
235
BUPRENORPHINE
opioid use may cause adrenal insufficiency (nausea, removed depots or implants with adequate security,
vomiting, anorexia, fatigue, weakness, dizziness and accountability, and proper disposal, per facility proce-
low blood pressure) or secondary hypogonadism, which dure for a Schedule III drug product, and per applicable
may lead to sexual dysfunction, infertility, mood disor- federal, state, and local regulations. To properly dispose
ders, and osteoporosis (Brennan 2013). Use with cau- of transdermal patch, fold it over on itself and flush
tion in patients with renal impairment, morbid obesity, down the toilet; alternatively, seal the used patch in
toxic psychosis, thyroid dysfunction, or prostatic hyper- the provided Patch-Disposal Unit and dispose of in
plasia and/or urinary stricture. Potentially significant the trash. When used for chronic pain (outside of end-
drug-drug interactions may exist, requiring dose or of-life or palliative care, active cancer treatment, sickle
frequency adjustment, additional monitoring, and/or cell disease, or medication-assisted treatment for opioid
selection of alternative therapy. [US Boxed Warning]: use disorder) in outpatient setting in adults, opioids
Buccal film, extended-release and immediate- should not be used as first-line therapy for chronic pain
release injection, transdermal patch: Concomitant management (pain >3-month duration or beyond time of
use of benzodiazepines or other CNS depressants, normal tissue healing) due to limited short-term bene-
including alcohol and opioids, may result in pro- fits, undetermined long-term benefits, and association
found sedation, respiratory depression, coma, and with serious risks (eg, overdose, MI, auto accidents, risk
death. Reserve concomitant prescribing of opioids of developing opioid use disorder). Preferred manage-
and benzodiazepines or other CNS depressants for ment includes nonpharmacologic therapy and nonop-
use in patients for whom alternative treatment ioid therapy (eg, NSAIDs, acetaminophen, certain
options are inadequate. Limit dosages and dura- anticonvulsants and antidepressants). If opioid therapy
tions to the minimum required. Follow patients for is initiated, it should be combined with nonpharmaco-
signs and symptoms of respiratory depression and logic and nonopioid therapy, as appropriate. Prior to
sedation. Prohibiting medication-assisted treatment of initiation, known risks of opioid therapy should be
opioid use disorder may increase the risk of morbidity discussed and realistic treatment goals for pain/function
and mortality, therefore patients should be educated on should be established, including consideration for dis-
the risks of concomitant use with benzodiazepines, continuation if benefits do not outweigh risks. Therapy
sedatives, opioid analgesics, and alcohol. Strategies should be continued only if clinically meaningful
should be developed to manage use of prescribed or improvement in pain/function outweighs risks. Therapy
illicit benzodiazepines or other CNS depressants at should be initiated at the lowest effective dosage using
initiation of or during treatment with buprenorphine; immediate-release opioids (instead of extended-
adjustments to induction procedures and additional release/long-acting opioids). Risk associated with use
monitoring may be required. If appropriate, delay or increases with higher opioid dosages. Risks and bene-
omit buprenorphine dose if a patient is sedated at time fits should be re-evaluated when increasing dosage to
of buprenorphine dosing. Discontinuation of benzodia- ≥50 morphine milligram equivalents (MME)/day orally;
zepines or other CNS depressants is preferred; gradual dosages ≥90 MME/day orally should be avoided unless
tapering of benzodiazepine or other CNS depressant, carefully justified (Dowell [CDC 2016]).
decreasing to lowest effective dose, or monitoring in a
Buprenorphine has been observed to cause QTc pro-
higher level of care for taper may be appropriate.
longation. Do not exceed a dose of 900 mcg every 12
Benzodiazepines are not the treatment of choice for
hours buccal film or one 20 mcg/hour transdermal
anxiety or insomnia for patients in buprenorphine treat-
patch. Avoid using in patients with a personal or family
ment; make sure patients are appropriately diagnosed
history of long QT syndrome or in patients taking
and consider alternative medications for anxiety and
concurrent class IA or III antiarrhythmics or other med-
insomnia prior to co-administration of benzodiazepines
ications that prolong the QT interval. Use with caution in
and buprenorphine.
patients with hypokalemia, hypomagnesemia, or clin-
[US Boxed Warning]: Use exposes patients and ically unstable cardiac disease, including unstable heart
other users to the risks of addiction, abuse, and failure, unstable atrial fibrillation, symptomatic bradycar-
misuse, potentially leading to overdose and death. dia, or active MI. Avoid exposure of transdermal patch
Assess each patient's risk before prescribing; mon- application site and surrounding area to direct external
itor all patients regularly for development of these heat sources (eg, heating pads, electric blankets, heat
behaviors or conditions. Use with caution in patients or tanning lamps, hot baths/saunas, hot water bottles,
with a history of drug abuse or acute alcoholism; or direct sunlight). Buprenorphine release from the
potential for drug dependency exists. Other factors patch is temperature-dependent and may result in over-
associated with increased risk for misuse include dose. Patients who experience fever or increase in core
younger age and psychotropic medication use. Con- temperature should be monitored closely and adjust
sider offering naloxone prescriptions in patients with dose if signs or respiratory depression or CNS depres-
factors associated with an increased risk for overdose, sion occur. Application-site reactions, including rare
such as history of overdose or substance use disorder, cases of severe reactions (eg, vesicles, discharge,
higher opioid dosages (≥50 morphine milligram equiv- "burns"), have been observed with transdermal patch
alents/day orally), and concomitant benzodiazepine use use; onset varies from days to months after initiation;
(Dowell [CDC 2016]). The misuse of buccal film by patients should be instructed to report severe reactions
swallowing or of transdermal patch by placing it in the promptly and discontinue therapy. Oral mucositis may
mouth, chewing it, swallowing it, or using it in ways result in more rapid absorption and higher buprenor-
other than indicated may cause choking, overdose, and phine plasma levels in patients using buccal film;
death. Use with caution in patients with delirium tre- reduce dose in patients with oral mucositis and monitor
mens. Buccal film and transdermal patch are indicated closely for signs and symptoms of toxicity or overdose.
for the management of pain severe enough to require [US Boxed Warning]: Prolonged use during preg-
daily, around-the-clock, long-term opioid treatment; nancy can cause neonatal withdrawal syndrome,
should not be used for as-needed pain relief. Therapy which may be life-threatening if not recognized
with the buccal film or transdermal patch is not appro- and treated according to according to protocols
priate for use in the management of addictions. Handle developed by neonatology experts. If opioid use is
236
BUPRENORPHINE
required for a prolonged period in a pregnant anesthesia, patients should be continuously monitored
woman, advise the patient of the risk of neonatal in an anesthesia care setting by persons not involved in
withdrawal syndrome and ensure that appropriate in the conduct of the surgical or diagnostic procedure.
treatment will be available. Signs and symptoms This guidance applies to anyone who has been treated
include irritability, hyperactivity and abnormal sleep with extended release buprenorphine injection within
pattern, high-pitched cry, tremor, vomiting, diarrhea, the past 6 months. The decision whether to discontinue
and failure to gain weight. Onset, duration, and severity buprenorphine prior to elective surgery should be made
depend on the drug used, duration of use, maternal in consultation with the surgeon and anesthesiologist
dose, and rate of drug elimination by the newborn. (Kampman [ASAM 2015]).
Reversal of partial opioid agonists or mixed opioid [US Boxed Warning]: Insertion and removal of
agonist/antagonists (eg, buprenorphine, pentazocine) implant are associated with the risk of implant
may be incomplete and large doses of naloxone may migration, protrusion, and expulsion. Rare but seri-
be required. Concurrent use of opioid agonist/antago- ous complications including nerve damage and
nist analgesics may precipitate withdrawal symptoms migration resulting in embolism and death may
and/or reduced analgesic efficacy in patients following result from improper insertion in the upper arm.
prolonged therapy with mu opioid agonists. Abrupt Additional complications may include local migra-
discontinuation following prolonged use may also lead tion, protrusion, and expulsion. Incomplete inser-
to withdrawal symptoms and is not recommended; tions or infections may lead to protrusion or
taper dose gradually when discontinuing. Withdrawal expulsion. Because of the risks associated with
signs and symptoms will be delayed in patients who insertion and removal, buprenorphine implant is
discontinue the extended-release injection or have it available only through a restricted program. All
removed; transmucosal buprenorphine may be needed health care providers must successfully complete
to treat withdrawal in these patients. a live training program on the insertion and removal
Tablets, which are used for induction treatment of opioid procedures and become certified, prior to perform-
dependence, should not be started until objective and ing insertions or prescribing buprenorphine
clear signs of moderate withdrawal are evident. If implants. Patients must be monitored to ensure that
subdermal implants are not immediately replaced in the implant is removed by a health care provider
contralateral arm after removal, maintain patients on certified to perform insertions. Infection may occur at
their previous dosage of sublingual buprenorphine. site of insertion or removal, with excessive palpation
shortly after insertion and improper removal increasing
[US Boxed Warning]: Serious harm or death could the risk. Examine the insertion site one week following
result if extended-release injection is administered insertion for signs of infection or problems with wound
IV. The injection forms a solid mass upon contact healing. Use subdermal implants with caution in
with body fluids and may cause occlusion, local patients with a history of keloid formation, connective
tissue damage, and thromboembolic events, includ- tissue disease (ie, scleroderma) or history of recurrent
ing life-threatening pulmonary emboli if adminis- MRSA infections. Subdermal implant is not appropriate
tered IV. Because of the risk of serious harm or for patients who are new to treatment or have not
death that could result from IV self-administration, sustained prolonged clinical stability on buprenorphine
buprenorphine extended-release injection is only ≤8 mg/day.
available through a restricted program called the Drug Interactions
Sublocade REMS Program. Health care settings and Metabolism/Transport Effects Substrate of
pharmacies that order and dispense buprenorphine CYP3A4 (major); Note: Assignment of Major/Minor
extended-release injection must be certified in this substrate status based on clinically relevant drug
program and comply with the REMS requirements. interaction potential
Administer via subcutaneous route only. Do not admin- Avoid Concomitant Use
ister IM or IV. Avoid concomitant use of Buprenorphine with any of
There is no maximum recommended duration for the the following: Atazanavir; Azelastine (Nasal); Brom-
use of buprenorphine sublingual tablets in the main- peridol; Conivaptan; Eluxadoline; Fusidic Acid (Sys-
tenance treatment of opioid addiction; patients may temic); Idelalisib; Monoamine Oxidase Inhibitors;
require treatment indefinitely. Advise patients of the Opioid Agonists; Opioids (Mixed Agonist / Antagonist);
potential to relapse to illicit drug use following discontin- Orphenadrine; Oxomemazine; Paraldehyde; Thalido-
uation of opioid agonist/partial agonist medication- mide
assisted treatment. If the extended-release injection is Increased Effect/Toxicity
discontinued or the depot is removed, monitor the Buprenorphine may increase the levels/effects of:
patient for several months for signs and symptoms of Alvimopan; Azelastine (Nasal); Blonanserin; Desmo-
withdrawal. After steady-state has been achieved (4 to pressin; Diuretics; Eluxadoline; Flunitrazepam; Metho-
6 months), patients discontinuing extended-release trimeprazine; MetyroSINE; Monoamine Oxidase
injections may have detectable plasma levels of bupre- Inhibitors; Orphenadrine; Paraldehyde; Piribedil; Pra-
norphine for 12 months or longer. mipexole; QT-prolonging Agents (Highest Risk);
Ramosetron; ROPINIRole; Rotigotine; Selective Sero-
In patients undergoing elective surgery (excluding cae- tonin Reuptake Inhibitors; Serotonin Modulators;
sarean section), discontinuation of buprenorphine 24 to Suvorexant; Thalidomide; Zolpidem
36 hours before anticipated need for surgical anesthe-
sia may be considered. Short-acting opioids may be The levels/effects of Buprenorphine may be increased
given during and/or after surgery. In patients unable to by: Alcohol (Ethyl); Alizapride; Amphetamines; Anti-
abruptly discontinue buprenorphine prior to surgery, full cholinergic Agents; Aprepitant; Atazanavir; Brimoni-
opioid agonists may be added to the buprenorphine to d i n e ( To p i c a l ) ; B r o m o p r i d e ; B r o m p e r i d o l ;
maintain proper anesthesia; however, increased doses Cannabidiol; Cannabis; Chlormethiazole; Chlorphene-
may be required to overcome buprenorphine receptor sin Carbamate; Clofazimine; CNS Depressants; Cobi-
blockade. If opioid therapy is required as part of cistat; Conivaptan; CYP3A4 Inhibitors (Moderate);
237
BUPRENORPHINE
CYP3A4 Inhibitors (Strong); Daclatasvir; Dimethin- during pregnancy ranged from day 1 to day 8 of life,
dene (Topical); Dronabinol; Droperidol; Duvelisib; most occurring on day 1. Symptoms of withdrawal may
Fosaprepitant; Fosnetupitant; Fusidic Acid (Systemic); include agitation, apnea, bradycardia, convulsions,
Idelalisib; Kava Kava; Larotrectinib; Lofexidine; Mag- hypertonia, myoclonus, respiratory depression, and
nesium Sulfate; Methotrimeprazine; MiFEPRIStone; tremor. Based on available data, there does not appear
Minocycline; Nabilone; Netupitant; Ombitasvir, Pari- to be a dose-response relationship with the incidence of
taprevir, and Ritonavir; Ombitasvir, Paritaprevir, Rito- neonatal abstinence syndrome.
navir, and Dasabuvir; Oxomemazine; Palbociclib;
Perampanel; PHENobarbital; Primidone; Rufinamide; Buprenorphine is currently considered an alternate
Simeprevir; Sodium Oxybate; Stiripentol; Succinylcho- treatment for pregnant women who need therapy for
line; Tetrahydrocannabinol; Tetrahydrocannabinol and opioid addiction (CSAT 2004; Dow 2012; Kampman
Cannabidiol [ASAM 2015]); however, use in pregnancy for this
Decreased Effect purpose is increasing (ACOG 2012; Soyka 2013).
Buprenorphine may decrease the levels/effects of: Because dose adjustments cannot be made, it may
Atazanavir; Diuretics; Gastrointestinal Agents (Proki- not be appropriate to initiate use of the implant in
netic); Opioid Agonists; Pegvisomant; Sincalide pregnant women; women who become pregnant while
using the implant should be closely monitored. Bupre-
The levels/effects of Buprenorphine may be
norphine should not be used to treat pain during labor.
decreased by: Bosentan; CYP3A4 Inducers (Moder-
Women receiving buprenorphine for the treatment of
ate); CYP3A4 Inducers (Strong); Dabrafenib; Defera-
addiction should be maintained on their daily dose of
sirox; Efavirenz; Enzalutamide; Etravirine; Ivosidenib;
buprenorphine in addition to receiving the same pain
Lorlatinib; Mitotane; Nalmefene; Naltrexone; Opioids
(Mixed Agonist / Antagonist); PHENobarbital; Pitoli- management options during labor and delivery as
sant; Primidone; Sarilumab; Siltuximab; St John's opioid-naive women; maintenance doses of buprenor-
Wort; Tocilizumab phine will not provide adequate pain relief. Opioid
Pharmacodynamics/Kinetics agonist-antagonists should be avoided for the treatment
Onset of Action Analgesic: Immediate-release IM: of labor pain in women maintained on buprenorphine
≥15 minutes; Peak effect: Immediate-release IM: ~1 due to the risk of precipitating acute withdrawal. In
hour addition, buprenorphine should not be given to women
Duration of Action Immediate-release IM: ≥6 hours; in labor taking methadone (ACOG 2012).
Extended-release SubQ: 28 days Amenorrhea may develop secondary to substance
Half-life Elimination abuse; pregnancy may occur following the initiation of
Premature neonates (GA: 27 to 32 weeks): Immedi- buprenorphine maintenance treatment. Contraception
ate-release IV: 20 ± 8 hours (Barrett 1993) counseling is recommended to prevent unplanned
Children 4 to 7 years: Immediate-release IV: ~1 hour pregnancies (Dow 2012). Long-term opioid use may
(Olkkola 1989) cause secondary hypogonadism, which may lead to
Adults: Immediate-release IV: 2.2 to 3 hours; Buccal
sexual dysfunction or infertility (Brennan 2013).
film: 27.6 ± 11.2 hours; Apparent terminal half-life:
Sublingual tablet: ~37 hours; Transdermal patch:
~26 hours. Note: Extended elimination half-life for Buprenorphine is present in breast milk.
sublingual administration may be due to depot effect Based on data from six women taking a median oral
(Kuhlman 1996) dose of buprenorphine 0.29 mg/kg/day, 5 to 8 days
Time to Peak Plasma: Buccal film: 2.5 to 3 hours; postpartum, the concentrations of buprenorphine and
Extended-release SubQ: 24 hours, with steady state its metabolite in breast milk were low (0.2% and 0.12%
achieved after 4 to 6 months; Subdermal implant: 12 of the weight adjusted maternal dose, respectively).
hours after insertion, with steady state achieved by Using data from seven women taking an average oral
week 4; Sublingual: 30 minutes to 1 hour (Kuhlman dose of buprenorphine 7 mg/day, ~1 month postpar-
1996); Transdermal patch: Steady state achieved by tum, the concentrations of buprenorphine and its
day 3 metabolite in breast milk were also low (0.38% and
Pregnancy Considerations 0.18% of the weight adjusted maternal dose, respec-
[US Boxed Warning]: Prolonged use of opioids tively). When used for pain management (immediate-
during pregnancy can result in neonatal opioid release injection, patch), the manufacturers do not
withdrawal syndrome, which may be life-threaten- recommend use in breastfeeding women. When used
ing if not recognized and requires management for opioid addiction (sublingual tablet, extended-
according to protocols developed by neonatology release injection), the manufacturer recommends that
experts. If opioid use is required for a prolonged caution be used if breastfeeding. Breastfed infants
period in a pregnant woman, advise the patient of exposed to large doses of opioids should be moni-
the risk of neonatal opioid withdrawal syndrome tored for apnea and sedation (Montgomery 2012).
and ensure appropriate treatment will be available. When buprenorphine is used to treat opioid addiction in
Buprenorphine crosses the placenta; buprenorphine breastfeeding women, most guidelines allow breast-
and norbuprenorphine can be detected in newborn feeding as long as the infant is tolerant to the dose and
serum, urine, and meconium following in utero expo- other contraindications do not exist (eg, not using
sure (CSAT 2004). Based on available data, an additional drugs or alcohol, HIV negative); caution
increased risk of major malformations has not been should be used when breastfed infants not previously
observed. Following chronic opioid therapy in preg- exposed (ACOG 2012; CSAT 2004; Kampman [ASAM
nancy, adverse events in the newborn (including with- 2015]; Montgomery 2012). If additional illicit substan-
drawal) may occur; monitoring of the neonate is ces are being abused, women treated with buprenor-
recommended. The minimum effective dose should be phine should pump and discard breast milk until
used if opioids are needed (Chou 2009). The onset of sobriety is established (ACOG 2012; Dow 2012).
withdrawal in infants of women receiving buprenorphine Controlled Substance C-III
238
BUPRENORPHINE AND NALOXONE
Prescribing and Access Restrictions General information: Buprenorphine/naloxone should

Extended-release injection: Prescribing of the extended be used as part of a complete treatment plan to
release injection is limited to healthcare providers who include counseling and psychosocial support.
meet qualifying requirements, have notified the Sec- Local Anesthetic/Vasoconstrictor Precautions
retary of Health and Human Services (HHS) of their No information available to require special precautions
intent to prescribe this product for the treatment of Effects on Dental Treatment No significant effects or
opioid dependence and have been assigned a unique complications reported
identification number to include on every prescription. Effects on Bleeding No information available to
Subdermal implant: Prescribing of implants and insert- require special precautions
ing or removing implants are limited to healthcare Adverse Reactions Also see individual agents.
providers who have completed a live training program. >10%:
Additionally, inserting or removing implants is limited Central nervous system: Headache (7% to 37%),
to healthcare providers who have demonstrated pro- pain (22%)
cedural competency. As a prerequisite for participating Dermatologic: Diaphoresis (>1% to 14%)
in the live training program, the healthcare provider Gastrointestinal: Nausea (sublingual tablet: 5% to
must have performed at least one qualifying surgical 15%), constipation (>1% to 12%), abdominal
procedure in the last 3 months. Qualifying procedures pain (11%)
are those performed under local anesthesia using 1% to 10%:
aseptic technique and include, at a minimum, making Cardiovascular: Vasodilatation (9%), palpitations (sub-
skin incisions or placing sutures. Buprenorphine sublingual film: >1%)
dermal implant will only be distributed to certified Central nervous system: Disturbance in attention (sub-
prescribers through a restricted distribution program. lingual film: >1%), insomnia (>1%), intoxicated feel-
ing (sublingual film: >1%), withdrawal
Information concerning the insertion and removal pro-
syndrome (>1%)
cedures can be obtained by calling 1-844-859-6341.
Gastrointestinal: Vomiting (5% to 8%), glossalgia (sub-
Sublingual tablet: Prescribing of tablets for opioid
lingual film: >1%), oral hypoesthesia (sublingual film:
dependence is limited to physicians who have met
>1%), oral mucosa erythema (sublingual film: >1%)
the qualification criteria and have received a DEA Ophthalmic: Blurred vision (sublingual film: >1%)
number specific to prescribing this product. Tablets Frequency not defined:
will be available through pharmacies and wholesalers Central nervous system: Anxiety, irritability, rest-
which normally provide controlled substances. lessness
Dosage Forms Considerations Note: Subdermal Dermatologic: Piloerection
implant and subcutaneous implant both refer to Probu- Gastrointestinal: Stomach discomfort
phine. Neuromuscular & skeletal: Arthralgia
Dosage Forms: US Ophthalmic: Increased lacrimation
Film, Buccal: Respiratory: Rhinorrhea
Belbuca: 75 mcg (1 ea, 60 ea); 150 mcg (1 ea, 60 ea); <1%, postmarketing, and/or case reports: Glossitis, oral
300 mcg (1 ea, 60 ea); 450 mcg (1 ea, 60 ea); 600 bullae, oral mucosa ulcer, peripheral edema, stoma-
mcg (1 ea, 60 ea); 750 mcg (1 ea, 60 ea); 900 mcg (1 titis
ea, 60 ea) Mechanism of Action
Implant, Subcutaneous: Buprenorphine: Buprenorphine exerts its analgesic
Probuphine Implant Kit: 74.2 mg (4 ea) effect via high affinity binding to mu opiate receptors
Patch Weekly, Transdermal: in the CNS; displays partial mu agonist and weak
Butrans: 5 mcg/hr (4 ea); 7.5 mcg/hr (4 ea); 10 mcg/hr kappa antagonist activity
(4 ea); 15 mcg/hr (4 ea); 20 mcg/hr (4 ea) Naloxone: Pure opioid antagonist that competes and
Generic: 5 mcg/hr (1 ea, 4 ea); 7.5 mcg/hr (4 ea); 10 displaces opioids at opioid receptor sites
mcg/hr (1 ea, 4 ea); 15 mcg/hr (1 ea, 4 ea); 20 mcg/ Pharmacodynamics/Kinetics
hr (1 ea, 4 ea) Half-life Elimination Suboxone: Buprenorphine 24 to
Solution, Injection: 42 hours; Naloxone 2 to 12 hours; Bunavail: Bupre-
Buprenex: 0.3 mg/mL (1 mL) norphine 16.4 to 27.5 hours; Naloxone 1.9 to 2.4
Generic: 0.3 mg/mL (1 mL) hours; Cassipa: Buprenorphine 35 to 37 hours; Nalox-
Solution Prefilled Syringe, Subcutaneous: one 5.6 to 6.6 hours
Sublocade: 100 mg/0.5 mL (0.5 mL); 300 mg/1.5 mL Pregnancy Considerations Neonatal opioid with-
(1.5 mL) drawal syndrome may occur after chronic maternal
Tablet Sublingual, Sublingual: exposure to opioids. In the treatment of addiction
Generic: 2 mg, 8 mg involving opioid use in pregnant women, the buprenor-
phine/naloxone combination product is not recom-
mended for use (insufficient evidence); however, the
Buprenorphine and Naloxone buprenorphine monoproduct is a reasonable and rec-
(byoo pre NOR feen & nal OKS one) ommended option for use (Kampman [ASAM 2015]).
Related Information Women who become pregnant while on this combina-
tion should generally be transitioned to the single agent
Buprenorphine on page 230
(buprenorphine) product (ACOG 2012). See individual
Naloxone on page 944 agents.
Brand Names: US Bunavail; Suboxone; Zubsolv Product Availability Cassipa (buprenorphine 16 mg
Brand Names: Canada Suboxone and naloxone 4 mg) sublingual film: FDA approved
Pharmacologic Category Analgesic, Opioid; Analge- September 2018; anticipated availability is currently
sic, Opioid Partial Agonist unknown. Information pertaining to this product within
Use the monograph is pending revision. Consult the pre-
Opioid dependence: Treatment of opioid dependence. scribing information for additional information.
239
BUPRENORPHINE AND NALOXONE
Controlled Substance C-III 1% to 10%:

Prescribing and Access Restrictions In the US Cardiovascular: Palpitations (2% to 6%), cardiac
prescribing of tablets for opioid dependence is limited arrhythmia (5%), chest pain (≤4%), flushing (≤4%),
to physicians who have met the qualification criteria and hypertension (1% to 4%; may be severe), hypoten-
have received a DEA number specific to prescribing this sion (3%)
product. Tablets will be available through pharmacies Central nervous system: Lack of concentration (9%),
and wholesalers which normally provide controlled sub- confusion (≤8%), anxiety (3% to 8%), hostility (≤6%),
stances. nervousness (4% to 5%), abnormal dreams (3% to
5%), abnormal sensory symptoms (4%), sleep dis-
order (4%), migraine (≤4%), irritability (3%), memory
BuPROPion (byoo PROE pee on) impairment (≤3%), drowsiness (2% to 3%), pain
(3%), akathisia (≤2%), central nervous system stim-
Related Information
ulation (≤2%), paresthesia (≤2%), twitching (≤2%),
Cardiovascular Diseases on page 1442 dystonia (≥1%), abnormality in thinking (1%),
Dentin Hypersensitivity, Acid Erosion, High Caries depression
Index, Management of Alveolar Osteitis, and Xerosto- Dermatologic: Skin rash (1% to 8%), pruritus (2% to
mia on page 1548 4%), xeroderma (2%), urticaria (1% to 2%)
Vasoconstrictor Interactions With Antidepressants on Endocrine & metabolic: Weight gain (9%), menstrual
page 1606 disease (2% to 5%), decreased libido (≤3%), hot
Brand Names: US Aplenzin; Buproban [DSC]; Forfivo flash (1% to 3%)
XL; Wellbutrin SR; Wellbutrin XL; Wellbutrin [DSC]; Gastrointestinal: Abdominal pain (2% to 9%), diarrhea
Zyban (4% to 7%), flatulence (6%), anorexia (1% to 5%),
Brand Names: Canada Wellbutrin SR; Wellbutrin XL; dysgeusia (2% to 4%), increased appetite (2% to
Zyban 4%), vomiting (≥1% to 4%), dyspepsia (3%), oral
Pharmacologic Category Antidepressant, Dopamine/ mucosa ulcer (2%), dysphagia (≤2%)
Norepinephrine-Reuptake Inhibitor; Smoking Cessation Genitourinary: Urinary frequency (≥1% to 5%), urinary
Aid urgency (≤2%), vaginal hemorrhage (≤2%), urinary
Use tract infection (≤1%)
Major depressive disorder (unipolar [excluding Hypersensitivity: Hypersensitivity reaction (1%)
Zyban]): Treatment of major depressive disorder Infection: Infection (8% to 9%)
(MDD) Neuromuscular & skeletal: Myalgia (2% to 6%),
Seasonal affective disorder (24-hour extended arthralgia (4% to 5%), asthenia (4%), neck pain
release [Aplenzin, Wellbutrin XL]): Prevention of (2%), arthritis (≤2%), dyskinesia (≥1%)
seasonal major depressive episodes in patients with Ophthalmic: Diplopia (≤3%)
a diagnosis of seasonal affective disorder (SAD) Otic: Tinnitus (1% to 6%), auditory disturbance (5%)
Smoking cessation (12-hour extended release [sus- Renal: Polyuria (≤1%)
tained release; Zyban]): As an aid to smoking ces- Respiratory: Upper respiratory infection (9%), sinusitis
sation treatment (2% to 5%), cough (2% to 4%), increased cough (2%
Local Anesthetic/Vasoconstrictor Precautions to 3%), epistaxis (2%), bronchitis (≤2%)
Part of the mechanism of bupropion is to block reuptake Miscellaneous: Accidental injury (2%), fever (1%
of norepinephrine along with dopamine. Because of the to 2%)
potential for norepinephrine elevation within CNS syn-
stools, accommodation disturbance, aggressive
apses, it is suggested that vasoconstrictor be adminis-
behavior, akinesia, alopecia, amnesia, anaphylactic
tered with caution and to monitor vital signs in dental
shock, anaphylactoid reaction, anaphylaxis, anemia,
patients taking antidepressants that affect norepinephr-
angioedema, angle-closure glaucoma, aphasia,
ine in this way.
ataxia, atrioventricular block, bronchospasm, bruxism,
Effects on Dental Treatment Key adverse event(s) cerebrovascular accident, change in prothrombin time,
related to dental treatment: Significant xerostomia (nor- chills, colitis, coma, complete atrioventricular block,
mal salivary flow resumes with discontinuation); infre- cystitis, deafness, delirium, delusion, depersonaliza-
quent occurrence of abnormal taste, oral mucosal tion, derealization, drug-induced Parkinson disease,
ulcers; rare occurrence of stomatitis, tongue edema, dry eye syndrome, dysarthria, dyspareunia, dysphoria,
gingivitis, glossitis. dysuria, ecchymoses, edema, EEG pattern changes,
Effects on Bleeding Thrombocytopenia (<1%) as ejaculatory disorder, emotional lability, erythema multi-
been reported; rare occurrence of gingival hemorrhage. forme, esophagitis, euphoria, exfoliative dermatitis,
Adverse Reactions extrapyramidal reaction, extrasystoles, facial edema,
>10%: gastric ulcer, gastroesophageal reflux disease, gastro-
Cardiovascular: Tachycardia (≤11%) intestinal hemorrhage, gingival hemorrhage, gingivitis,
Central nervous system: Insomnia (11% to 40%), glossitis, glycosuria, gynecomastia, hallucination, hep-
headache (25% to 34%), agitation (2% to 32%), atic injury, hepatic insufficiency, hepatitis, hirsutism,
dizziness (6% to 22%) homicidal ideation, hyperglycemia, hyperkinetic
Dermatologic: Diaphoresis (5% to 22%) muscle activity, hypertonia, hypoesthesia, hypoglyce-
Endocrine & metabolic: Weight loss (14% to 23%) mia, hypokinesia, hypomania, hyponatremia, impo-
Gastrointestinal: Xerostomia (10% to 28%), constipa- tence, increased intraocular pressure, increased
tion (8% to 26%), nausea and vomiting (23%), libido, increased thirst, inguinal hernia, intestinal per-
nausea (1% to 18%) foration, jaundice, leukocytosis, leukopenia, lower limb
Neuromuscular & skeletal: Tremor (1% to 21%) cramp, lymphadenopathy, maculopapular rash,
Ophthalmic: Blurred vision (3% to 15%) malaise, manic behavior, menopause, muscle rigidity,
Respiratory: Nasopharyngitis (13%), pharyngitis (3% musculoskeletal chest pain, myasthenia, mydriasis,
to 13%), rhinitis (12%) myocardial infarction, myoclonus, neuralgia,
240
BUSPIRONE
neuropathy, orthostatic hypotension, painful erection, related to the use of bupropion to recommend use in
pancreatitis, pancytopenia, panic, paranoid ideation, pregnancy (ACOG 2010).
peripheral edema, phlebitis, pneumonia, prostatic dis-
Pregnant women exposed to antidepressants during
ease, psychiatric signs and symptoms, psychosis,
pregnancy are encouraged to enroll in the National
pulmonary embolism, restlessness, rhabdomyolysis,
Pregnancy Registry for Antidepressants (NPRAD).
salpingitis, sciatica, seizure (dose-related), serum
Women 18 to 45 years of age or their health care
sickness-like reaction, SIADH, sialorrhea, skin photo-
providers may contact the registry by calling
sensitivity, Stevens-Johnson syndrome, stomatitis,
844-405-6185. Enrollment should be done as early in
suicidal ideation, syncope, tardive dyskinesia, throm-
pregnancy as possible.
bocytopenia, tongue edema, type IV hypersensitivity
reaction, urinary incontinence, urinary retention, vag-
initis, vasodilatation, vertigo BusPIRone (byoo SPYE rone)
Mechanism of Action Aminoketone antidepressant
structurally different from all other marketed antidepres- Related Information
sants; like other antidepressants the mechanism of Management of the Patient With Anxiety or Depression
bupropion's activity is not fully understood. Bupropion on page 1564
is a relatively weak inhibitor of the neuronal uptake of Pharmacologic Category Antianxiety Agent, Miscel-
norepinephrine and dopamine, and does not inhibit laneous
monoamine oxidase or the reuptake of serotonin. Use Generalized anxiety disorder: Management of
Metabolite inhibits the reuptake of norepinephrine. generalized anxiety disorder or the short-term relief of
The primary mechanism of action is thought to be the symptoms of anxiety
dopaminergic and/or noradrenergic. Local Anesthetic/Vasoconstrictor Precautions
Pharmacodynamics/Kinetics No information available to require special precautions
Onset of Action 1 to 2 weeks Effects on Dental Treatment Key adverse event(s)
Duration of Action 1 to 2 days related to dental treatment: Xerostomia (normal salivary
Half-life Elimination flow resumes upon discontinuation).
Distribution: 3 to 4 hours Effects on Bleeding No information available to
Elimination: require special precautions
Hydrochloride salt: ~21 hours after chronic dosing (± Adverse Reactions
9 hours); Metabolites (after a single dose): Hydrox- >10%: Central nervous system: Dizziness (3% to 12%)
ybupropion: 20 ± 5 hours; Erythrohydrobupropion: 1% to 10%:
33 ± 10 hours; Threohydrobupropion: 37 ± 13 hours Cardiovascular: Chest pain (≥1%)
Hydrobromide salt: 21 ± 7 hours; Metabolites: Central nervous system: Drowsiness (10%), head-
Hydroxybupropion: 24 ± 5 hours; Erythrohydrobu- ache (6%), nervousness (5%), confusion (2%),
propion: 31 ± 8 hours; Threohydrobupropion: 51 ± 9 excitement (2%), numbness (2%), outbursts of anger
hours (2%), abnormal dreams (≥1%), ataxia (1%) pares-
Time to Peak thesia (1%)
Bupropion: Immediate release: Within 2 hours; 12- Dermatologic: Diaphoresis (1%), skin rash (1%)
hour extended release (sustained release): Within 3 Gastrointestinal: Nausea (8%), diarrhea (2%), sore
hours; 24-hour extended release: ~5 hours; 12 hours throat (≥1%)
(fed) Neuromuscular & skeletal: Weakness (2%), muscu-
Metabolite: Hydroxybupropion: Immediate release: ~3 loskeletal pain (1%), tremor (1%)
hours; Extended release: ~6 to 7 hours Ophthalmic: Blurred vision (2%)
Pregnancy Risk Factor C Otic: Tinnitus (≥1%)
Pregnancy Considerations Adverse events have Respiratory: Nasal congestion (≥1%)
been observed in some animal reproduction studies. <1%, postmarketing, and/or case reports: Acne vulga-
Bupropion and its metabolites were found to cross the ris, akathisia, alcohol abuse, alopecia, altered sense
placenta in in vitro studies (Earhart 2010). An increased of smell, amenorrhea, angioedema, anorexia, apathy,
risk of congenital malformations has not been observed arthralgia, bradycardia, bruise, cardiac failure, cardio-
following maternal use of bupropion during pregnancy; myopathy, cerebrovascular accident, change in libido,
however, data specific to cardiovascular malformations claustrophobia, cogwheel rigidity, cold intolerance,
is inconsistent. The long-term effects on development conjunctivitis, delayed ejaculation, depersonalization,
and behavior have not been studied. dissociative reaction, dysgeusia, dyskinesia, dyspho-
ria, dyspnea, dystonia, dysuria, edema, emotional
The ACOG recommends that antidepressant therapy lability, eosinophilia, epistaxis, euphoria, extrapyrami-
during pregnancy be individualized; treatment of dal reaction, eye pain, facial edema, fear, fever, flat-
depression during pregnancy should incorporate the ulence, flushing, galactorrhea, glossopyrosis,
clinical expertise of the mental health clinician, obste- hallucination, hemorrhagic diathesis, hiccups, hyper-
trician, primary health care provider, and pediatrician. acusis, hypersensitivity reaction, hypertension, hyper-
According to the American Psychiatric Association ventilation, hypotension, impotence, increased
(APA), the risks of medication treatment should be appetite, increased intraocular pressure, increased
weighed against other treatment options and untreated serum ALT, increased serum AST, increased serum
depression. For women who discontinue antidepres- transaminases, inner ear disturbance, involuntary
sant medications during pregnancy and who may be muscle movements, irritable bowel syndrome, laryng-
at high risk for postpartum depression, the medications itis, leukopenia, malaise, memory impairment, men-
can be restarted following delivery. Treatment algo- strual disease, muscle cramps, muscle spasm,
rithms have been developed by the ACOG and the myocardial infarction, nocturia, parkinsonian-like syn-
APA for the management of depression in women prior drome, pelvic inflammatory disease, personality dis-
to conception and during pregnancy (ACOG 2008; APA order, photophobia, pruritus, psychosis, rectal
2010; Yonkers 2009). There is insufficient information hemorrhage, restless leg syndrome, restlessness,
241
BUSPIRONE
roaring sensation in head, salivation, seizure, seroto- Genitourinary: Diuresis

nin syndrome, skin blister, slowed reaction time, Hypersensitivity: Hypersensitivity reaction
slurred speech, stiffness, stupor, suicidal ideation, Neuromuscular & skeletal: Leg pain, muscle fatigue
syncope, thinning of nails, thrombocytopenia, thyroid Otic: Otalgia, tinnitus
disease, urinary frequency, urinary hesitancy, urinary Respiratory: Dyspnea, nasal congestion
incontinence, urinary retention, urticaria, vertigo, vis- Miscellaneous: Fever, heavy eyelids
ual disturbance (tunnel vision), weight gain, weight Postmarketing and/or case reports: Hypogonadism
loss, xeroderma (Brennan 2013; Debono 2011)
Mechanism of Action The mechanism of action of Note: Potential reactions associated with components
buspirone is unknown. Buspirone has a high affinity for of Fioricet with Codeine include agranulocytosis, car-
serotonin 5-HT1A and 5-HT2 receptors, without affecting diac stimulation, dependence, erythema multiforme,
benzodiazepine-GABA receptors. Buspirone has mod- hyperglycemia, irritability, nephrotoxicity, rash, throm-
erate affinity for dopamine D2 receptors. bocytopenia, toxic epidermal necrolysis, tremor
Pharmacodynamics/Kinetics Mechanism of Action
Half-life Elimination 2 to 3 hours; increased with Acetaminophen: Although not fully elucidated, the anal-
renal or hepatic impairment gesic effects are believed to be due to activation of
Time to Peak Serum: 40 to 90 minutes descending serotonergic inhibitory pathways in the
Pregnancy Risk Factor B CNS. Interactions with other nociceptive systems
Pregnancy Considerations Adverse events have not may be involved as well (Smith 2009). Antipyresis is
been observed in animal reproduction studies. produced from inhibition of the hypothalamic heat-
regulating center.
Butalbital: Short- to intermediate-acting barbiturate;
Butalbital, Acetaminophen, Caffeine, depresses the sensory cortex, decreases motor activ-
and Codeine ity, alters cerebellar function, and produces drowsi-
(byoo TAL bi tal, a seet a MIN oh fen, KAF een, & KOE deen) ness, sedation, hypnosis, and dose-dependent
Related Information respiratory depression.
Caffeine: CNS stimulant; use with acetaminophen and
Acetaminophen on page 60
dihydrocodeine increases the level of analgesia pro-
Caffeine on page 245
vided by each agent.
Codeine on page 357 Codeine: Binds to opiate receptors in the CNS, causing
Brand Names: US Fioricet/Codeine inhibition of ascending pain pathways, altering the
Pharmacologic Category Analgesic Combination perception of and response to pain; produces gener-
(Opioid); Analgesic, Opioid; Barbiturate alized CNS depression.
Use Pregnancy Considerations Withdrawal seizures
Tension or muscle contraction headache: Manage- were reported in an infant 2 days after birth following
ment of the symptom complex of tension (muscle maternal use of a butalbital product during the last 2
contraction) headache when nonopioid analgesic months of pregnancy; butalbital was detected in the
and alternative treatments are inadequate. newborns serum. [US Boxed Warning]: Prolonged
Limitations of use: Reserve for use in patients for whom use of opioids during pregnancy can cause neo-
alternative treatment options (eg, nonopioid, non-bar- natal withdrawal syndrome, which may be life-
biturate analgesics) are ineffective, not tolerated, or threatening if not recognized and treated according
would be otherwise inadequate to provide sufficient to protocols developed by neonatology experts. If
management of pain. opioid use is required for a prolonged period in a
Local Anesthetic/Vasoconstrictor Precautions pregnant woman, advise the patient of the risk of
No information available to require special precautions neonatal opioid withdrawal syndrome and ensure
Effects on Dental Treatment No significant effects or that appropriate treatment will be available. Refer to
complications reported (see Dental Health Professional the acetaminophen, caffeine, or codeine monographs
Considerations) for additional information.
Effects on Bleeding As a single agent, acetamino- Controlled Substance C-III
phen does not appear to affect bleeding or platelet Dental Health Professional Considerations
aggregation. Acetaminophen may prolong the INR Although the OTC product labeling for acetaminophen
and increase bleeding in patients taking warfarin (Cou- products state to limit the maximum dose to 3,000 mg
madin). For patients taking warfarin, single acetamino- daily (for extra strength) or 3,250 mg (for regular
phen doses or acetaminophen therapy of short duration strength) (see this site for details: http://www.-
should be safe, but if large (>1.3 g/day) doses are tylenolprofessional.com/products-and-dosages.html), it
administered for longer than 10-14 days, then the INR is still appropriate for patients to take up to 4,000 mg
should be monitored (see Dental Health Professional daily "under the direction of a health care provider"
Considerations). (http://www.tylenolprofessional.com/dosage.html).
Cardiovascular: Syncope, tachycardia The acetaminophen component requires use with cau-
Central nervous system: Agitation, confusion, depres- tion in patients who use alcohol, with preexisting liver
sion, dizziness, drowsiness, euphoria, excitement, disease, and those receiving more than one source of
fatigue, headache, increased energy, intoxicated feel- acetaminophen-containing medication.
ing, lethargy, numbness, paresthesia, sedation, seiz- Hepatotoxicity caused by acetaminophen is potentiated
ure, shakiness
by chronic alcohol consumption. People who are taking
Dermatologic: Hyperhidrosis, pruritus
acetaminophen, even at therapeutic doses, and con-
Endocrine & metabolic: Hot flash
sume alcohol are at risk of developing hepatotoxicity.
Gastrointestinal: Abdominal pain, constipation, dyspha-
gia, flatulence, heartburn, nausea, vomiting, xero- Acetaminophen may increase the levels and enhance
stomia the anticoagulant effects of vitamin K antagonists
242
BUTORPHANOL
acenocoumarol and warfarin (Coumadin). Studies have Pharmacologic Category Analgesic, Opioid; Analge-
reported that acetaminophen has increased the INR in sic, Opioid Partial Agonist
warfarin treated patients with daily acetaminophen Use
doses as low as 2 g, particularly when taking acetami- Pain management: Management of pain severe
nophen for >1 week (Antlitz, 1968; Boeijinga, 1982; enough to require an opioid analgesic and for which
Gebauer, 2003; Hylek, 1998; Rubin, 1984). In addition, alternative treatments are inadequate
case reports of bleeding as a result of increased INR Limitations of use: Reserve for use in patients for
have been published (Bagheri, 1999; Bartle, 1991). whom alternative treatment options (eg, nonopioid
There is no known mechanism of the interaction; fur- analgesics, opioid combination products) are ineffec-
thermore, some studies have failed to demonstrate this tive, not tolerated, or would be otherwise inadequate
interaction (Gadisseur, 2003; Kwan, 1995; van den to provide sufficient management of pain.
Bemt, 2002). In terms of risk, the data suggest that Pain during labor (injection only): Management of
acetaminophen and warfarin could interact in some pain during labor.
clinically significant manner but that the benefits of Preoperative medication (injection only): Preopera-
concomitant use of acetaminophen for pain control in tive or preanesthetic medication
dental patients taking warfarin usually outweigh the Supplement to balanced anesthesia (injection
risks. An appropriate monitoring plan should be in place only): Supplement to balanced anesthesia
to identify potential negative effects and dosage adjust- Local Anesthetic/Vasoconstrictor Precautions
ments may be necessary in a minority of patients. The No information available to require special precautions
interaction may be more likely to occur with daily Effects on Dental Treatment Key adverse event(s)
acetaminophen doses of >1.3 g for >1 week. related to dental treatment: Xerostomia (normal salivary
flow resumes upon discontinuation) and unpleasant
There are no reports of acetaminophen interacting with aftertaste.
antiplatelet drugs such as aspirin, clopidogrel (Plavix),
or prasugrel (Effient). Also, there are no reports of
acetaminophen in combination with hydrocodone,
Adverse Reactions
codeine, or oxycodone interacting with warfarin (Cou-
>10%:
madin).
Central nervous system: Drowsiness (43%), dizziness
(19%), insomnia (nasal spray 11%)
Butoconazole (byoo toe KOE na zole) Gastrointestinal: Nausea and vomiting (13%)
Respiratory: Nasal congestion (nasal spray 13%)
Brand Names: US Gynazole-1 1% to 10%:
Pharmacologic Category Antifungal Agent, Imida- Cardiovascular: Palpitations, vasodilatation
zole Derivative; Antifungal Agent, Vaginal Central nervous system: Anxiety, burning sensation,
Use Vulvovaginal candidiasis: Local treatment of vul- confusion, euphoria, floating feeling, headache, leth-
vovaginal candidiasis due to Candida albicans argy, nervousness, paresthesia
Local Anesthetic/Vasoconstrictor Precautions Dermatologic: Cold and clammy skin, diaphoresis,
No information available to require special precautions pruritus
Effects on Dental Treatment No significant effects or Gastrointestinal: Anorexia, constipation, stomach
complications reported pain, unpleasant taste, xerostomia
Effects on Bleeding No information available to Neuromuscular & skeletal: Tremor, weakness
require special precautions Ophthalmic: Blurred vision
Adverse Reactions Frequency not defined. Otic: Otalgia, tinnitus
Gastrointestinal: Abdominal cramps, abdominal pain Respiratory: Bronchitis, cough, dyspnea, epistaxis,
Genitourinary: Pelvic pain, vulvovaginal burning, vulvo- nasal discomfort, pharyngitis, rhinitis, sinus conges-
vaginal disease (soreness), vulvovaginal pruritus tion, sinusitis, upper respiratory tract infection
Local: Local swelling <1%, postmarketing, and/or case reports: Abnormal
dreams, agitation, apnea, chest pain, convulsions,
Mechanism of Action Inhibits biosynthesis of ergo-
delusions, depression, drug dependence, dysphoria,
sterol, damaging the fungal cell wall membrane, which
edema, hallucination, hostility, hypertension, hypogo-
increases permeability in susceptible fungi (Candida),
nadism (Brennan, 2013; Debono, 2011), hypotension,
causing leaking of nutrients
respiratory depression, seizure, shallow respiration,
skin rash, speech disturbance, syncope, tachycardia,
Time to Peak Plasma: 12 to 24 hours urination disorder, urticaria, vertigo, withdrawal syn-
Pregnancy Risk Factor C drome
Pregnancy Considerations Adverse events have Mechanism of Action Agonist of kappa opiate recep-
been observed in some animal reproduction studies. tors and partial agonist of mu opiate receptors in the
Following vaginal administration, small amounts are CNS, causing inhibition of ascending pain pathways,
absorbed systemically. Single dose, topical azole regi- altering the perception of and response to pain; produ-
mens are not recommended for the treatment of vulvo- ces analgesia, respiratory depression, and sedation
vaginal candidiasis; only topical azole therapies with 7 similar to opioids
day regimens are recommended in pregnant women Pharmacodynamics/Kinetics
with vulvovaginal candidiasis. This product may weaken Onset of Action IM, Nasal: ≤15 minutes; IV: Within a
latex or rubber condoms or diaphragms (CDC [Work- few minutes
owski 2015]). Peak effect: IM, IV: 0.5 to 1 hour; Nasal: 1 to 2 hours
Duration of Action IM, IV: 3 to 4 hours; Nasal: 4 to 5
Butorphanol (byoo TOR fa nole) hours
Brand Names: Canada Butorphanol (Nasal Spray); IV, nasal: ~2 to 9 hours; Hydroxybutorphanol: ~18
PMS-Butorphanol hours
243
BUTORPHANOL
Elderly: IV, nasal: ~3 to 9 hours Adverse Reactions

Renal impairment (CrCl <30 mL/minute): ~10.5 hours >10%:
Hepatic impairment: ~16.8 hours Central nervous system: Headache (26%), dizziness
Time to Peak Plasma: IM: 20 to 40 minutes; Nasal: 30 (15% to 17%)
to 60 minutes Gastrointestinal: Nausea (27% to 29%)
Pregnancy Risk Factor C 1% to 10%:
Pregnancy Considerations Cardiovascular: Orthostatic hypotension (4%), hypo-
Adverse events have been observed in some animal tension (1%), palpitations (1%), peripheral edema
reproduction studies. Butorphanol crosses the placenta. (1%), syncope (1%)
Butorphanol injection is approved for the management Central nervous system: Fatigue (5% to 7%), drowsi-
of pain during labor; apnea or respiratory distress in the ness (2% to 5%), vertigo (1% to 4%), depression
newborn may occur. When used for pain relief during (3%), pain (2%), nervousness (1% to 2%), paresthe-
labor, opioids may temporarily affect the heart rate of sia (1% to 2%), anxiety (1%), insomnia (1%), lack of
the fetus (ACOG 2002). The manufacturer recommends concentration (1%), malaise (1%)
that caution be used if abnormal fetal heart rate patterns Dermatologic: Acne vulgaris (1%), pruritus (1%)
Endocrine & metabolic: Hot flash (1% to 3%), depend-
are present.
ent edema (1%)
[US Boxed Warning]: Prolonged use of opioids Gastrointestinal: Constipation (7% to 10%), abdominal
during pregnancy can cause neonatal withdrawal pain (5%), dyspepsia (2% to 5%), vomiting (2% to
syndrome, which may be life-threatening if not 4%), diarrhea (2%), flatulence (2%), xerostomia
recognized and treated according to protocols (2%), anorexia (1%), toothache (1%)
developed by neonatology experts. If opioid use is Genitourinary: Mastalgia (1% to 2%), dysmenor-
required for a prolonged period in a pregnant rhea (1%)
woman, advise the patient of the risk of neonatal Neuromuscular & skeletal: Weakness (6% to 9%),
opioid withdrawal syndrome and ensure that appro- arthralgia (1%)
priate treatment will be available. If chronic opioid Ophthalmic: Periorbital edema (1%), visual disturb-
exposure occurs in pregnancy, adverse events in the ance (1%)
newborn (including withdrawal) may occur; monitoring Respiratory: Flu-like symptoms (1%), rhinitis (1%),
of the neonate is recommended. The minimum effective throat irritation (1%)
dose should be used if opioids are needed (Chou <1%, postmarketing, and/or case reports: Aggressive
2009). Neonatal abstinence syndrome following opioid behavior, alopecia, cardiac failure (in Parkinson's dis-
exposure may present with autonomic (eg, fever, tem- ease [PD] patients), confusion (in PD patients), con-
perature instability), gastrointestinal (eg, diarrhea, vom- strictive pericarditis (in PD patients), duodenal ulcer
iting, poor feeding/weight gain), or neurologic (eg, high (in PD patients), dyskinesia (in PD patients), epistaxis,
pitched crying, increased muscle tone, irritability, seiz- facial edema, gastric ulcer (in PD patients), hallucina-
ure, tremor) symptoms (Dow 2012; Hudak 2012). tion (in PD patients), heart valve disease, increased
libido (including hypersexuality), pathological gam-
Controlled Substance C-IV
bling, pleural effusion (in PD patients), psychosis,
pulmonary fibrosis (in PD patients), weight gain,
Cabergoline (ca BER goe leen) weight loss
Mechanism of Action Cabergoline is a long acting
Brand Names: Canada ACT Cabergoline; Dostinex dopamine receptor agonist with a high affinity for D2
Pharmacologic Category Ergot Derivative receptors; prolactin secretion by the anterior pituitary is
Use predominantly under hypothalamic inhibitory control
Hyperprolactinemic disorders: Treatment of hyper- exerted through the release of dopamine. It is a potent
prolactinemic disorders, either idiopathic or caused 5-HT 2B -receptor agonist, which may contribute to
by pituitary adenomas. observed fibrotic/valvulopathic events.
Limitations of use: Not indicated for inhibition or Pharmacodynamics/Kinetics
suppression of physiologic lactation. Half-life Elimination 63 to 69 hours
Canadian labeling: Additional use (not in US labeling):
Prevention of the onset of physiological lactation in the
Information related to the use of cabergoline for the
puerperium when clinically indicated (eg, still born
treatment of hyperprolactinemia in pregnancy is avail-
baby or neonatal death, conditions that interfere with
able but limited compared to the use of other agents
suckling, severe acute or chronic mental illness,
(Almistehi 2018; Auriemma 2013; Colao 2008; Lebbe
maternal disease which may be transmitted to the
2010; Moltich 2015; Ricci 2002; Robert 1996; Stall-
baby that require medications which are excreted in
decker 2010). Although available evidence suggests
the milk). cabergoline use early in pregnancy does not cause
Limitations of use: Not indicated for suppression of harm to the fetus, it is recommended that therapy be
already established postpartum lactation. discontinued once pregnancy is discovered. If treatment
Local Anesthetic/Vasoconstrictor Precautions of hyperprolactinemia during pregnancy is required,
Cabergoline is a semisynthetic ergot alkaloid derivative; cabergoline may be used, but other agents are pre-
there is a possibility that it has vasoconstricting effects; ferred. Monitoring of prolactin levels should be sus-
use vasoconstrictor with caution pended during pregnancy (Endocrine Society [Melmed
Effects on Dental Treatment Key adverse event(s) 2011]). If treatment for acromegaly (off-label use) is
related to dental treatment: Xerostomia (normal salivary required during pregnancy for worsening symptoms
flow resumes upon discontinuation), throat irritation, (such as headache) or evidence of tumor growth, use
and toothache. of cabergoline may be considered. Monitoring of insu-
Effects on Bleeding No information available to lin-like growth factor 1 and/or growth hormone (GH) are
require special precautions not recommended during pregnancy as an active
244
CALASPARGASE PEGOL-MKNL
placental GH variant present in maternal blood limits Time to Peak Serum: Oral: Within 30 minutes to 2
the usefulness of the results (Endocrine Society [Katz- hours
nelson 2014]). Information related to cabergoline for the Pregnancy Considerations
treatment of Cushing Syndrome (off-label use) during Caffeine crosses the placenta; serum concentrations in
pregnancy is limited; agents other than cabergoline are the fetus are similar to those in the mother (Grosso
recommended (Nakhleh 2016; Nieman 2015; Sek 2005).
2017).
Based on current studies, usual dietary exposure to
Cabergoline is contraindicated in patients with uncon- caffeine is unlikely to cause congenital malformations
trolled hypertension; use is not recommended by the (Brent 2011). However, available data show conflicting
manufacturer in women with pregnancy-induced hyper- results related to maternal caffeine use and the risk of
tension (eg, preeclampsia, eclampsia, postpartum other adverse events, such as spontaneous abortion or
hypertension) unless benefit outweighs potential risk. growth retardation (Brent 2011; Jahanfar 2013; Nehlig
1994). Chronic maternal consumption of high amounts
Dose-related decreases in prolactin occur with cabergo- of caffeine during pregnancy may lead to neonatal
line therapy. Treatment may restore fertility in previously withdrawal at delivery (eg, apnea, irritability, jitteriness,
infertile women. vomiting) (Martin 2007).
The half-life of caffeine is prolonged during the second
Caffeine (KAF een) and third trimesters of pregnancy and maternal and
fetal exposure is also influenced by maternal tobacco
Brand Names: US Cafcit; Keep Alert [OTC]; No Doz or alcohol consumption (Brent 2011; Koren 2000).
Maximum Strength [OTC]; Stay Awake Maximum Current guidelines recommend limiting caffeine intake
Strength [OTC]; Stay Awake [OTC]; Vivarin [OTC] from all sources to ≤200 mg/day during pregnancy
Pharmacologic Category Central Nervous System (ACOG 2010).
Stimulant; Phosphodiesterase Enzyme Inhibitor, Non-
selective
Use Calaspargase Pegol-mknl
(kal AS par jase PEG ol mknl)
Caffeine citrate: Treatment of idiopathic apnea of pre-
maturity Pharmacologic Category Antineoplastic Agent,
Caffeine and sodium benzoate: See Off-Label uses. Enzyme; Antineoplastic Agent, Miscellaneous
Caffeine [OTC labeling]: Restore mental alertness or Use Acute lymphoblastic leukemia: Treatment of
wakefulness when experiencing fatigue acute lymphoblastic leukemia (ALL) (as part of a combi-
Local Anesthetic/Vasoconstrictor Precautions nation chemotherapy regimen) in children and adults
No information available to require special precautions age 1 month to 21 years.
Effects on Dental Treatment Key adverse event(s) Local Anesthetic/Vasoconstrictor Precautions
related to dental treatment: Caffeine causes tachycar- No information available to require special precautions
dia, increases in blood pressure, and palpitations. Con- Effects on Dental Treatment Key adverse event(s)
sider monitoring blood pressure prior to using local related to dental treatment: Decreased blood pressure
anesthetic with a vasoconstrictor. Symptoms associ- associated with the use of calaspargase pegol-mknl;
ated with bruxism have been observed in some patients may experience orthostatic hypotension as
patients. they stand up after treatment, especially if lying in
Effects on Bleeding No information available to dental chair for extended periods of time. Use caution
require special precautions with sudden changes in position during and after dental
Adverse Reactions Frequency not specified; primarily treatment.
serum-concentration related. Effects on Bleeding Hemorrhage: Hemorrhage asso-
Cardiovascular: Angina pectoris, chest pain, flushing, ciated with increased prothrombin time (PT), increased
palpitations, sinus tachycardia, supraventricular tachy- partial thromboplastin time (PTT), and hypofibrinogene-
cardia, vasodilatation, ventricular arrhythmia mia have been reported in patients receiving calaspar-
gase pegol-mknl.
Central nervous system: Agitation, delirium, dizziness,
hallucination, headache, insomnia, irritability, psycho- Adverse Reactions
>10%:
sis, restlessness
Cardiovascular: Decreased blood pressure
Dermatologic: Urticaria
Gastrointestinal: Pancreatitis (12% to 16%)
Gastrointestinal: Esophageal motility disorder (sphinc-
Hematologic & oncologic: Disorder of hemostatic com-
ter tone decreased), gastritis
ponents of blood (grades 3/4: 14%)
Genitourinary: Diuresis
Hepatic: Increased serum transaminases (grades 3/4:
Neuromuscular & skeletal: Fasciculations 52%), increased serum bilirubin (grades 3/4: 20%)
Ophthalmic: Increased intraocular pressure (>180 mg Hypersensitivity: Hypersensitivity (grades 3/4: 7% to
caffeine), miosis 21%), angioedema
Mechanism of Action Increases levels of 3'5' cyclic Ophthalmic: Swelling of eye
AMP by inhibiting phosphodiesterase; CNS stimulant Respiratory: Bronchospasm
which increases medullary respiratory center sensitivity 1% to 10%:
to carbon dioxide, stimulates central inspiratory drive, Cardiovascular: Embolism (grades 3/4: ≤8%), throm-
and improves skeletal muscle contraction (diaphrag- bosis (grades 3/4: ≤8%), cardiac arrhythmia (grades
matic contractility); prevention of apnea may occur by 3/4: 2%), cardiac failure (grades 3/4: 2%)
competitive inhibition of adenosine Gastrointestinal: Diarrhea (grades 3/4: 9%)
Pharmacodynamics/Kinetics Hematologic & oncologic: Hemorrhage (grades
Half-life Elimination 3/4: 4%)
Neonates: 72 to 96 hours (range: 40 to 230 hours) Infection: Sepsis (grades 3/4: 5%), fungal infection
Children >9 months and Adults: 5 hours (grades 3/4: 3%)
245
CALASPARGASE PEGOL-MKNL
Respiratory: Dyspnea (grades 3/4: 4%), pneumonia Renal: Increased serum creatinine (5%)
(grades 3/4: 3%) Respiratory: Nasopharyngitis (5%), cough (4%), dysp-
Frequency not defined: nea (4%), bronchitis (3%), chronic obstructive pulmo-
Hematologic & oncologic: Hypofibrinogenemia, pro- nary disease (1%), pneumonia (1%)
longed partial thromboplastin time, prolonged pro- Mechanism of Action Calcifediol, a prohormone of
thrombin time the active form of vitamin D3, calcitriol (1,25 dihydrox-
Hypersensitivity: Anaphylaxis yvitamin D3), is catalyzed to calcitriol by the 1-alpha-
Mechanism of Action Calaspargase pegol-mknl con- hydroxylase enzyme, CYP27B1, primarily in the kidney.
tains an E. coli-derived asparagine-specific enzyme, as Calcitriol binds to vitamin D receptors in target tissues
a conjugate of L-asparaginase and monomethoxypoly- activating vitamin D responsive pathways resulting in
ethylene glycol (mPEG) with a succinimidyl carbonate increased intestinal absorption of calcium and phospho-
linker which produces a stable bond between the rus and reduced parathyroid hormone synthesis.
mPEG component and the L-asparaginase lysine Pharmacodynamics/Kinetics
groups. L-asparaginase is an enzyme which catalyzes Onset of Action ~2 weeks; maximum effect: ~3
the deamidation of asparagine to aspartic acid and months
ammonia, reducing circulating levels of asparagine. Half-life Elimination Healthy adults: ~11 days; Stage
Leukemic cells with low asparagine synthetase expres- 3 and 4 CKD: ~25 days
sion have a reduced ability to synthesize L-asparagine.
L-asparaginase reduces the exogenous asparagine
source for the leukemic cells, resulting in cytotoxicity Pregnancy Considerations Adverse events were
specific to leukemic cells. observed in animal reproduction studies. Endogenous
Pharmacodynamics/Kinetics calcifediol crosses the placenta in concentrations gen-
Half-life Elimination 16.1 days erally lower than those in the maternal plasma; supple-
Time to Peak 1.17 hours mentation increases cord blood 25OHD concentrations
Pregnancy Considerations (IOM 2011).
Based on animal reproduction studies conducted with
L-asparaginase, adverse effects to the fetus may be Calcitriol (Systemic) (kal si TRYE ole)
expected if exposure occurs during pregnancy.
Brand Names: US Rocaltrol
Evaluate pregnancy status prior to use in females of Brand Names: Canada Calcijex; Calcitriol Injection;
reproductive potential. Effective contraception (which
Calcitriol-Odan; Rocaltrol
includes a barrier method) should be used during
Pharmacologic Category Vitamin D Analog
therapy and for at least 3 months after the last cala-
spargase pegol-mknl dose. Oral contraceptives may not Use
be effective and are not recommended as a form of Hypoparathyroidism/pseudohypoparathyroidism:
contraception. Management of hypocalcemia in patients with hypo-
Product Availability Asparlas: FDA approved Decem- parathyroidism or pseudohypoparathyroidism (oral)
ber 2018; anticipated availability is currently undeter- Secondary hyperparathyroidism in patients with
mined chronic kidney disease: Management of secondary
hyperparathyroidism in patients with moderate to
severe chronic kidney disease (CKD) not on dialysis
Calcifediol (kal si fe DYE ole) (oral) or in patients on dialysis (oral or IV). Note:
Although the manufacturer’s labeling states that calci-
Brand Names: US Rayaldee
triol may be used specifically to treat hypocalcemia in
Pharmacologic Category Vitamin D Analog
dialysis patients, due to the risk of hypercalcemia, use
Use should generally be reserved for patients with severe
Secondary hyperparathyroidism: Treatment of sec-
and progressive hyperparathyroidism (KDIGO 2017).
ondary hyperparathyroidism in adults with stage 3 or 4
chronic kidney disease and serum total 25-hydroxyvi-
tamin D levels less than 30 ng/mL.
Limitations of use: Not indicated for the treatment of Effects on Dental Treatment Key adverse event(s)
secondary hyperparathyroidism in patients with stage related to dental treatment: Metallic taste and xerosto-
5 chronic kidney disease or in patients with end-stage mia (normal salivary flow resumes upon discontinua-
renal disease (ESRD) on dialysis. tion).
Effects on Dental Treatment Key adverse event(s) Adverse Reactions
related to dental treatment: Nasopharyngitis has been >10%: Endocrine & metabolic: Hypercalcemia
reported 1% to 10%:
Effects on Bleeding No information available to Central nervous system: Headache
require special precautions Dermatologic: Skin rash
Adverse Reactions Endocrine & metabolic: Polydipsia
>10%: Hematologic & oncologic: Abnormal phosphorus Gastrointestinal: Abdominal pain, nausea
levels (increased: 45%; hyperphosphatemia: <1%) Genitourinary: Urinary tract infection
1% to 10%: Frequency not defined:
Cardiovascular: Cardiac failure (4%) Cardiovascular: Cardiac arrhythmia, hypertension
Endocrine & metabolic: Hypercalcemia (4%; patients Central nervous system: Apathy, drowsiness, hyper-
requiring dose reduction for hypercalcemia: 2%), thermia, metallic taste, psychosis, sensory dis-
hyperkalemia (3%), hyperuricemia (2%) turbance
Hematologic & oncologic: Anemia (5%), bruise (2%) Dermatologic: Erythema, erythema multiforme, pruri-
Neuromuscular & skeletal: Osteoarthritis (2%) tus, urticaria
246
CALCIUM AND VITAMIN D
Endocrine & metabolic: Albuminuria, calcinosis, Use Plaque psoriasis: Management of mild-to-moder-
decreased libido, dehydration, growth suppression, ate plaque psoriasis
hypercholesterolemia, weight loss Local Anesthetic/Vasoconstrictor Precautions
Gastrointestinal: Anorexia, constipation, pancreatitis, No information available to require special precautions
stomach pain, vomiting, xerostomia Effects on Dental Treatment Key adverse event(s)
Genitourinary: Hypercalciuria, nocturia related to dental treatment: Metallic taste and xerosto-
Hepatic: Increased serum ALT, increased serum AST mia (normal salivary flow resumes upon discontinua-
Hypersensitivity: Hypersensitivity reaction tion).
Local: Pain at injection site (mild)
Neuromuscular & skeletal: Dystrophy, myalgia, osteal-
gia, weakness
Ophthalmic: Conjunctivitis, photophobia Adverse Reactions
Renal: Calcium nephrolithiasis, increased blood urea >10%: Endocrine: Hypercalcemia (24%)
nitrogen, increased serum creatinine, polyuria 1% to 10%:
Respiratory: Rhinorrhea Dermatologic: Psoriasis (4%), pruritus (1% to 3%),
<1%, postmarketing and/or case reports: Agitation, skin discomfort
anaphylaxis, apprehension, hypermagnesemia, Genitourinary: Urine abnormality (4%), hypercalciu-
hyperphosphatemia, hypervitaminosis D, increased ria (3%)
hematocrit, increased hemoglobin, increased neutro- <1%, postmarketing, and/or case reports: Burning sen-
phils, increased serum alkaline phosphatase, insom- sation of skin, dermatitis (acute; blistering), eczema
nia, limb pain, lymphocytosis (including extensive flare up), erythema, nephrolithia-
Mechanism of Action Calcitriol, the active form of sis, skin atrophy
vitamin D (1,25 hydroxyvitamin D3), binds to and acti- Mechanism of Action The mechanism by which calci-
vates the vitamin D receptor in kidney, parathyroid triol is beneficial in the treatment of psoriasis has not
gland, intestine, and bone, stimulating intestinal calcium been established.
transport and absorption. It reduces parathyroid hor- Pharmacodynamics/Kinetics
mone (PTH) levels and improves calcium and phos- Duration of Action Oral, IV: 3 to 5 days
phate homeostasis by stimulating bone resorption of Half-life Elimination Children 1.8-16 years under-
calcium and increasing renal tubular reabsorption of going peritoneal dialysis: 27.4 hours; Healthy adults:
calcium. Decreased renal conversion of vitamin D to 5 to 8 hours; Hemodialysis: 16 to 22 hours
its primary active metabolite (1,25 hydroxyvitamin D) in Time to Peak Oral: 3 to 6 hours; Hemodialysis: 8 to 12
chronic renal failure leads to reduced activation of hours
vitamin D receptor, which subsequently removes inhib- Pregnancy Risk Factor C
itory suppression of parathyroid hormone (PTH)
Pregnancy Considerations Adverse effects have
release; increased serum PTH (secondary hyperpara-
thyroidism) reduces calcium excretion and enhances
When treatment for psoriasis in pregnancy is needed,
bone resorption.
Pharmacodynamics/Kinetics the use of other agents is generally preferred (Babalola
Onset of Action Oral: 2 hours; maximum effect: 10 2013; Bae 2012).
hours
Duration of Action Oral, IV: 3 to 5 days Calcium and Vitamin D
Half-life Elimination Children 1.8 to 16 years under- (KAL see um & VYE ta min dee)
going peritoneal dialysis: 27.4 hours; Healthy adults: 5
Brand Names: US Calcet Petites [OTC]; Calcitrate
to 8 hours; Hemodialysis: 16 to 22 hours
[OTC]; Caltrate 600+D [OTC] [DSC]; Caltrate 600+D3
Time to Peak Serum: Oral: 3 to 6 hours; Hemodial-
Soft [OTC]; Caltrate 600+D3 [OTC]; Caltrate 600+Soy
ysis: 8 to 12 hours
[OTC]; Caltrate ColonHealth [OTC]; Caltrate Gummy
Bites [OTC]; Citracal Maximum [OTC]; Citracal Petites
Pregnancy Considerations Adverse effects have [OTC]; Citracal Regular [OTC]; Os-Cal Calcium + D3
[OTC]; Os-Cal Extra D3 [OTC]; Os-Cal [OTC]; Oysco
Maternal calcitriol may be detected in the fetal circu-
500+D [OTC]; Oysco D [OTC] [DSC]
lation. Mild hypercalcemia has been reported in a new-
born following maternal use of calcitriol during Pharmacologic Category Calcium Salt; Electrolyte
pregnancy. Adverse effects on fetal development were Supplement, Oral; Vitamin, Fat Soluble
not observed with use of calcitriol during pregnancy in Use Dietary supplement: Use as a dietary supplement
women (N=9) with pseudovitamin D-dependent rickets. when calcium intake may be inadequate
Doses were adjusted every 4 weeks to keep calcium Local Anesthetic/Vasoconstrictor Precautions
concentrations within normal limits (Edouard 2011). If No information available to require special precautions
calcitriol is used for the management of hypoparathyr- Effects on Dental Treatment No significant effects or
oidism in pregnancy, dose adjustments may be needed complications reported
as pregnancy progresses and again following delivery. Effects on Bleeding No information available to
Vitamin D and calcium levels should be monitored require special precautions
closely and kept in the lower normal range (Callies Adverse Reactions Frequency not defined; also see
1998). individual agents
Central nervous system: Headache
Calcitriol (Topical) (kal si TRYE ole) Endocrine & metabolic: Hypercalcemia
Gastrointestinal: Gastrointestinal distress
Brand Names: US Vectical Genitourinary: Hypercalciuria
Brand Names: Canada Silkis Pregnancy Considerations Available evidence sug-
Pharmacologic Category Vitamin D Analog gests safe use during pregnancy.
247
CANAGLIFLOZIN
Neuromuscular & skeletal: Asthenia (≤1%)

Canagliflozin (kan a gli FLOE zin) Frequency not defined:
Endocrine & metabolic: Hypermagnesemia, increased
Brand Names: US Invokana serum cholesterol (non-HDL), increased serum
Brand Names: Canada Invokana phosphate
Pharmacologic Category Antidiabetic Agent, Neuromuscular & skeletal: Bone fracture, decreased
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor; bone mineral density
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Renal: Increased serum creatinine
Use <1%, postmarketing, and/or case reports: Acute renal
Diabetes mellitus, type 2: Treatment of type 2 diabe- failure, anaphylaxis, angioedema, increased LDL cho-
tes mellitus (noninsulin dependent, NIDDM) as an lesterol, ketoacidosis, necrotizing fasciitis (perineum),
adjunct to diet and exercise to improve glycemic pancreatitis, phimosis, pyelonephritis, skin photosen-
control; risk reduction of major cardiovascular events sitivity, urinary tract infection with sepsis
(cardiovascular death, nonfatal MI, and nonfatal Mechanism of Action By inhibiting sodium-glucose
stroke) in adults with type 2 diabetes mellitus and cotransporter 2 (SGLT2) in the proximal renal tubules,
established cardiovascular disease canagliflozin reduces reabsorption of filtered glucose
Guideline recommendation: In patients with established from the tubular lumen and lowers the renal threshold
atherosclerotic cardiovascular disease (ASCVD) on for glucose (RTG). SGLT2 is the main site of filtered
metformin, addition of canagliflozin may be considered glucose reabsorption; reduction of filtered glucose reab-
to reduce major adverse cardiovascular events, based
sorption and lowering of RTG result in increased urinary
on drug-specific and patient factors (ADA 2018d)
excretion of glucose, thereby reducing plasma glucose
Local Anesthetic/Vasoconstrictor Precautions concentrations.
No information available to require special precautions Pharmacodynamics/Kinetics
Effects on Dental Treatment Key adverse event(s) Onset of Action Within 24 hours (dose-dependent)
related to dental treatment: Hypoglycemia reported;
Duration of Action Suppression of the renal thresh-
patients should be appointed for dental treatment in
old for glucose (RTG) occurs throughout the 24-hour
the morning in order to minimize chance of stress-
dosing interval; maximal RTG suppression occurred
induced hypoglycemia. Dizziness and syncope have
with the 300 mg dose (RTG decreased from baseline
been reported; patients may experience orthostatic
hypotension as they stand up after treatment; especially of ~240 mg/dL to a mean of 70 to 90 mg/dL over 24
if lying in dental chair for extended periods of time. Use hours).
caution with sudden changes in position during and Half-life Elimination Apparent terminal half-life:
after dental treatment. 100 mg dose: 10.6 hours; 300 mg dose: 13.1 hours
Canagliflozin-dependent patients with diabetes (non- Pregnancy Considerations
insulin dependent, type 2) should be questioned by Based on animal data, adverse fetal effects on renal
the dental professional at each dental visit to assess development may occur in humans following in utero
their risk for stress-induced hypoglycemia. The dental exposure during the second and third trimesters.
professional should inquire about the patient’s routine
(ie, work, sleep schedule, eating patterns), history of In women with diabetes, maternal hyperglycemia can
hypoglycemia, time of last medication dose, last meal, be associated with congenital malformations as well as
and most recent blood sugar assessment. Keep a adverse effects in the fetus, neonate, and the mother
supply of glucose tablets and other carbohydrates in (ACOG 2005; ADA 2018c; Metzger 2007). To prevent
the office to prepare for a hypoglycemic event. Seek adverse outcomes, prior to conception and throughout
medical attention when necessary (American Diabetes pregnancy, maternal blood glucose and HbA1c should
Association 2016). be kept as close to target goals as possible but without
Effects on Bleeding No information available to causing significant hypoglycemia (ADA 2018c; Blumer
require special precautions 2013). Agents other than canagliflozin are currently
Adverse Reactions recommended to treat diabetes in pregnant women
>10%: (ADA 2018c).
Endocrine & metabolic: Increased serum potassium
(>5.4 mEq/mL [eGFR 30 to 50]: 27%; >5.4 mEq/mL
[eGFR 45 to 60]: 9%; ≥6.5 mEq/mL [eGFR 30 to
Candesartan (kan de SAR tan)
50]: 2%) Related Information
Infection: Genitourinary fungal infection (females: 11% Cardiovascular Diseases on page 1442
to 12%; males: 4%; patients who developed infec-
Brand Names: US Atacand
tions were more likely to experience recurrence)
Renal: Renal insufficiency (≥30% decrease in eGFR Brand Names: Canada Atacand
from baseline: 1% to 23%; eGFR decline was more Pharmacologic Category Angiotensin II Receptor
common in patients with moderate renal impairment) Blocker; Antihypertensive
1% to 10%: Use
Central nervous system: Falling (2%), fatigue (2%) Heart failure: Treatment of heart failure (HF) (NYHA
Endocrine & metabolic: Hypoglycemia (4%), hypovo- class II to IV)
lemia (2% to 3%), increased thirst (2% to 3%) Guideline recommendations: The American College
Gastrointestinal: Abdominal pain (2%), constipation of Cardiology/American Heart Association (ACC/
(2%), nausea (2%) AHA) 2013 heart failure guidelines recommend the
Genitourinary: Urinary tract infection (6%), increased use of ARBs (ie, candesartan, losartan, and valsar-
urine output (5%), vulvovaginal pruritus (2% to 3%) tan) in patients with HF with reduced ejection fraction
Hematologic & oncologic: Increased hemoglobin (3% who cannot tolerate ACE inhibitors to reduce morbid-
to 4%) ity and mortality. They also suggest that ARBs are
Hypersensitivity: Hypersensitivity reaction (4%) reasonable first-line alternatives to ACE inhibitors in
248
CANGRELOR
patients already maintained on an ARB for other can cause injury and death to the developing fetus.
indications (ACC/AHA [Yancy 2013]). Discontinue as soon as possible once pregnancy is
Hypertension: Management of hypertension detected. The use of drugs which act on the renin-
Guideline recommendations: The 2017 Guideline angiotensin system are associated with oligohydram-
for the Prevention, Detection, Evaluation, and Man- nios. Oligohydramnios, due to decreased fetal renal
agement of High Blood Pressure in Adults recom- function, may lead to fetal lung hypoplasia and skeletal
mends if monotherapy is warranted, in the absence malformations. Use is also associated with anuria,
of comorbidities (eg, cerebrovascular disease, hypotension, renal failure, skull hypoplasia, and death
chronic kidney disease, diabetes, heart failure, ische- in the fetus/neonate. The exposed fetus should be
mic heart disease, etc.), that thiazide-like diuretics or monitored for fetal growth, amniotic fluid volume, and
dihydropyridine calcium channel blockers may be organ formation. Infants exposed in utero should be
preferred options due to improved cardiovascular monitored for hyperkalemia, hypotension, and oliguria
endpoints (eg, prevention of heart failure and stroke). (exchange transfusions or dialysis may be needed).
ACE inhibitors and ARBs are also acceptable for These adverse events are generally associated with
monotherapy. Combination therapy may be required maternal use in the second and third trimesters.
to achieve blood pressure goals and is initially pre-
ferred in patients at high risk (stage 2 hypertension or Untreated chronic maternal hypertension is also asso-
atherosclerotic cardiovascular disease [ASCVD] risk ciated with adverse events in the fetus, infant, and
≥10%) (ACC/AHA [Whelton 2017]). mother. The use of angiotensin II receptor blockers is
not recommended to treat chronic uncomplicated
hypertension in pregnant women and should generally
be avoided in women of reproductive potential
(ACOG 2013).
ment; especially if lying in dental chair for extended Cangrelor (KAN grel or)
position during and after dental treatment. Brand Names: US Kengreal
Effects on Bleeding No information available to Pharmacologic Category Antiplatelet Agent; Antipla-
require special precautions telet Agent, Non-thienopyridine
Adverse Reactions Use Percutaneous coronary intervention (PCI):
>10%: Adjunct to PCI to reduce the risk of periprocedural
Cardiovascular: Hypotension (19%) myocardial infarction (MI), repeat coronary revasculari-
Renal: Renal function abnormality (13%) zation, and stent thrombosis in patients who have not
1% to 10%: been treated with a P2Y12 platelet inhibitor and are not
Central nervous system: Dizziness (4%) being given a glycoprotein IIb/IIIa inhibitor
Endocrine & metabolic: Hyperkalemia (6%) Local Anesthetic/Vasoconstrictor Precautions
Neuromuscular & skeletal: Back pain (3%) No information available to require special precautions
Respiratory: Upper respiratory tract infection (6%), Effects on Dental Treatment No significant effects or
pharyngitis (2%), rhinitis (2%) complications reported
Frequency not defined: Effects on Bleeding Cangrelor increases the risk of
Central nervous system: Headache bleeding. However, it is indicated as an intravenous
Renal: Exacerbation of renal disease (children & infusion prior to and during percutaneous coronary
adolescents), increased serum creatinine intervention and has a short elimination half-life. No
<1%, postmarketing, and/or case reports: Abnormal antiplatelet effect is observed an hour after discontinua-
hepatic function tests, agranulocytosis, angioedema, tion. There is no information to require any special
cough, hepatitis, hyponatremia, leukopenia, neutrope- precautions for dental procedures in patients previously
nia, pruritus, skin rash, urticaria exposed to Cangrelor.
Mechanism of Action Candesartan is an angiotensin Adverse Reactions
receptor antagonist. Angiotensin II acts as a vasocon- Hematologic & oncologic: Hemorrhage (GUSTO: 16%;
strictor. In addition to causing direct vasoconstriction, TIMI: <1%)
angiotensin II also stimulates the release of aldoster- Renal: Renal insufficiency (3%; severe; creatinine
one. Once aldosterone is released, sodium as well as clearance <30 mL/minute)
water are reabsorbed. The end result is an elevation in Respiratory: Dyspnea (1%)
blood pressure. Candesartan binds to the AT1 angio- <1%, postmarketing, and/or case reports: Hypersensi-
tensin II receptor. This binding prevents angiotensin II tivity reaction
from binding to the receptor thereby blocking the vaso- Mechanism of Action Cangrelor, a nonthienopyridine
constriction and the aldosterone secreting effects of adenosine triphosphate analogue, is a direct P2Y12
angiotensin II. platelet receptor inhibitor that blocks adenosine diphos-
Pharmacodynamics/Kinetics phate (ADP)-induced platelet activation and aggrega-
Onset of Action tion. Cangrelor binds selectively and reversibly to the
2 to 3 hours; antihypertensive effect: Within 2 weeks P2Y12 receptor, preventing further signaling and platelet
Peak effect: 6 to 8 hours; maximum antihypertensive activation.
effect: 4 to 6 weeks Pharmacodynamics/Kinetics
Duration of Action >24 hours Onset of Action Platelet inhibition occurs within 2
Half-life Elimination Dose dependent: 5 to 9 hours minutes
Time to Peak Children (1 to 17 years); Adults: 3 to 4 Duration of Action Antiplatelet effect is maintained
hours throughout duration of infusion. After discontinuation,
Pregnancy Risk Factor D platelet function returns to normal within 1 hour
Pregnancy Considerations [US Boxed Warning]: Half-life Elimination ~3 to 6 minutes
Drugs that act on the renin-angiotensin system Time to Peak Within 2 minutes
249
CANGRELOR
Pregnancy Risk Factor C Cannabidiol can be detected in the umbilical cord

Pregnancy Considerations Adverse events were serum and meconium following maternal use of inhaled,
observed in some animal reproduction studies. non-medicinal cannabis during pregnancy (Kim 2018).
Patients exposed to cannabidiol during pregnancy are
Cannabidiol (kan a bi DYE ol) encouraged to enroll in the North American Antiepileptic
Drug (NAAED) Pregnancy Registry by calling
Brand Names: US Epidiolex 1-888-233-2334. Additional information is available at
Pharmacologic Category Anticonvulsant; Cannabi- www.aedpregnancyregistry.org.
noid Controlled Substance C-V
Use Seizure disorders: Treatment of seizures associ-
ated with Lennox-Gastaut syndrome (LGS) or Dravet
syndrome (DS) in patients ≥2 years of age. Capsaicin (kap SAY sin)
No information available to require special precautions Related Information
Effects on Dental Treatment Key adverse event(s) Capsicum Peppers on page 1389
related to dental treatment: Sedation is most common Brand Names: US Aflexeryl-MC [OTC] [DSC]; Allev-
early in treatment and may resolve with continued use. ess [OTC]; Captracin [DSC]; Capzasin-HP [OTC]; Cap-
Excessive salivation has been reported. zasin-P [OTC]; DiabetAid Pain and Tingling Relief
Effects on Bleeding No information available to [OTC]; Flexin; Levatio; MaC Patch [DSC]; MenCaps
require special precautions [OTC]; Neuvaxin [DSC]; Qroxin [DSC]; Qutenza; Rel-
Adverse Reactions eevia MC [DSC]; Releevia [DSC]; RelyyT [DSC]; Ren-
>10%: ovo; Salonpas Gel-Patch Hot [OTC]; Salonpas Hot
Central nervous system: Drowsiness (≤32%), lethargy [OTC] [DSC]; Sinelee [DSC]; Solaice [DSC]; Sure
(≤32%), sedation (≤32%), fatigue (≤12%), malaise Result SR Relief [OTC]; Trixaicin HP [OTC]; Trixaicin
(≤12%), insomnia (≤11%), sleep disorder (≤11%), [OTC] [DSC]; Zostrix HP [OTC]; Zostrix Maximum
sleep disturbance (≤11%) Strength Natural Foot Pain Relief [OTC]; Zostrix Max-
Dermatologic: Skin rash (7% to 13%) imum Strength Natural Pain Relief [OTC]; Zostrix Orig-
Endocrine & metabolic: Weight loss (3% to 18%) inal Strength Natural Pain Relief [OTC]
Gastrointestinal: Decreased appetite (16% to 22%), Brand Names: Canada Zostrix; Zostrix H.P.
diarrhea (9% to 20%) Generic Availability (US) Yes: Cream
Hematologic & oncologic: Anemia (30%) Pharmacologic Category Analgesic, Topical; Topical
Hepatic: Increased serum alanine aminotransferase Skin Product; Transient Receptor Potential Vanilloid 1
(>3x ULN: 13% to 17%), increased serum trans- (TRPV1) Agonist
aminases (8% to 16%) Dental Use Potential use as topical agent in burning
Infection: Infection (25% to 41%), viral infection (7% mouth syndrome and oral mucositis
to 11%) Use
Neuromuscular & skeletal: Asthenia (≤12%) Muscle/Joint pain: Temporary relief of minor aches
1% to 10%: and pain of muscles and joints associated with back-
Central nervous system: Agitation (≤9%), irritability ache, strains, sprains, arthritis, bruises, cramps, or
(≤9%), aggressive behavior (≤5%), outbursts of muscle stiffness or soreness.
anger (≤5%), drooling (≤4%), abnormal gait (2% Neuropathic pain: Management of neuropathic pain
to 3%) associated with diabetic neuropathy or postherpetic
Gastrointestinal: Gastroenteritis (4%), sialorrhea neuralgia.
(≤4%), abdominal distress (≤3%), abdominal Local Anesthetic/Vasoconstrictor Precautions
pain (≤3%) No information available to require special precautions
Infection: Fungal infection (1% to 3%) Effects on Dental Treatment No significant effects or
Respiratory: Pneumonia (5% to 8%), hypoxia (≤3%), complications reported
respiratory failure (≤3%) Effects on Bleeding No information available to
Frequency not defined: require special precautions
Hematologic & oncologic: Decreased hematocrit, Adverse Reactions The following adverse events
decreased hemoglobin occurred with topical patch administration.
Hepatic: Increased serum aspartate aminotransfer- >10%: Local: Localized erythema (63%), local
ase, increased serum transaminases (>20x ULN) pain (42%)
Hypersensitivity: Hypersensitivity reaction 1% to 10%:
Renal: Increased serum creatinine Cardiovascular: Hypertension (2%; transient)
<1%, postmarketing, and/or case reports: Angioedema, Dermatologic: Papule (6%), local dryness (2%), pruri-
tus (2%)
erythema, pruritus
Gastrointestinal: Nausea (5%), vomiting (3%)
Mechanism of Action The exact antiepileptic mecha- Local: Local pruritus (6%), localized edema (4%), local
nism of action of cannabidiol is unknown; however, it
swelling (2%)
does not appear to involve its effects on cannabinoid Respiratory: Nasopharyngitis (4%), sinusitis (3%),
receptors. bronchitis (2%)
Pharmacodynamics/Kinetics <1%, postmarketing, and/or case reports: Abnormal
Onset of Action Within 4 weeks skin odor, application site reactions (includes bruise,
Half-life Elimination 56 to 61 hours dermatitis, desquamation, excoriation, hyperesthesia,
Time to Peak 2.5 to 5 hours at steady state inflammation, paresthesia, urticaria), burning sensa-
Pregnancy Considerations tion of skin, cough, dizziness, dysgeusia, headache,
Adverse events were observed in animal reproduction hypoesthesia, peripheral edema, peripheral sensory
studies. neuropathy, throat irritation
250
CAPSAICIN
Dental Usual Dosage Topical: Apply cream or gel to spinal cord; capsaicin exposure results in subsequent
affected area 3-4 times/day desensitization of the sensory axons and inhibition of
Dosing pain transmission initiation. In arthritis, capsaicin indu-
Adult & Geriatric ces release of substance P, the principal chemomedia-
Muscle/joint pain: Topical: tor of pain impulses from the periphery to the CNS, from
Cream, gel, liquid, lotion: Apply thin film to affected peripheral sensory neurons; after repeated application,
areas 3 to 4 times daily. capsaicin depletes the neuron of substance P and
Patch: prevents reaccumulation. The functional link between
0.025%, 0.03%, 0.0375%, 0.05% (Sinelee only): substance P and the capsaicin receptor, TRPV1, is not
Apply 1 patch to affected area for up to 8 hours well understood.
(maximum: 4 patches/day); do not use for >5 Contraindications
consecutive days (product specific) Hypersensitivity to capsaicin, menthol, or any compo-
0.05% (Solaice only): Apply 1 patch to affected nent of the formulation.
area for up to 8 hours (maximum: 4 patches/day) OTC labeling: When used for self-medication, do not
Neuropathic pain: Topical: Patch (Qutenza): Apply use on wounds, damaged, broken, or irritated skin; do
patch to most painful area for 60 minutes. Up to 4 not cover with bandage; do not use in combination
patches may be applied in a single application. Treat- with external heat source (eg, heating pad).
ment may be repeated ≥3 months as needed for Warnings/Precautions May cause serious burns (eg,
return of pain (do not apply more frequently than first- to third-degree chemical burns) at the application
every 3 months). Area should be pretreated with a site. In some cases, hospitalization has been required.
topical anesthetic prior to patch application. Discontinue use and seek medical attention if signs of
Diabetic neuropathy (off-label use): Topical: Cream skin injury (eg, pain, swelling, or blistering) occur follow-
(0.075%): Apply 4 times/day (Bril 2011) ing application (FDA Drug Safety Communication,
Renal Impairment: Adult There are no dosage 2012). May cause CNS depression, which may impair
adjustments provided in the manufacturer’s labeling. physical or mental abilities; patients must be cautioned
Hepatic Impairment: Adult There are no dosage about performing tasks that require mental alertness
adjustments provided in the manufacturer’s labeling. (eg, operating machinery or driving). Use with caution in
Pediatric patients with uncontrolled hypertension, or a history of
Muscle ache and joint pain, minor: Topical: cardiovascular or cerebrovascular events; transient
Lotion 0.025% (DiabetAid Tingling and Pain Relief) increases in blood pressure due to treatment-related
Children ≥2 years and Adolescents: Topical: Apply pain have occurred during and after application of RX
to affected area not more than 3 to 4 times/day patch.
Patch: Note: With OTC products, approved ages
For external use only; avoid contact with eyes, mouth,
and uses may vary; consult product specific
genitals, or any or other mucous membranes. Do not
labeling.
use immediately before or after activities such as bath-
Product strength <0.05%: Adolescents ≥12 years:
ing, swimming, showering, sun bathing, strenuous exer-
Topical:
cise, steam bath, sauna, or other heat or sunlight
Flexin (0.0375%): Apply 1 patch to affected area;
exposure to the treated area. Stop use and consult a
may change 2 to 3 times/day; maximum daily
healthcare provider if excessive redness, blistering
dose: 3 patches/day
burning or irritation develops, symptoms get worse,
Levatio (0.03%): Apply 1 patch to affected area for
symptoms persist for >7 days, symptoms resolve and
up to 8 hours; change patch 1 to 2 times daily;
then recur, or if difficulty breathing or swallowing occurs.
maximum daily dose: 4 patches/day; do not use
Do not handle contact lenses for 1 hour after handling,
for >5 consecutive days
applying, or removing capsaicin (product specific).
MaC (0.0375%): Apply 1 patch to affected area for
up to 8 hours; change patch 2 to 3 times/day; RX labeling: Do not cover with bandage or compres-
maximum daily dose: 4 patches/24 hours sion. Use only on intact skin; do not use on wounds,
MenCaps (0.0225%): Apply 1 patch to affected damaged, broken, infected, sensitive or inflamed skin.
area for up to 8 hours; may change patch up to 3 Do not apply to face or scalp. Do not use concurrently
times daily with other external pain-relieving products.
Releevia MC (0.0375%), Renovo (0.0375%):
OTC labeling: Transient burning may occur and gen-
Apply 1 patch to affected area; may change
erally disappears after several days.
patch 1 to 2 times daily; maximum daily dose:
3 patches/day Patch: Avoid inhaling airborne material from dried res-
Salonpas Pain Relieving Hot Patch (0.025%): idue. Remove patches gently and slowly to decrease
Apply 1 patch to affected area for up to 8 hours; risk of aerosolization; inhalation of airborne capsaicin
may change patch up to 3 to 4 times daily may result in coughing or sneezing.
Product strength 0.05%: Adolescents ≥16 years:
Topical: Allevess patch: Apply 1 patch to affected Qutenza: If skin not intended to be treated comes in
area; may change patch 1 to 2 times daily contact with capsaicin, apply provided cleansing gel for
one minute and wipe off with dry gauze; then wash the
Renal Impairment: Pediatric There are no dosage
area with soap and water. Post-application pain should
adjustments provided in the manufacturer’s labeling.
be treated with local cooling methods (ice pack) and/or
Hepatic Impairment: Pediatric There are no dos-
analgesics.
age adjustments provided in the manufacturer’s label-
ing. Benzyl alcohol and derivatives: Some dosage forms
Mechanism of Action Capsaicin, a transient receptor may contain benzyl alcohol; large amounts of benzyl
potential vanilloid 1 receptor (TRPV1) agonist, activates alcohol (≥99 mg/kg/day) have been associated with a
TRPV1 ligand-gated cation channels on nociceptive potentially fatal toxicity ("gasping syndrome") in neo-
nerve fibers, resulting in depolarization, initiation of nates; the "gasping syndrome" consists of metabolic
action potential, and pain signal transmission to the acidosis, respiratory distress, gasping respirations,
251
CAPSAICIN
CNS dysfunction (including convulsions, intracranial

hemorrhage), hypotension and cardiovascular collapse Captopril (KAP toe pril)
(AAP ["Inactive" 1997]; CDC, 1982); some data sug-
gests that benzoate displaces bilirubin from protein Related Information
binding sites (Ahlfors, 2001); avoid or use dosage forms Cardiovascular Diseases on page 1442
containing benzyl alcohol with caution in neonates. See Pharmacologic Category Angiotensin-Converting
manufacturer’s labeling. Enzyme (ACE) Inhibitor; Antihypertensive
Drug Interactions Use
Metabolism/Transport Effects Substrate of Diabetic nephropathy: Treatment of diabetic nephrop-
CYP2E1 (minor); Note: Assignment of Major/Minor athy (proteinuria >500 mg/day) in patients with type 1
substrate status based on clinically relevant drug insulin-dependent diabetes mellitus and retinopathy
interaction potential Heart failure: Treatment of heart failure
Avoid Concomitant Use There are no known inter- Guideline recommendations: The American College
actions where it is recommended to avoid concomitant of Cardiology/American Heart Association (ACC/
use. AHA) 2013 Heart Failure Guidelines recommend
Increased Effect/Toxicity There are no known sig- the use of ACE inhibitors, along with other guide-
nificant interactions involving an increase in effect. line-directed medical therapies, to prevent progres-
Decreased Effect There are no known significant sion of HF and reduced ejection fraction in
interactions involving a decrease in effect. asymptomatic patients with or without a history of
Pharmacodynamics/Kinetics myocardial infarction (Stage B HF), or to treat those
Onset of Action OTC products (capsaicin 0.025% to with symptomatic heart failure and reduced ejection
0.1%): 2 to 4 weeks of continuous therapy; Qutenza fraction to reduce morbidity and mortality (Stage C
patch: 1 week after application HFrEF).
Half-life Elimination Topical patch (capsaicin 8%): Hypertension: Management of hypertension
1.64 hours (Babbar 2009) Guideline recommendations: The 2017 Guideline
Pregnancy Risk Factor B for the Prevention, Detection, Evaluation, and Man-
Pregnancy Considerations Adverse events have not agement of High Blood Pressure in Adults recom-
been observed in animal reproduction studies with mends if monotherapy is warranted, in the absence
capsaicin patch or liquid. Systemic absorption is limited of comorbidities (eg, cerebrovascular disease,
following topical administration of the patch; plasma chronic kidney disease, diabetes, heart failure, ische-
concentrations are below the limit of detection 3 to 6 mic heart disease, etc.), that thiazide-like diuretics or
hours after the patch is removed. dihydropyridine calcium channel blockers may be
Breastfeeding Considerations It is not known if preferred options due to improved cardiovascular
capsaicin is excreted in breast milk following topical endpoints (eg, prevention of heart failure and stroke).
administration. Some manufacturers recommend not ACE inhibitors and ARBs are also acceptable for
breastfeeding on the day of treatment after the patch monotherapy. Combination therapy may be required
has been applied to reduce any potential infant expo- to achieve blood pressure goals and is initially pre-
sure. ferred in patients at high risk (stage 2 hypertension or
Dosage Forms: US atherosclerotic cardiovascular disease [ASCVD] risk
Cream, topical: ≥10%) (ACC/AHA [Whelton 2017]).
Capzasin-HP [OTC]: 0.1% (42.5 g) Myocardial infarction with left ventricular dysfunc-
Capzasin-P [OTC]: 0.035% (42.5 g) tion: To improve survival following myocardial infarc-
Sure Result SR Relief [OTC]: 0.025% (118 mL) tion in clinically stable patients with left ventricular
Trixaicin HP [OTC]: 0.075% (60 g) dysfunction manifested as an ejection fraction of
Zostrix HP [OTC]: 0.1% (60 g) ≤40%, and to reduce the incidence of overt heart
Zostrix Maximum Strength Natural Pain Relief [OTC]: failure and subsequent hospitalizations for heart fail-
0.1% (56.6 g) ure in these patients.
Zostrix Maximum Strength Natural Foot Pain Relief Guideline recommendations: Based on the 2013
[OTC]: 0.1% (56.6 g) ACC/AHA guidelines for the management of patients
Zostrix Original Strength Natural Pain Relief [OTC]: with ST-elevation acute coronary syndromes (STE-
0.033% (56.6 g) ACS), an ACE inhibitor should be initiated within the
Generic: 0.025% (60 g) first 24 hours to all patients with STE-ACS with
Gel, topical: anterior location, HF, or left ventricular ejection frac-
Capzasin-P [OTC]: 0.025% (42.5 g) [contains tion (LVEF) ≤40% unless contraindicated. It is also
menthol] reasonable to initiate an ACE inhibitor in all patients
Liquid, topical: with STE-ACS.
Capzasin-P [OTC]: 0.15% (29.5 mL) Local Anesthetic/Vasoconstrictor Precautions
Lotion, topical: No information available to require special precautions
DiabetAid Pain and Tingling Relief [OTC]: 0.025% Effects on Dental Treatment Key adverse event(s)
(120 mL) related to dental treatment: Loss or diminished percep-
Patch, topical: tion of taste; Patients may experience orthostatic hypo-
Allevess [OTC]: 0.05% (15s) [contains menthol 5%] tension as they stand up after treatment; especially if
Flexin: 0.0375% (15s) [contains menthol 5%] lying in dental chair for extended periods of time. Use
Levatio: 0.03% (15s) [contains menthol 5%] caution with sudden changes in position during and
MenCaps [OTC]: 0.0225% (15s) [contains men- after dental treatment.
thol 4.5%]
Qutenza: 8% (1s, 2s) An angiotensin-converting enzyme (ACE) Inhibitor
RelyyT: 0.025% (15s) [contains menthol 5%] cough is a dry, hacking, nonproductive cough that can
Renovo: 0.0375% (15s) [contains menthol 5%] potentially interfere with longer dental procedures if
Salonpas Gel-Patch Hot [OTC]: 0.025% (3s, 6s) patient has this side effect.
252
CAPTOPRIL
Effects on Bleeding No information available to visual hallucination (Doane, 2013), vomiting, xero-
require special precautions stomia
Adverse Reactions Mechanism of Action Competitive inhibitor of angio-
Frequency not defined: tensin-converting enzyme (ACE); prevents conversion
Cardiovascular: Angina pectoris, cardiac arrest, car- of angiotensin I to angiotensin II, a potent vasoconstric-
diac arrhythmia, cardiac failure, flushing, myocardial tor; results in lower levels of angiotensin II which causes
infarction, orthostatic hypotension, Raynaud's phe- an increase in plasma renin activity and a reduction in
nomenon, syncope aldosterone secretion.
Central nervous system: Ataxia, cerebrovascular Pharmacodynamics/Kinetics
insufficiency, confusion, depression, drowsiness, Onset of Action Within 15 minutes; Peak effect:
myasthenia, nervousness Blood pressure reduction: 1 to 1.5 hours after dose;
Dermatologic: Bullous pemphigoid, erythema multi- Maximum effect: Antihypertensive: 60 to 90 minutes;
forme, exfoliative dermatitis, pallor, Stevens-Johnson may require several weeks of therapy before full
syndrome hypotensive effect is seen
Endocrine & metabolic: Gynecomastia, hyponatremia Duration of Action Dose related, may require several
(symptomatic) weeks of therapy before full hypotensive effect
Gastrointestinal: Cholestasis, dyspepsia, glossitis, Half-life Elimination
pancreatitis
Infants with CHF: 3.3 hours; range: 1.2-12.4 hours
Genitourinary: Impotence, nephrotic syndrome, oligu-
(Pereira 1991)
ria, urinary frequency
Children: 1.5 hours; range: 0.98-2.3 hours (Levy 1991)
Hematologic & oncologic: Agranulocytosis, anemia,
Adults: Healthy volunteers: ~1.7 hours (Duchin 1982).
pancytopenia, thrombocytopenia
In 2 studies, patients with chronic renal failure dem-
Hepatic: Hepatic necrosis (rare), hepatitis, increased
serum alkaline phosphatase, increased serum bilir- onstrated ~2-fold longer half-lives as compared to
ubin, increased serum transaminases, jaundice normal subjects (Giudicelli 1984; Onoyama 1981).
Hypersensitivity: Anaphylactoid reaction, angioedema Half-life was up to 21 hours in patients with severe
Neuromuscular & skeletal: Myalgia, weakness renal impairment and up to 32 hours in patients on
Ophthalmic: Blurred vision chronic hemodialysis in another study (Duchin 1984)
Renal: Polyuria, renal failure, renal insufficiency Time to Peak Within 1 to 2 hours
Respiratory: Bronchospasm, eosinophilic pneumoni- Pregnancy Risk Factor D
tis, rhinitis Pregnancy Considerations
1% to 10%: [US Boxed Warning]: Drugs that act on the renin-
Cardiovascular: Hypotension (1% to 3%), chest pain angiotensin system can cause injury and death to
(1%), palpitations (1%), tachycardia (1%) the developing fetus. Discontinue as soon as pos-
Dermatologic: Skin rash (maculopapular or urticarial sible once pregnancy is detected.
[4% to 7%]; in patients with rash, a positive ANA and/
or eosinophilia has been noted in 7% to 10%), Captopril crosses the placenta (Hurault de Ligny 1987).
pruritus (2%) Drugs that act on the renin-angiotensin system are
Endocrine & metabolic: Hyperkalemia (1% to 11%) associated with oligohydramnios. Oligohydramnios,
Gastrointestinal: Dysgeusia (2% to 4%; loss of taste or due to decreased fetal renal function, may lead to fetal
diminished perception) lung hypoplasia and skeletal malformations. Their use
Genitourinary: Proteinuria (1%) in pregnancy is also associated with anuria, hypoten-
Hematologic & oncologic: Neutropenia (≤4%; in sion, renal failure, skull hypoplasia, and death in the
patients with renal insufficiency or collagen-vascular fetus/neonate. Teratogenic effects may occur following
disease) maternal use of an ACE inhibitor during the first trimes-
Hypersensitivity: Hypersensitivity reaction (rash, pru- ter, although this finding may be confounded by mater-
ritus, fever, arthralgia, and eosinophilia: 4% to 7%; nal disease. Because adverse fetal events are well
depending on dose and renal function) documented with exposure later in pregnancy, ACE
Renal: Increased serum creatinine, renal insufficiency inhibitor use in pregnant women is not recommended
(worsening; may occur in patients with bilateral renal (Seely 2014; Weber 2014). Infants exposed to an ACE
artery stenosis or hypovolemia) inhibitor in utero should be monitored for hyperkalemia,
Respiratory: Cough (<1% to 2%) hypotension, and oliguria. Oligohydramnios may not
Miscellaneous: Hypersensitivity reactions (rash, pruri- appear until after irreversible fetal injury has occurred.
tus, fever, arthralgia, and eosinophilia) have occurred Exchange transfusions or dialysis may be required to
in 4% to 7% of patients (depending on dose and reverse hypotension or improve renal function, although
renal function); dysgeusia - loss of taste or dimin- data related to the effectiveness in neonates is limited.
ished perception (2% to 4%)
<1%, postmarketing, and/or case reports: Abdominal Chronic maternal hypertension itself is also associated
pain, alopecia, angina pectoris, anorexia, aphthous with adverse events in the fetus/infant and mother. ACE
stomatitis, aplastic anemia, arthralgia, cholestatic inhibitors are not recommended for the treatment of
jaundice, constipation, diarrhea, dizziness, dyspnea, uncomplicated hypertension in pregnancy (ACOG
eosinophilia, fatigue, fever, gastric irritation, glomeru- 2013) and they are specifically contraindicated for the
lonephritis, Guillain-Barre syndrome, headache, treatment of hypertension and chronic heart failure
hemolytic anemia, Huntington's chorea (exacerba- during pregnancy by some guidelines (Regitz-Zagrosek
tion), hyperthermia, increased erythrocyte sedimenta- [ESC 2018]). In addition, ACE inhibitors should gener-
tion rate, insomnia, interstitial nephritis, Kaposi's ally be avoided in women of reproductive age (ACOG
sarcoma, malaise, myalgia, nausea, paresthesia, pep- 2013). If treatment for hypertension or chronic heart
tic ulcer, pericarditis, psoriasis, seizure (in premature failure in pregnancy is needed, other agents should
infants), systemic lupus erythematosus, vasculitis, be used (ACOG 2013; Regitz-Zagrosek [ESC 2018]).
253
CARBAMAZEPINE
hyponatremia, porphyria cutanea tarda, porphyria

CarBAMazepine (kar ba MAZ e peen) (variegate), SIADH
Gastrointestinal: Abdominal pain, anorexia, diarrhea,
Related Information gastric distress, glossitis, pancreatitis, stomatitis
Temporomandibular Dysfunction (TMD), Chronic Pain, Genitourinary: Acute urinary retention, azotemia,
and Fibromyalgia on page 1559 defective spermatogenesis, impotence, microscopic
Brand Names: US Carbatrol; Epitol; Equetro; TEGre- urine deposits, oliguria, reduced fertility (male), uri-
tol; TEGretol-XR nary frequency
Brand Names: Canada Mazepine; Tegretol Hematologic & oncologic: Adenopathy, agranulocyto-
Pharmacologic Category Anticonvulsant, Miscella- sis, aplastic anemia, bone marrow depression, eosi-
neous nophilia, hypogammaglobulinemia, leukocytosis,
Use leukopenia, lymphadenopathy, pancytopenia, pur-
Bipolar 1 disorder (Equetro only): Treatment of acute pura, thrombocytopenia
manic or mixed episodes associated with bipolar 1 Hepatic: Abnormal hepatic function tests, cholestatic
disorder jaundice, hepatic failure, hepatitis, hepatocellular
Epilepsy: Treatment of partial seizures with complex jaundice, increased liver enzymes
symptomatology (psychomotor, temporal lobe), gener- Hypersensitivity: Hypersensitivity reaction
alized tonic-clonic seizures (grand mal), or mixed Immunologic: DRESS syndrome
seizure patterns Neuromuscular & skeletal: Arthralgia, exacerbation of
Limitations of use: Carbamazepine is not indicated for systemic lupus erythematosus, leg cramps, lupus-
the treatment of absence seizures (petit mal); it has like syndrome, myalgia, osteoporosis
been associated with increased frequency of gener- Ophthalmic: Conjunctivitis, diplopia, increased intra-
alized convulsions in these patients. ocular pressure, punctate cataract, nystagmus, ocu-
Trigeminal or glossopharyngeal neuralgia (oral lomotor disturbance
only): Treatment of pain associated with trigeminal Otic: Tinnitus
or glossopharyngeal neuralgia Renal: Increased blood urea nitrogen, renal failure
Respiratory: Dry throat, pulmonary hypersensitivity
<1%, postmarketing, and/or case reports: Anaphylaxis,
angioedema, aseptic meningitis, decreased thyroid
hormones, dysgeusia (Syed 2016), eyelid edema,
flow resumes upon discontinuation).
glottis edema, hepatotoxicity (idiosyncratic: Chalasani
Effects on Bleeding No information available to 2014), intrahepatic cholestasis (vanishing bile duct
require special precautions syndrome), laryngeal edema, lip edema, suicidal ten-
Adverse Reactions dencies
>10%: Mechanism of Action In addition to anticonvulsant
Central nervous system: Dizziness (44%), drowsiness effects, carbamazepine has anticholinergic, antineural-
(32%), ataxia (15%) gic, antidiuretic, muscle relaxant, antimanic, antidepres-
Gastrointestinal: Nausea (29%), vomiting (18%) sive, and antiarrhythmic properties; may depress
1% to 10%: activity in the nucleus ventralis of the thalamus or
Cardiovascular: Hypertension (3%) decrease synaptic transmission or decrease summation
Central nervous system: Speech disturbance (6%), of temporal stimulation leading to neural discharge by
abnormality in thinking (2%), paresthesia (2%), limiting influx of sodium ions across cell membrane or
twitching (2%), vertigo (2%) other unknown mechanisms; stimulates the release of
Dermatologic: Pruritus (8%), skin rash (7%) ADH and potentiates its action in promoting reabsorp-
Gastrointestinal: Constipation (10%), xerostomia (8%) tion of water; chemically related to tricyclic antidepres-
Neu romusc ula r & skeletal: Weakness (8%), sants
tremor (3%) Pharmacodynamics/Kinetics
Ophthalmic: Blurred vision (5% to 6%) Half-life Elimination Half-life is variable because of
Frequency not defined: autoinduction which is usually complete 3 to 5 weeks
Cardiovascular: Arterial insufficiency (cerebral artery), after initiation of a fixed carbamazepine regimen.
atrioventricular block, cardiac arrhythmia, cardiac Carbamazepine: Initial: 25 to 65 hours; Extended
failure, collapse, coronary artery disease (aggrava- release: 35 to 40 hours; Multiple doses: Children
tion), edema, exacerbation of hypertension, hypoten- and Adolescents: Mean range: 3.1 to 20.8 hours
sion, pulmonary embolism, syncope, (Battino 1995); Adults: 12 to 17 hours
thromboembolism, thrombophlebitis Epoxide metabolite: Initial: 34 ± 9 hours
Central nervous system: Agitation, chills, confusion, Time to Peak Unpredictable:
depression, fatigue, headache, hyperacusis, involun- Immediate release: Suspension: Multiple doses: 1.5
tary body movements, neuroleptic malignant syn- hour; tablet: 4 to 5 hours
drome, peripheral neuritis, talkativeness, Extended release: Carbatrol, Equetro: 12 to 26 hours
unsteadiness, visual hallucination (single dose), 4 to 8 hours (multiple doses); Tegre-
Dermatologic: Acute generalized exanthematous pus- tol®-XR: 3 to 12 hours
tulosis, alopecia, diaphoresis, dyschromia, erythema Pregnancy Considerations Studies in pregnant
multiforme, erythema nodosum, erythematous rash, women have demonstrated a risk to the fetus. Carba-
exfoliative dermatitis, maculopapular rash, onycho- mazepine and its metabolites can be found in the fetus
madesis, pruritic rash, skin photosensitivity, Stevens- and may be associated with teratogenic effects, includ-
Johnson syndrome, toxic epidermal necrolysis, urti- ing spina bifida, craniofacial defects, cardiovascular
caria malformations, and hypospadias. The risk of terato-
Endocrine & metabolic: Acute porphyria, albuminuria, genic effects is higher with anticonvulsant polytherapy
decreased serum calcium, glycosuria, hirsutism, than monotherapy.
254
CARBIDOPA
Developmental delays have also been observed follow-

ing in utero exposure to carbamazepine (per manufac- Carbidopa (kar bi DOE pa)
turer); however, socioeconomic factors, maternal and
paternal IQ, and polytherapy may contribute to these Brand Names: US Lodosyn
findings. Pregnancy may cause small decreases of Pharmacologic Category Anti-Parkinson Agent,
carbamazepine plasma concentrations in the second Decarboxylase Inhibitor
and third trimesters; monitoring should be considered. Use
Parkinsonism: Given with carbidopa/levodopa in the
When used for the treatment of bipolar disorder, use of
treatment of idiopathic Parkinson disease, postence-
carbamazepine should be avoided during the first tri-
phalitic parkinsonism, and symptomatic parkinsonism,
mester of pregnancy if possible. The use of a single
which may follow injury to the nervous system by
medication for the treatment of bipolar disorder or carbon monoxide and/or manganese intoxication.
epilepsy in pregnancy is preferred. Carbamazepine Note: Administration of carbidopa allows use of a lower
may decrease plasma concentrations of hormonal con- dosage of levodopa, more rapid titration, and a
traceptives; breakthrough bleeding or unintended preg- decrease in nausea and vomiting associated with
nancy may occur and alternate or back-up methods of levodopa; use with carbidopa/levodopa in patients
contraception should be considered. requiring additional carbidopa; has no effect without
Patients exposed to carbamazepine during pregnancy levodopa.
are encouraged to enroll themselves into the AED Local Anesthetic/Vasoconstrictor Precautions
Pregnancy Registry by calling 1-888-233-2334. Addi- No information available to require special precautions
t i o n a l i n f o r m a t i o n i s a v a i l a b l e a t w w w. - Effects on Dental Treatment Key adverse event(s)
related to dental treatment: Dopaminergic therapy in
aedpregnancyregistry.org.
Parkinson's disease includes the use of carbidopa in
Product Availability Carnexiv (carbamazepine injec- combination with levodopa. Carbidopa/levodopa combi-
tion): FDA approved October 2016; anticipated avail- nation is associated with orthostatic hypotension.
ability is currently unknown. Consult the prescribing Patients may experience orthostatic hypotension as
information for additional information. they stand up after treatment; especially if lying in
dental chair for extended periods of time. Use caution
Carbamide Peroxide (KAR ba mide per OKS ide) with sudden changes in position during and after dental
treatment.
Brand Names: US Auraphene-B [OTC]; Clearcanal Effects on Bleeding No information available to
Earwax Softener [OTC]; E-R-O Ear Drops [OTC] require special precautions
[DSC]; E-R-O Ear Wax Removal System [OTC] Adverse Reactions Adverse reactions are associated
[DSC]; Ear Drops Earwax Aid [OTC]; Ear Drops with concomitant administration with levodopa.
[OTC]; Earwax Treatment Drops [OTC] [DSC]; Gly- Cardiovascular: Cardiac arrhythmia, chest pain, edema,
Oxide [OTC]; GoodSense Ear Wax Removal [OTC] flushing, hypertension, hypotension, myocardial
Pharmacologic Category Anti-inflammatory, Locally infarction, orthostatic hypotension, palpitation, phlebi-
Applied; Otic Agent, Cerumenolytic tis, syncope
Use Central nervous system: Abnormal dreams, abnormal
Oral: Temporary use in cleansing of canker sore and gait, agitation, anxiety, ataxia, confusion, decreased
mental acuity, delusions, dementia, depression (with
minor wounds or gum inflammation due to minor
or without suicidal tendencies), disorientation, dizzi-
dental procedures, dentures, orthodontic appliances,
ness, drowsiness, euphoria, extrapyramidal reaction,
accidental injury, or other irritations of mouth and
falling, fatigue, glossopyrosis, hallucination, head-
gums; aids in removal of phlegm, mucus, or other ache, Horner's syndrome, impulse control disorder,
secretions associated with occasional sore mouth. insomnia, malaise, memory impairment, nervousness,
Otic: Aid to soften, loosen, and remove excessive neuroleptic malignant syndrome, nightmares, numb-
earwax. ness, on-off phenomenon, paranoia, paresthesia,
Local Anesthetic/Vasoconstrictor Precautions pathological gambling, peripheral neuropathy, psycho-
No information available to require special precautions sis, seizure (causal relationship not established),
Effects on Dental Treatment No significant effects or trismus
complications reported (see Dental Health Professional Dermatologic: Alopecia, bulla, diaphoresis, discolora-
Considerations) tion of sweat, skin rash
Effects on Bleeding No information available to Endocrine & metabolic: Abnormal lactate dehydrogen-
require special precautions ase, glycosuria, hot flash, hyperglycemia, hypokale-
Adverse Reactions Frequency not defined. mia, increased libido (including hypersexuality),
Dermatologic: Localized erythema, skin rash increased uric acid, weight changes
Infection: Superinfection Gastrointestinal: Abdominal distress, abdominal pain,
anorexia, bruxism, constipation, diarrhea, discolora-
Local: Local irritation, redness
tion of saliva, duodenal ulcer, dysgeusia, dyspepsia,
Mechanism of Action Carbamide peroxide releases dysphagia, flatulence, gastrointestinal hemorrhage,
hydrogen peroxide which serves as a source of nascent heartburn, hiccups, nausea, sialorrhea, sore throat,
oxygen upon contact with catalase; deodorant action is vomiting, xerostomia
probably due to inhibition of odor-causing bacteria; Genitourinary: Priapism, proteinuria, urinary frequency,
softens impacted cerumen due to its foaming action urinary incontinence, urinary retention, urinary tract
Pharmacodynamics/Kinetics infection, urine discoloration
Onset of Action ~24 hours Hematologic & oncologic: Abnormal Coombs' test,
Dental Health Professional Considerations When agranulocytosis, anemia, decreased hematocrit,
used as tooth whitening product, most common side decreased hemoglobin, hemolytic anemia, leukope-
effect is tooth sensitivity. nia, malignant melanoma, thrombocytopenia
255
CARBIDOPA
Hepatic: Abnormal alanine aminotransferase, abnormal extended periods of time. Use caution with sudden
alkaline phosphatase, abnormal aspartate transami- changes in position during and after dental treatment.
nase, abnormal bilirubin levels, abnormal lactate Effects on Bleeding No information available to
dehydrogenase require special precautions
Hypersensitivity: Angioedema, hypersensitivity reaction Adverse Reactions
(bulla, IgA vasculitis, pruritus, urticaria) >10%:
Neuromuscular & skeletal: Back pain, dyskinesia Cardiovascular: Orthostatic hypotension (enteral sus-
(including choreiform, dystonic, and other involuntary pension: 70% to 73%; oral: 1% to 5%)
movements), leg pain, muscle cramps, muscle twitch- Central nervous system: Dizziness (2% to 19%),
ing, shoulder pain, tremor, weakness headache (oral: 1% to 17%), depression (enteral
Ophthalmic: Blepharospasm, blurred vision, diplopia, suspension: 11%; oral: 1% to 2%)
mydriasis, oculogyric crisis (may be associated with Gastrointestinal: Nausea (enteral suspension: 30%;
acute dystonic reactions) oral: 3% to 20%), constipation (enteral suspension:
Renal: Increased blood urea nitrogen, increased serum 22%; oral: ≤6%)
creatinine Neuromuscular & skeletal: Dyskinesia (2% to 17%),
Respiratory: Cough, dyspnea, hoarseness, upper res- increased creatine phosphokinase (enteral suspen-
piratory tract infection sion: ≤17%)
Mechanism of Action Carbidopa is a peripheral Renal: Increased blood urea nitrogen (enteral suspen-
decarboxylase inhibitor with little or no pharmacological sion: ≤13%)
activity when given alone in usual doses. It inhibits the 1% to 10%:
peripheral decarboxylation of levodopa to dopamine; Cardiovascular: Hypertension (enteral suspension:
and as it does not cross the blood-brain barrier, unlike 8%), peripheral edema (enteral suspension: 8%),
levodopa, effective brain concentrations of dopamine ischemia (oral: ≤2%), chest pain (oral: ≤1%)
are produced with lower doses of levodopa. At the Central nervous system: Insomnia (oral: 1% to 9%),
same time, reduced peripheral formation of dopamine anxiety (2% to 8%), confusion (2% to 8%), abnormal
reduces peripheral side-effects, notably nausea and dreams (oral: ≤6%), polyneuropathy (enteral suspen-
vomiting, and cardiac arrhythmias, although the dyski- sion: 5%), sleep disorder (enteral suspension: 5%),
nesias and adverse mental effects associated with hallucination (≤5%), psychosis (≤5%), dystonia (oral:
levodopa therapy tend to develop earlier. ≤2%), on-off phenomenon (oral: 1% to 2%), pares-
Pregnancy Considerations Adverse events have not thesia (oral: ≤1%)
been observed in animal reproduction studies. Carbi- Dermatologic: Skin rash (enteral suspension: 5%)
dopa can be detected in the umbilical cord but absorp- Endocrine & metabolic: Increased serum glu-
tion in fetal tissue is minimal (Merchant, 1995). The cose (≥1%)
incidence of Parkinson's disease in pregnancy is rela- Gastrointestinal: Xerostomia (oral: 1% to 7%), diar-
tively rare and information related to the use of carbi- rhea (≤5%), dyspepsia (≤5%), vomiting (oral: 2% to
dopa in pregnant women is limited to use with other 5%), anorexia (oral: 1%)
agents. Refer to the carbidopa and levodopa mono- Genitourinary: Bacteriuria (enteral suspension: 5%;
graph for additional information. oral: ≥1%), urinary tract infection (oral: 2%), hema-
turia (oral: ≥1%), urinary frequency (oral: ≤1%)
Hematologic & oncologic: Leukocyturia (enteral sus-
Carbidopa and Levodopa pension: 5%; oral: ≥1%), decreased hematocrit (oral:
(kar bi DOE pa & lee voe DOE pa) ≥1%), decreased hemoglobin (oral: ≥1%)
Related Information Neuromuscular & skeletal: Back pain (oral: ≤2%),
Carbidopa on page 255 muscle cramps (oral: ≤ 1%), s houlder pain
(oral: ≤1%)
Brand Names: US Duopa; Rytary; Sinemet; Sinemet
Respiratory: Atelectasis (enteral suspension: 8%),
CR
oropharyngeal pain (enteral suspension: 8%), upper
Brand Names: Canada Apo-Levocarb; Apo-Levocarb respiratory tract infection (enteral suspension: 8%;
CR; Dom-Levo-Carbidopa; Duodopa; Levocarb CR; oral: 1% to 2%), dyspnea (oral: ≤2%)
PMS-Levocarb CR; PRO-Levocarb; Sinemet; Sinemet Miscellaneous: Fever (enteral suspension: 5%)
CR; Teva-Levocarbidopa <1%, postmarketing, and/or case reports: Abdominal
Pharmacologic Category Anti-Parkinson Agent, distress, abdominal pain, abnormal behavior, abnor-
Decarboxylase Inhibitor; Anti-Parkinson Agent, Dopa- mal gait, abnormality in thinking, agitation, agranulo-
mine Precursor cytosis, alopecia, anemia, angioedema, asthenia,
Use Parkinson disease: Treatment of Parkinson dis- ataxia, blepharospasm, blurred vision, bruxism, bul-
ease, postencephalitic parkinsonism, and symptomatic lous rash (including pemphigus-like reactions), cardiac
parkinsonism that may follow carbon monoxide and/or arrhythmia, common cold, cough, decreased mental
manganese intoxication; treatment of motor fluctuations acuity, decreased serum potassium, delirium, delu-
in advanced Parkinson disease (intestinal suspension sions, dementia, diaphoresis, diplopia, discoloration
[Duopa] only). of saliva, discoloration of sweat, disorientation, drowsi-
Local Anesthetic/Vasoconstrictor Precautions ness, duodenal ulcer, dysgeusia, dysphagia, edema,
No information available to require special precautions euphoria, extrapyramidal reaction, falling, fatigue, flat-
Effects on Dental Treatment Key adverse event(s) ulence, flushing, gastrointestinal hemorrhage, glosso-
related to dental treatment: Xerostomia (normal salivary pyrosis, glycosuria, heartburn, hemolytic anemia,
flow resumes upon discontinuation) and taste altera- Henoch-Schonlein purpura, hiccups, hoarseness,
tions; Dopaminergic therapy in Parkinson's disease (ie, Horner syndrome (reactivation), hot flash, hypoten-
treatment with levodopa and carbidopa combination) is sion, impulse control disorder, increased lactate dehy-
associated with orthostatic hypotension. Patients may drogenase, increased libido (including
experience orthostatic hypotension as they stand up hypersexuality), increased serum alanine aminotrans-
after treatment; especially if lying in dental chair for ferase, increased serum alkaline phosphatase,
256
CARBOPLATIN
increased serum aspartate transaminase, increased Use Allergies: For the symptomatic treatment of sea-
serum bilirubin, increased tremors, increased uric sonal and perennial allergic rhinitis; vasomotor rhinitis;
acid, leukopenia, lower extremity pain, malaise, malig- allergic conjunctivitis caused by inhalant allergens and
nant melanoma, memory impairment, muscle twitch- foods; mild, uncomplicated allergic skin manifestations
ing, mydriasis, myocardial infarction, narcolepsy, of urticaria and angioedema; dermatographism; as
nervousness, neuroleptic malignant syndrome, night- therapy for anaphylactic reactions adjunctive to epi-
mares, numbness, oculogyric crisis, palpitations, para- nephrine and other standard measures after the acute
noia, pathological gambling, peripheral neuropathy, manifestations have been controlled; amelioration of
phlebitis, positive direct Coombs test, priapism, pro- the severity of allergic reactions to blood or plasma.
teinuria, pruritus, seizure, sense of stimulation, sialor- Local Anesthetic/Vasoconstrictor Precautions
rhea, suicidal ideation, suicidal tendencies, syncope, No information available to require special precautions
thrombocytopenia, trismus, urinary incontinence, uri-
nary retention, urine discoloration, urticaria, weight
gain, weight loss
flow resumes upon discontinuation).
Mechanism of Action Parkinson disease symptoms
are due to a lack of striatal dopamine; levodopa circu-
lates in the plasma to the blood-brain-barrier (BBB), require special precautions
where it crosses, to be converted by striatal enzymes Adverse Reactions Frequency not defined.
to dopamine; carbidopa inhibits the peripheral plasma Cardiovascular: Chest tightness, extrasystoles, hypo-
breakdown of levodopa by inhibiting its decarboxyla- tension, palpitations, tachycardia
tion, and thereby increases available levodopa at the Central nervous system: Ataxia (most frequent), chills,
BBB confusion, dizziness (most frequent), drowsiness
Pharmacodynamics/Kinetics (most frequent), euphoria, excitability, fatigue, head-
Half-life Elimination Immediate release: Levodopa ache, hysteria, insomnia, irritability, nervousness, neu-
(in presence of carbidopa): 1.5 hours; Half-life may be ritis, paresthesia, restlessness, sedation (most
prolonged with controlled and extended release for- frequent), seizure, vertigo
mulations due to continuous absorption. Dermatologic: Diaphoresis, skin photosensitivity, skin
Time to Peak Immediate release: 0.5 hours; Con- rash, urticaria
trolled and extended release: 2 hours; Intestinal gel Endocrine & metabolic: Increased uric acid
[Canadian product]: Therapeutic plasma levels Gastrointestinal: Anorexia, constipation, diarrhea, epi-
reached 10 to 30 minutes following morning bolus gastric distress (most frequent), nausea, vomiting,
dose; Intestinal suspension: 2.5 hours xerostomia
Pregnancy Risk Factor C Genitourinary: Difficulty in micturition, early menses,
Pregnancy Considerations Adverse events have urinary frequency, urinary retention
been observed in some animal reproduction studies Hematologic & oncologic: Agranulocytosis, hemolytic
using this combination. Carbidopa can be detected in anemia, thrombocytopenia
the umbilical cord, but absorption in fetal tissue is Hypersensitivity: Anaphylactic shock, hypersensitivity
minimal. Levodopa crosses the placenta and can be reaction
metabolized by the fetus and detected in fetal tissue Neuromuscular & skeletal: Tremor
(Merchant 1995). The incidence of Parkinson disease in Ophthalmic: Blurred vision, diplopia
pregnancy is relatively rare, and information related to Otic: Labyrinthitis, tinnitus
the use of carbidopa/levodopa in pregnant women is Respiratory: Dry nose, dry throat, nasal congestion,
limited (Ball 1995; Cook 1985; Golbe 1987; Serikawa thickening of bronchial secretions (most frequent),
2011; Shulman 2000). Current guidelines note that the wheezing
available information is insufficient to make a recom- Mechanism of Action Carbinoxamine competes with
mendation for the treatment of restless legs syndrome histamine for H1-receptor sites on effector cells in the
in pregnant women (Aurora 2012). gastrointestinal tract, blood vessels, and respiratory
Prescribing and Access Restrictions Duodopa tract.
intestinal gel [Canadian product]: In Canada, the Pharmacodynamics/Kinetics
Duodopa Education Program is a risk mitigation pro- Duration of Action ~4 hours (immediate release)
gram established to provide safe and effective use of Half-life Elimination 17 hours (extended release)
Duodopa in advanced Parkinson patients. The program
Time to Peak Serum: 1.5 to 5 hours
involves:
- Education of prescribing neurologists and other health Pregnancy Risk Factor C
care providers on suitable candidates for treatment, Pregnancy Considerations Animal reproduction
surgical procedures (PEG tube placement), and fol- studies have not been conducted. Maternal antihist-
low-up care including infusion device education. amine use has generally not resulted in an increased
- Distribution of educational materials to patients and risk of birth defects; however, information specific for
caregivers describing Duodopa intestinal gel and its the use of carbinoxamine during pregnancy has not
proper use, PEG tube placement, and complications been located. Although antihistamines are recom-
associated with the mode of administration and/or mended for some indications in pregnant women, the
PEG tube placement. use of other agents with specific pregnancy data may
be preferred.
Carbinoxamine (kar bi NOKS a meen)
CARBOplatin (KAR boe pla tin)
Brand Names: US Arbinoxa [DSC]; Karbinal ER;
RyVent Brand Names: Canada Carboplatin Injection; Carbo-
Pharmacologic Category Ethanolamine Derivative; platin Injection BP
Histamine H1 Antagonist; Histamine H1 Antagonist, Pharmacologic Category Antineoplastic Agent, Alky-
First Generation lating Agent; Antineoplastic Agent, Platinum Analog
257
CARBOPLATIN
Use Ovarian cancer, advanced: Initial treatment of Pregnancy Considerations Adverse events have
advanced ovarian cancer in combination with other been observed in animal reproduction studies. May
established chemotherapy agents; palliative treatment cause fetal harm if administered during pregnancy.
of recurrent ovarian cancer after prior chemotherapy, Women of childbearing potential should avoid becom-
including cisplatin-based treatment ing pregnant during treatment.
Effects on Dental Treatment Key adverse event(s) Cariprazine (kar IP ra zeen)
related to dental treatment: Stomatitis, mucositis, and Brand Names: US Vraylar
taste dysgeusia.
Pharmacologic Category Second Generation (Atyp-
Effects on Bleeding Hemorrhagic complication (ie,
ical) Antipsychotic
bleeding) has been reported in 5% of patients. Throm-
bocytopenia is one of the dose-limiting complications of Use
carboplatin's myelosuppression. A medical consult is Schizophrenia: Treatment of schizophrenia
suggested. Bipolar I disorder, manic or mixed episode: Acute
Adverse Reactions Percentages reported with single- treatment of manic or mixed episodes associated with
agent therapy. bipolar I disorder
>10%: Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Pain (23%) No information available to require special precautions
Endocrine & metabolic: Hyponatremia (29% to 47%), Effects on Dental Treatment
hypomagnesemia (29% to 43%), hypocalcemia Key adverse event(s) related to dental treatment: Tooth-
(22% to 31%), hypokalemia (20% to 28%) ache and xerostomia has been reported
Gastrointestinal: Vomiting (65% to 81%), abdominal Effects on Bleeding No information available to
pain (17%), nausea (without vomiting: 10% to 15%) require special precautions
Hematologic & oncologic: Bone marrow depression Adverse Reactions
(dose related and dose limiting; nadir at ~21 days >10%:
with single-agent therapy), anemia (71% to 90%; Central nervous system: Drug-induced extrapyramidal
grades 3/4: 21%), leukopenia (85%; grades 3/4: reaction (15% to 41%), Parkinsonian-like syndrome
15% to 26%), neutropenia (67%; grades 3/4: 16%
(13% to 21%), akathisia (9% to 20%), headache
to 21%), thrombocytopenia (62%; grades 3/4: 25%
(14%), insomnia (9% to 13%)
to 35%)
Gastrointestinal: Nausea (7% to 13%)
Hepatic: Increased serum alkaline phosphatase (24%
to 37%), increased serum AST (15% to 19%) 1% to 10%:
Hypersensitivity: Hypersensitivity (2% to 16%) Cardiovascular: Hypertension (2% to 5%), tachycar-
Neuromuscular & skeletal: Weakness (11%) dia (2%)
Renal: Decreased creatinine clearance (27%), Central nervous system: Drowsiness (7% to 8%), rest-
increased blood urea nitrogen (14% to 22%) lessness (4% to 7%), dizziness (3% to 7%), anxiety
1% to 10%: (5% to 6%), agitation (5%), dystonia (2% to 5%),
Central nervous system: Peripheral neuropathy (4% to fatigue (3% to 4%), suicidal ideation
6%), neurotoxicity (5%) Dermatologic: Hyperhidrosis
Dermatologic: Alopecia (2% to 3%) Endocrine & metabolic: Weight gain (2% to 8%),
Gastrointestinal: Constipation (6%), diarrhea (6%), hyponatremia
dysgeusia (1%), mucositis (≤1%), stomatitis (≤1%) Gastrointestinal: Vomiting (4% to 10%), constipation
Hematologic & oncologic: Bleeding complications (6% to 7%), dyspepsia (5% to 7%), abdominal pain
(5%), hemorrhage (5%) (6%), diarrhea (4%), toothache (4%), decreased
Hepatic: Increased serum bilirubin (5%) appetite (3%), xerostomia (3%)
Infection: Infection (5%) Genitourinary: Pollakiuria
Ophthalmic: Visual disturbance (1%) Hepatic: Increased serum transaminases (≥3x ULN;
Otic: Ototoxicity (1%) 2% to 4%), increased liver enzymes (1%)
Renal: Increased serum creatinine (6% to 10%) Neuromuscular & skeletal: Increased creatine phos-
<1%, postmarketing, and/or case reports (Limited to phokinase (2% to 6%), limb pain (4%), back pain
important or life-threatening): Anaphylaxis, anorexia, (3%), muscle rigidity (2% to 3%), arthralgia (2%)
bronchospasm, cardiac failure, cerebrovascular acci- Ophthalmic: Blurred vision (4%)
dent, dehydration, embolism, erythema, febrile neu-
<1%, postmarketing, and/or case reports: Cerebro-
tropenia, hemolytic anemia (acute), hemolytic-uremic
vascular accident, dysphagia, gastritis, gastroeso-
syndrome, hypertension, hypotension, injection site
phageal reflux disease, hepatitis, leukopenia,
reaction (pain, redness, swelling), limb ischemia
neutropenia, rhabdomyolysis, Stevens-Johnson syn-
(acute), malaise, metastases, pruritus, skin rash, tis-
sue necrosis (associated with extravasation), urticaria, drome
vision loss Mechanism of Action Cariprazine is a second gen-
Mechanism of Action Carboplatin is a platinum com- eration antipsychotic which displays partial agonist
pound alkylating agent which covalently binds to DNA; activity at dopamine D2 and serotonin 5-HT1A receptors
interferes with the function of DNA by producing inter- and antagonist activity at serotonin 5-HT2A receptors. It
strand DNA cross-links. Carboplatin is apparently not exhibits high affinity for dopamine (D2 and D3) and
cell-cycle specific. serotonin (5-HT1A) receptors and has low affinity for
Pharmacodynamics/Kinetics serotonin 5-HT2C and alpha1A-adrenergic receptors.
Half-life Elimination CrCl >60 mL/minute: Carbopla- Cariprazine functions as an antagonist for 5-HT2B (high
tin: 2.6 to 5.9 hours (based on a dose of 300 to affinity) and 5-HT2A receptors (moderate affinity), binds
500 mg/m2); Platinum (from carboplatin): ≥5 days to histamine H 1 receptors, and has no affinity for
Pregnancy Risk Factor D muscarinic (cholinergic) receptors.
258
CARVEDILOL
Pharmacodynamics/Kinetics rash, syncope, tachycardia, transient flushing of face,

Half-life Elimination Cariprazine: 2 to 4 days; DCAR: tremor, urticaria, vertigo, vomiting, weakness, with-
1 to 2 days; DDCAR: 1 to 3 weeks drawal syndrome (abdominal cramps, headache,
Time to Peak Plasma: Cariprazine: 3 to 6 hours insomnia, nausea, seizure)
Pregnancy Considerations Antipsychotic use during Mechanism of Action Precise mechanism is not yet
the third trimester of pregnancy has a risk for abnormal clear, but many effects have been ascribed to its central
muscle movements (extrapyramidal symptoms [EPS]) depressant actions. In animals, carisoprodol blocks
and/or withdrawal symptoms in newborns following interneuronal activity and depresses polysynaptic neu-
delivery. Symptoms in the newborn may include agita- ron transmission in the spinal cord and reticular for-
tion, feeding disorder, hypertonia, hypotonia, respiratory mation of the brain. It is also metabolized to
distress, somnolence, and tremor; these effects may be meprobamate, which has anxiolytic and sedative
self-limiting or require hospitalization. effects.
The ACOG recommends that therapy during pregnancy Onset of Action Rapid
be individualized; treatment with psychiatric medica- Duration of Action 4 to 6 hours
tions during pregnancy should incorporate the clinical
Half-life Elimination Carisoprodol: ~2 hours; Mepro-
expertise of the mental health clinician, obstetrician,
bamate: ~10 hours
primary health care provider, and pediatrician. Safety
Time to Peak Plasma: 1.5 to 2 hours
data related to atypical antipsychotics during pregnancy
are limited and routine use is not recommended. How- Pregnancy Considerations Postmarketing data with
ever, if a woman is inadvertently exposed to an atypical meprobamate (the active metabolite) do not show a
antipsychotic while pregnant, continuing therapy may consistent association between maternal use and an
be preferable to switching to a typical antipsychotic that increased risk or pattern of major congenital malforma-
the fetus has not yet been exposed to; consider risk: tions. In one study, maternal use did not adversely
benefit (ACOG 2008). affect mental or motor development, or IQ scores in
children exposed in utero.
Health care providers are encouraged to enroll women Controlled Substance C-IV
exposed to cariprazine during pregnancy in the National
Pregnancy Registry for Atypical Antipsychotics
(866-961-2388 or http://www.womensmentalhealth.org/ Carvedilol (KAR ve dil ole)
clinical-and-research-programs/pregnancyregistry/). Related Information
Carisoprodol (kar eye soe PROE dole) Brand Names: US Coreg; Coreg CR
Brand Names: Canada Apo-Carvedilol; Auro-Carve-
Brand Names: US Soma dilol; Dom-Carvedilol; JAMP-Carvedilol; Mylan-Carvedi-
Pharmacologic Category Skeletal Muscle Relaxant lol; Novo-Carvedilol; PMS-Carvedilol; RAN-Carvedilol;
Use ratio-Carvedilol
Musculoskeletal conditions: Short-term (2 to 3 Pharmacologic Category Antihypertensive; Beta-
weeks) treatment of discomfort associated with acute Blocker With Alpha-Blocking Activity
painful musculoskeletal conditions. Use
Limitations of use: Carisoprodol should only be used for Heart failure with reduced ejection fraction (HFrEF):
short periods (up to 2 or 3 weeks); adequate evidence Mild to severe chronic heart failure of ischemic or
of effectiveness for more prolonged use has not been cardiomyopathic origin.
established and acute, painful musculoskeletal con- Hypertension: Management of hypertension. Note:
ditions are generally of short duration. Beta-blockers are not recommended as first-line ther-
Local Anesthetic/Vasoconstrictor Precautions apy (ACC/AHA [Whelton 2017]).
No information available to require special precautions Left ventricular dysfunction following MI: Left ven-
Effects on Dental Treatment No significant effects or tricular dysfunction following MI (clinically stable with
complications reported LVEF ≤40%)
require special precautions Carvedilol is a nonselective beta-blocker, but also has
Adverse Reactions alpha-adrenergic blocking actions. No intrinsic sympa-
>10%: Central nervous system: Drowsiness (13% to thomimetic activity has been documented for carvedilol.
17%) Unlike other nonselective beta-blockers such as pro-
1% to 10%: Central nervous system: Dizziness (7% to pranolol, with which epinephrine has interacted with to
8%), headache (3% to 5%) result in initial hypertensive episode followed by tachy-
Postmarketing and/or case reports: Abdominal cramps, cardia, any interaction with carvedilol and vasoconstric-
agitation, allergic dermatitis, anaphylaxis, angioe- tor to result in hypertensive episode would not be
dema, ataxia, burning sensation of eyes, depression, expected. There is no information available to require
drug dependence, dyspnea, epigastric pain, eosino- special precautions.
philia, erythema multiforme, exacerbation of asthma, Effects on Dental Treatment Key adverse event(s)
fixed drug eruption, hallucination, headache, hiccups, related to dental treatment: Patients may experience
hypersensitivity reaction, idiosyncratic reaction (symp- orthostatic hypotension as they stand up after treat-
toms may include agitation, ataxia, confusion, diplo- ment; especially if lying in dental chair for extended
pia, disorientation, dysarthria, euphoria, extreme periods of time. Use caution with sudden changes in
weakness, muscle twitching, mydriasis, temporary position during and after dental treatment. Periodontitis
vision loss, and/or transient quadriplegia); insomnia, has been reported in product labeling for carvedilol; no
irritability, leukopenia, nausea, orthostatic hypoten- other reports have confirmed this effect; any possible
sion, pancytopenia, paradoxical central nervous sys- mechanism for this effect is unknown. Many nonster-
tem stimulation, pruritus, psychosis, seizure, skin oidal anti-inflammatory drugs, such as ibuprofen and
259
CARVEDILOL
indomethacin, can reduce the hypotensive effect of Ophthalmic: Visual disturbance (5%), blurred vision
beta-blockers after 3 or more weeks of therapy with (>1% to ≤3%)
the NSAID. Short-term NSAID use (ie, 3 days) requires Otic: Tinnitus (≤1%)
no special precautions in patients taking beta-blockers. Renal: Increased blood urea nitrogen (≤6%),
Effects on Bleeding No information available to increased serum creatinine (>1% to ≤3%), renal
require special precautions insufficiency (>1% to ≤3%)
Adverse Reactions Respiratory: Increased cough (5%), nasopharyngitis
>10%: (4%), rales (4%), dyspnea (>3%), flu-like symptoms
Cardiovascular: Hypotension (≤20%), orthostatic (>1% to ≤3%), nasal congestion (1%), paranasal
hypotension (≤20%) sinus congestion (1%), asthma (≤1%)
Central nervous system: Dizziness (2% to 32%), Miscellaneous: Fever (>1% to ≤3%)
fatigue (24%) Frequency not defined:
Endocrine & metabolic: Weight gain (10% to 12%), Hematologic & oncologic: Anemia
hyperglycemia (5% to 12%) Respiratory: Pulmonary edema
Gastrointestinal: Diarrhea (1% to 12%) <1%, postmarketing, and/or case reports: Abnormal
Neuromuscular & skeletal: Asthenia (11%) lymphocytes, alopecia, anaphylactoid shock, anaphy-
1% to 10%: laxis, angioedema, aplastic anemia, amnesia, auditory
Cardiovascular: Bradycardia (≤10%), syncope (≤8%), impairment, bronchospasm, bundle branch block, cer-
peripheral edema (1% to 7%), angina pectoris (6%), ebrovascular disease, complete atrioventricular block,
edema (5% to 6%), atrioventricular block (>1% to decreased HDL cholesterol, erythema multiforme,
≤3%), cerebrovascular accident (>1% to ≤3%), exac- exfoliative dermatitis, gastrointestinal hemorrhage,
erbation of angina pectoris (>1% to ≤3%), hyper- interstitial pneumonitis, ischemic heart disease,
tension (>1% to ≤3%), lower extremity edema (>1% migraine, neuralgia, pancytopenia, paresis, respira-
to ≤3%), palpitations (>1% to ≤3%), peripheral vas- tory alkalosis, seizure, Stevens-Johnson syndrome,
cular disease (>1% to ≤3%), peripheral ischemia toxic epidermal necrolysis, urinary incontinence
(≤1%), tachycardia (≤1%) Mechanism of Action As a racemic mixture, carvedilol
Central nervous system: Headache (5% to 8%), has nonselective beta-adrenoreceptor and alpha-adre-
depression (>1% to ≤3%), drowsiness (>1% to nergic blocking activity. No intrinsic sympathomimetic
≤3%), hypoesthesia (>1% to ≤3%), hypotonia (>1% activity has been documented. Associated effects in
to ≤3%), malaise (>1% to ≤3%), vertigo (>1% to hypertensive patients include reduction of cardiac out-
≤3%), paresthesia (1% to ≤3%), insomnia (1% to put, exercise- or beta-agonist-induced tachycardia,
2%), abnormality in thinking (≤1%), emotional lability reduction of reflex orthostatic tachycardia, vasodilation,
(≤1%), exacerbation of depression (≤1%), lack of decreased peripheral vascular resistance (especially in
concentration (≤1%), nervousness (≤1%), night- standing position), decreased renal vascular resistance,
mares (≤1%), sleep disorder (≤1%) reduced plasma renin activity, and increased levels of
Dermatologic: Diaphoresis (≤1%), erythematous rash atrial natriuretic peptide. In CHF, associated effects
(≤1%), maculopapular rash (≤1%), pruritus (≤1%), include decreased pulmonary capillary wedge pressure,
psoriasiform eruption (≤1%), skin photosensitiv- decreased pulmonary artery pressure, decreased heart
ity (≤1%) rate, decreased systemic vascular resistance,
Endocrine & metabolic: Increased nonprotein nitrogen increased stroke volume index, and decreased right
(6%), dependent edema (4%), hypercholesterolemia atrial pressure (RAP).
(4%), albuminuria (>1% to ≤3%), diabetes mellitus Pharmacodynamics/Kinetics
(>1% to ≤3%), glycosuria (>1% to ≤3%), gout (>1% Onset of Action Antihypertensive effect: Alpha-block-
to ≤3%), hyperkalemia (>1% to ≤3%), hyperuricemia ade: Within 30 minutes; Beta-blockade: Within 1 hour.
(>1% to ≤3%), hypervolemia (>1% to ≤3%), hypo- Peak antihypertensive effect: ~1 to 2 hours
glycemia (>1% to ≤3%), hyponatremia (>1% to ≤3%), Half-life Elimination
hypovolemia (>1% to ≤3%), impotence (>1% to Infants and Children 6 weeks to 3.5 years (n=8): 2.2
≤3%), increased gamma-glutamyl transferase (>1% hours (Laer 2002)
to ≤3%), weight loss (>1% to ≤3%), decreased libido Children and Adolescents 5.5 to 19 years (n=7): 3.6
(≤1%), hypertriglyceridemia (≤1%), hypokale- hours (Laer 2002)
mia (≤1%) Adults 7 to 10 hours; some have reported lower
Gastrointestinal: Nausea (2% to 9%), vomiting (6%), values: Adults 24 to 37 years (n=9): 5.2 hours (Laer
melena (>1% to ≤3%), periodontitis (>1% to ≤3%), 2002)
gastrointestinal pain (1% to ≤3%), xerostomia (≤1%) R(+)-carvedilol: 5 to 9 hours
Genitourinary: Hematuria (>1% to ≤3%), urinary fre- S(-)-carvedilol: 7 to 11 hours
quency (≤1%) Time to Peak Extended release: ~5 hours
Hematologic & oncologic: Hypoprothrombinemia Pregnancy Considerations Adverse events have
(>1% to ≤3%), nonthrombocytopenic purpura (>1% been observed in animal reproduction studies. Adverse
to ≤3%), thrombocytopenia (1% to ≤3%), leukope- events, such as fetal/neonatal bradycardia, hypoglyce-
nia (≤1%) mia, and reduced birth weight, have been observed
Hepatic: Increased serum alanine aminotransferase following in utero exposure to beta-blockers as a class.
(>1% to ≤3%), increased serum alkaline phospha- Adequate facilities for monitoring infants at birth is
tase (>1% to ≤3%), increased serum aspartate ami-
generally recommended.
notransferase (>1% to ≤3%), hyperbilirubinemia
(≤1%), increased liver enzymes (≤1%) Untreated chronic maternal hypertension and pree-
Hypersensitivity: Hypersensitivity reaction (>1% clampsia are also associated with adverse events in
to ≤3%) the fetus, infant, and mother (ACOG 2015; Magee
Neuromuscular & skeletal: Arthralgia (6%), arthritis 2014). Although beta-blockers may be used when treat-
(>1% to ≤3%), muscle cramps (>1% to ≤3%), hypo- ment of hypertension or heart failure in pregnancy is
kinesia (≤1%) indicated, agents other than carvedilol are preferred
260
CASPOFUNGIN
( A C O G 2 0 1 3 ; E S C [ R e g i t z - Z a g r o s e k 2 0 11 ] ; 1% to 10%:
Magee 2014). Cardiovascular: Hypertension (5% to 9%), atrial fibril-
lation (<5%), bradycardia (<5%), cardiac arrhythmia
(<5%), edema (<5%), flushing (<5%), myocardial
Caspofungin (kas poe FUN jin)
infarction (<5%)
Related Information Central nervous system: Anxiety (<5%), confusion
Fungal Infections on page 1538 (<5%), depression (<5%), dizziness (<5%), drowsi-
Brand Names: US Cancidas ness (<5%), fatigue (<5%), insomnia (<5%), seiz-
Brand Names: Canada Cancidas ure (<5%)
Dermatologic: Erythema (5% to 9%), pruritus (infants,
Pharmacologic Category Antifungal Agent, Paren-
children, and adolescents: 6%), skin lesion (<5%),
teral; Echinocandin
urticaria (<5%), decubitus ulcer (adults: 3% to 5%)
Use
Endocrine & metabolic: Hypomagnesemia (adults:
Aspergillosis, invasive: Treatment of invasive asper-
7%), hyperglycemia (adults: 6%), hypokalemia (5%
gillosis in patients ≥3 months of age who are refractory
to 6%), hypercalcemia (<5%), hypervolemia (<5%)
to or intolerant of other therapies (eg, amphotericin B,
Gastrointestinal: Abdominal pain (4% to 9%), mucosal
lipid formulations of amphotericin B, itraconazole).
inflammation (4% to 6%), abdominal distention
Limitations of use: Has not been studied as initial
(<5%), anorexia (<5%), constipation (<5%),
therapy for invasive aspergillosis.
decreased appetite (<5%), dyspepsia (<5%), upper
Candidemia and other Candida infections: Treat-
abdominal pain (<5%)
ment of candidemia and the following candida infec-
Genitourinary: Urinary tract infection (<5%), nephro-
tions in patients ≥3 months of age: Intra-abdominal
toxicity (adults: 3%; serum creatinine ≥2 x baseline
abscesses, peritonitis, and pleural space infections.
value or ≥1 mg/dL in patients with serum creatinine
Limitations of use: Has not been studied in endocardi-
above ULN range)
tis, osteomyelitis, and meningitis due to Candida.
Hematologic & oncologic: Blood coagulation disorder
Candidiasis, esophageal: Treatment of esophageal
(<5%), febrile neutropenia (<5%), neutropenia
candidiasis in patients ≥3 months of age.
(<5%), petechia (<5%), thrombocytopenia (<5%)
Limitations of use: Not approved for the treatment of
Hepatic: Decreased serum albumin (adults: 7%), hep-
oropharyngeal candidiasis (OPC).
atic failure (<5%), hepatomegaly (<5%), hepatotox-
Fungal infections, empiric therapy (neutropenic
icity (<5%), hyperbilirubinemia (<5%),
patients): Empiric therapy for presumed fungal infec-
jaundice (<5%)
tions in febrile, neutropenic patients ≥3 months of age.
Infection: Sepsis (adults: 5% to 7%), bactere-
mia (<5%)
Local: Catheter infection (infants, children, and ado-
Effects on Dental Treatment No significant effects or lescents: 9%), infusion site reaction (<5%; pain/pru-
complications reported ritus/swelling)
Effects on Bleeding No information available to Neuromuscular & skeletal: Arthralgia (<5%), back pain
require special precautions (<5%), limb pain (<5%), tremor (<5%), weak-
Adverse Reactions ness (<5%)
>10%: Renal: Hematuria (adults: 10%), increased blood urea
Cardiovascular: Hypotension (adults: 3% to 20%; nitrogen (adults: 4% to 9%), renal failure (<5%)
infants, children, and adolescents: 9%), peripheral Respiratory: Dyspnea (adults: 9%), pleural effusion
edema (adults: 6% to 11%), tachycardia (7% to 11%) (adults: 9%), respiratory distress (adults: ≤8%), rales
Central nervous system: Chills (adults: 9% to 23%; (adults: 7%), epistaxis (<5%), hypoxia (<5%),
infants, children, and adolescents: 13%), headache tachypnea (<5%)
(9% to 15%) <1%, postmarketing, and/or case reports: Anaphylaxis,
Dermatologic: Skin rash (4% to 23%) erythema multiforme, exfoliation of skin, hepatic
Gastrointestinal: Diarrhea (adults: 6% to 27%; infants, necrosis, hepatitis, histamine release (including facial
children, and adolescents: 7%), vomiting (6% to swelling, bronchospasm, sensation of warmth),
17%), nausea (adults: 5% to 15%; infants, children, increased gamma-glutamyl transferase, pancreatitis,
and adolescents: 4%) renal insufficiency, Stevens-Johnson syndrome, swel-
Hematologic & oncologic: Decreased hemoglobin ling, toxic epidermal necrolysis
(adults: 18% to 21%), decreased hematocrit (adults: Mechanism of Action Inhibits synthesis of β(1,3)-D-
13% to 18%), decreased white blood cell count glucan, an essential component of the cell wall of
(adults: 12%), anemia (adults: 11%) susceptible fungi. Highest activity is in regions of active
Hepatic: Increased serum alkaline phosphatase cell growth. Mammalian cells do not require β(1,3)-D-
(adults: 9% to 22%), increased serum ALT (adults: glucan, limiting potential toxicity.
4% to 18%; infants, children, and adolescents: 5%), Pharmacodynamics/Kinetics
increased serum AST (adults: 6% to 16%; infants, Half-life Elimination Beta (distribution): 9 to 11 hours
children, and adolescents: 2%), increased serum (~8 hours in children <12 years); Terminal: 40 to 50
bilirubin (adults: 5% to 13%) hours; beta phase half-life is 32% to 43% lower in
Local: Localized phlebitis (adults: 18%) pediatric patients than in adult patients
Renal: Increased serum creatinine (adults: 3% to 11%)
Respiratory: Respiratory failure (adults: 2% to 20%),
Based on the mechanism of action, in utero exposure to
cough (adults: 6% to 11%), pneumonia (adults: 4%
caspofungin may cause fetal harm.
to 11%)
Miscellaneous: Infusion related reaction (20% to When treatment of invasive Aspergillus or Candida
35%), fever (6% to 30%), septic shock (adults: 11% infections is needed during pregnancy, other agents
to 14%) are preferred (HHS [adult] 2017; IDSA [Pappas 2016]).
261
CEFACLOR
neutropenia, paresthesia, prolonged prothrombin

Cefaclor (SEF a klor) time, pruritus, pseudomembranous colitis, seizure,
serum sickness, Stevens-Johnson syndrome, throm-
Related Information bocytopenia, toxic epidermal necrolysis, urticaria,
Antibiotic Prophylaxis on page 1502 vomiting
Bacterial Infections on page 1525 Dental Usual Dosage Orofacial infections: Adults:
Brand Names: Canada Apo-Cefaclor; Ceclor; Novo- Oral: Dosing range: 250-500 mg every 8 hours
Cefaclor; Nu-Cefaclor; PMS-Cefaclor Dosing
Generic Availability (US) Yes Adult & Geriatric
Pharmacologic Category Antibiotic, Cephalosporin Treatment of susceptible infections: Oral:
(Second Generation) Immediate-release: 250 to 500 mg every 8 hours
Dental Use Alternative antibiotic for treatment of orofa- Extended-release: 500 mg every 12 hours
cial infections in patients allergic to penicillins; suscep-
tible bacteria including aerobic gram-positive bacteria Indication-specific dosing: Note: An extended-
and anaerobes release tablet dose of 500 mg twice daily is clinically
equivalent to an immediate-release capsule dose of
Use
250 mg 3 times daily; an extended-release tablet
Acute bacterial exacerbations of chronic bronchitis
dose of 500 mg twice daily is NOT clinically equiv-
(extended-release tablets only): Treatment of acute
alent to 500 mg 3 times daily of other cefaclor
bacterial exacerbations of chronic bronchitis due to
formulations.
Haemophilus influenzae (excluding beta-lactamase-
Acute bacterial exacerbations of chronic bron-
negative, ampicillin-resistant strains only), Moraxella
catarrhalis, or Streptococcus pneumoniae. chitis: Oral: Extended-release: 500 mg every 12
Lower respiratory tract infections (capsules and hours for 7 days
oral suspension only): Treatment of lower respira- Secondary bacterial infection of acute bronchi-
tory tract infections, including pneumonia, caused by tis: Oral: Extended-release: 500 mg every 12 hours
S. pneumoniae, H. influenzae, and Streptococcus for 7 days
pyogenes. Renal Impairment: Adult
Otitis media (capsules and oral suspension only): Manufacturer’s labeling:
Treatment of otitis media caused by S. pneumoniae, Oral, immediate-release: There are no dosage
H. influenzae, staphylococci, and S. pyogenes. adjustments provided in the manufacturer's label-
Pharyngitis and tonsillitis: Treatment of pharyngitis ing; however, half-life is increased in anuric
and tonsillitis due to S. pyogenes. patients; use with caution.
Secondary bacterial infections of acute bronchitis Oral, extended-release: There are no dosage adjust-
(extended-release tablets only): Treatment of sec- ments provided in the manufacturer’s labeling.
ondary bacterial infections of acute bronchitis due to Dialysis: Moderately dialyzable (20% to 50%)
H. influenzae (excluding beta-lactamase negative, Alternative recommendations (off-label dosing)
ampicillin-resistant strains), M. catarrhalis, or S. pneu- (Aronoff 2007):
moniae. Oral, immediate-release:
Skin and skin structure infections, uncomplicated: Mild to severe impairment: No dosage adjustment
Treatment of uncomplicated skin and skin structure necessary.
infections due to Staphylococcus aureus (methicillin- End-stage renal disease (ESRD) on intermittent
susceptible) or S. pyogenes (capsules and oral sus- hemodialysis (IHD) (administer after hemodialysis
pension only). on dialysis days): Supplement with 250 to 500 mg
Urinary tract infections (capsules and oral suspen- after dialysis.
sion only): Treatment of urinary tract infections, Peritoneal dialysis: Administer 250 to 500 mg every
including pyelonephritis and cystitis, caused by 8 hours.
Escherichia coli, Proteus mirabilis, Klebsiella spp, Hepatic Impairment: Adult There are no dosage
and coagulase-negative staphylococci. adjustments provided in the manufacturer’s labeling.
Local Anesthetic/Vasoconstrictor Precautions Pediatric
No information available to require special precautions General dosing, susceptible infection: Mild to
Effects on Dental Treatment No significant effects or moderate infection: Infants, Children, and Adoles-
complications reported (see Dental Health Professional cents: Oral, immediate release: 20 to 40 mg/kg/day
Considerations) divided every 8 to 12 hours. Maximum daily dose:
Effects on Bleeding No information available to 1,500 mg/day (Red Book [AAP 2015])
require special precautions Bronchitis: Adolescents ≥16 years: Extended
Adverse Reactions release tablet: Note: An extended release tablet
1% to 10%: dose of 500 mg twice daily is clinically equivalent to
Dermatologic: Rash (1% to 2%; includes erythema- an immediate release capsule dose of 250 mg 3
tous rash, maculopapular rash, or morbilliform rash) times daily; an extended release tablet dose of
Gastrointestinal: Diarrhea (3%) 500 mg twice daily is NOT clinically equivalent to
Genitourinary: Vaginitis (2%), vulvovaginal candidia- 500 mg 3 times daily of other cefaclor formulations.
sis (2%) Acute bacterial exacerbations of chronic bronchitis:
Hematologic & oncologic: Eosinophilia (2%) Oral: Extended release: 500 mg every 12 hours
Hepatic: Increased serum transaminases (3%) for 7 days
<1%, postmarketing, and/or case reports: Agitation, Secondary bacterial infection of acute bronchitis:
agranulocytosis, anaphylaxis, angioedema, aplastic Oral: Extended release: 500 mg every 12 hours
anemia, arthralgia, cholestatic jaundice, confusion, for 7 days
dizziness, drowsiness, hallucination, hemolytic ane- Lower respiratory tract infections: Infants, Chil-
mia, hepatitis, hyperactivity, insomnia, interstitial dren, and Adolescents: Oral immediate release:
n e p h r i t i s , i r r i t a b i l i t y, n a u s e a , n e r v o u s n e s s , 20 to 40 mg/kg/day divided every 8 hours;
262
CEFACLOR
maximum daily dose: 1,000 mg/day. If beta-hemo- Contraindications Hypersensitivity to cefaclor, any
lytic streptococcus/S. pyogenes suspected, treat for component of the formulation, or other cephalosporins
at least 10 days. Warnings/Precautions Anaphylactic reactions have
Otitis media: Infants, Children, and Adolescents: occurred. If a serious hypersensitivity reaction occurs,
Oral immediate release: 40 mg/kg/day divided discontinue and institute emergency supportive meas-
every 8 to 12 hours (oral suspension) or every 8 ures, including airway management and treatment (eg,
hours (capsule); maximum daily dose: 1,000 mg/ epinephrine, antihistamines and/or corticosteroids).
day. If beta-hemolytic streptococcus/S. pyogenes Use with caution in patients with a history of gastro-
suspected, treat for at least 10 days. Note: Cefaclor intestinal disease, particularly colitis. Use with caution
is not a recommended treatment option in the AAP in patients with renal impairment. Prolonged use may
guidelines (Lieberthal 2013). result in fungal or bacterial superinfection, including C.
Pharyngitis/tonsillitis: Infants, Children, and Ado- difficile-associated diarrhea (CDAD) and pseudomem-
lescents: Oral immediate release: 20 mg/kg/day branous colitis; CDAD has been observed >2 months
divided every 8 to 12 hours (oral suspension) or postantibiotic treatment. Use with caution in patients
every 8 hours (capsule); maximum daily dose: with a history of penicillin allergy. An extended-release
1,000 mg/day. If beta-hemolytic streptococcus/S. tablet dose of 500 mg twice daily is clinically equivalent
pyogenes confirmed, treat for at least 10 days. to an immediate-release capsule dose of 250 mg 3
Note: Cefaclor is not a recommended treatment times daily; an extended-release tablet dose of
option in the IDSA guidelines and is not considered 500 mg twice daily is NOT clinically equivalent to
preferred by the AHA due to its broad spectrum 500 mg 3 times daily of other cefaclor formulations.
(AHA [Gerber 2009], IDSA [Shulman 2012]). Potentially significant interactions may exist, requiring
Skin and skin structure infections, uncompli- dose or frequency adjustment, additional monitoring,
cated: Infants, Children, and Adolescents: Oral: and/or selection of alternative therapy.
Immediate release: 20 to 40 mg/kg/day divided
every 8 hours; maximum daily dose: 1,000 mg/
day. If due to beta-hemolytic streptococcus/S. pyo-
genes, treat for at least 10 days.
amounts of benzyl alcohol (≥99 mg/kg/day) have been
Urinary tract infections: Infants, Children, and Ado-
associated with a potentially fatal toxicity ("gasping
lescents: Oral: Immediate release: 20 to 40 mg/kg/
syndrome") in neonates; the "gasping syndrome" con-
day divided every 8 hours; maximum daily dose:
sists of metabolic acidosis, respiratory distress, gasping
1,000 mg/day
respirations, CNS dysfunction (including convulsions,
Renal Impairment: Pediatric intracranial hemorrhage), hypotension, and cardiovas-
Manufacturer's labeling: cular collapse (AAP ["Inactive" 1997]; CDC, 1982);
Oral, immediate release: Infants, Children, and some data suggests that benzoate displaces bilirubin
Adolescents: There are no dosage adjustments from protein binding sites (Ahlfors, 2001); avoid or use
provided in the manufacturer's labeling; however, dosage forms containing benzyl alcohol derivative with
half-life is increased in anuric patients; use with caution in neonates. See manufacturer’s labeling.
caution. Warnings: Additional Pediatric Considerations
Oral, extended release: There are no dosage May cause serum sickness-like reaction (estimated
adjustments provided in the manufacturer's incidence ranges from 0.024% to 0.2% per drug
labeling. course); majority of reactions have occurred in children
Alternative recommendations (Aronoff 2007): Dosing <5 years of age with symptoms of fever, rash, erythema
based on usual dose of 20 to 40 mg/kg/day in multiforme, and arthralgia, often occurring during the
divided doses every 8 to 12 hours second or third exposure.
Infants, Children, and Adolescents: Oral, immediate Drug Interactions
release: Metabolism/Transport Effects Substrate of OAT3
GFR ≥10 mL/minute/1.73 m2: No dosage adjust-
ment necessary.
Avoid concomitant use of Cefaclor with any of the
GFR <10 mL/minute/1.73 m2: Administer 50% of
following: BCG (Intravesical); Cholera Vaccine
the recommended dose.
Increased Effect/Toxicity
End-stage renal disease (ERD) on intermittent
Cefaclor may increase the levels/effects of: Amino-
hemodialysis (IHD) (supplemental dose posthe-
glycosides; Vitamin K Antagonists
modialysis needed): Administer 50% of the rec-
ommended dose. The levels/effects of Cefaclor may be increased by:
Peritoneal dialysis: Administer 50% of the recom- Probenecid; Teriflunomide; Tolvaptan
mended dose. Decreased Effect
Hemodialysis: Hemodialysis shortens half-life by Cefaclor may decrease the levels/effects of: BCG
25% to 35% (Intravesical); BCG Vaccine (Immunization); Cholera
Moderately dialyzable (20% to 50%) (Aronoff 2007) Vaccine; Lactobacillus and Estriol; Sodium Picosul-
Hepatic Impairment: Pediatric There are no dos- fate; Typhoid Vaccine
age adjustments provided in the manufacturer's label- Food Interactions The bioavailability of cefaclor
ing. extended-release tablets is decreased 23% and the
Mechanism of Action Inhibits bacterial cell wall syn- maximum concentration is decreased 67% when taken
thesis by binding to one or more of the penicillin-binding on an empty stomach. Management: Administer with
proteins (PBPs), which in turn inhibits the final trans- food.
peptidation step of peptidoglycan synthesis in bacterial Dietary Considerations Extended release tablets
cell walls, thus inhibiting cell wall biosynthesis. Bacteria should be taken with or within 1 hour of food.
eventually lyse due to ongoing activity of cell wall Pharmacodynamics/Kinetics
autolytic enzymes (autolysins and murein hydrolases) Half-life Elimination 0.6 to 0.9 hours; prolonged with
while cell wall assembly is arrested. renal impairment (2.3 to 2.8 hours in anuria)
263
CEFACLOR
Time to Peak Capsules, oral suspension: 30 to 60 candidiasis, hepatic failure, increased serum trans-
minutes; Extended-release tablets: 2.5 hours aminases, maculopapular rash, nausea, neutropenia,
Pregnancy Risk Factor B pruritus, pseudomembranous colitis, serum sickness,
Pregnancy Considerations Adverse events were not Stevens-Johnson syndrome, thrombocytopenia, urti-
observed in animal reproduction studies. An increased caria, vaginitis, vomiting
risk of teratogenic effects has not been observed follow- Dental Usual Dosage Orofacial infections: Oral:
ing maternal use of cefaclor. Adults: Dosage range: 250-500 mg every 8 hours
Breastfeeding Considerations Small amounts of Dosing
cefaclor are excreted in breast milk. The manufacturer Adult & Geriatric
recommends that caution be exercised when adminis- Prosthetic joint infection, staphylococci (oxacillin-
tering cefaclor to nursing women. Nondose-related susceptible), chronic oral antimicrobial suppres-
effects could include modification of bowel flora. sion (off-label use): 500 mg every 12 hours
Dosage Forms: US (Osmon 2013)
Capsule, Oral: Skin and skin structure infections: Oral: 1 g daily in
Generic: 250 mg, 500 mg a single or 2 divided doses
Suspension Reconstituted, Oral: Streptococcal pharyngitis (group A) (alternative
Generic: 125 mg/5 mL (150 mL); 250 mg/5 mL (150 agent for mild [non-anaphylactic] penicillin
mL); 375 mg/5 mL (100 mL) allergy): Oral: 1 g once daily for 10 days (IDSA
Tablet Extended Release 12 Hour, Oral: [Shulman 2012]; Pichichero 2018; manufacturer’s
Generic: 500 mg labeling)
Dental Health Professional Considerations Cefa- Manufacturer’s labeling: Dosing in the prescribing
clor is effective against anaerobic bacteria, but the information may not reflect current clinical practice.
sensitivity of alpha-hemolytic Streptococcus vary; 500 mg twice daily
approximately 10% of strains are resistant. Nearly Urinary tract infection (UTI) (alternative agent):
70% are intermediately sensitive. Patients allergic to Note: Use with caution and only when recom-
penicillins can use a cephalosporin; the incidence of
mended agents cannot be used (due to decreased
cross-reactivity between penicillins and cephalosporins
efficacy of oral beta-lactams compared to other
is 1% to 5% when the allergic reaction to penicillin is
agents) (Hooton 2018a; ESMID/IDSA [Gupta
delayed. If the patient has a history of anaphylaxis to
2011]; Greenberg 1986; Sandberg 1990).
penicillin, cephalosporins are contraindicated in these
patients. Cystitis, acute uncomplicated: Oral: 500 mg twice
daily (Greenberg 1986; Hooton 1995) for 5 to 7
days (Greenberg 1986; Hooton 2018a)
Cefadroxil (sef a DROKS il) UTI, complicated (including pyelonephritis): Oral:
1 g twice daily (Sandberg 1990) for 10 to 14 days
Related Information (Hooton 2018b; Sandberg 1990). Note: Oral ther-
Antibiotic Prophylaxis on page 1502 apy should follow appropriate parenteral therapy.
Bacterial Infections on page 1525 For outpatient treatment of mild infection, a single
Brand Names: Canada Apo-Cefadroxil; PRO-Cefa- dose of a long-acting parenteral agent is accept-
droxil; Teva-Cefadroxil able; for outpatients who are more ill or are at risk
Generic Availability (US) Yes for more severe illness, consider continuing paren-
Pharmacologic Category Antibiotic, Cephalosporin teral therapy until culture and susceptibility results
(First Generation) are available (ESMID/IDSA [Gupta 2011]; Hooton
Dental Use Alternative antibiotic for treatment of orofa- 2018b).
cial infections in patients allergic to penicillins; suscep- Renal Impairment: Adult
tible bacteria including aerobic gram-positive bacteria
Initial: 1 g as a single dose.
and anaerobes
Maintenance:
Use CrCl >50 mL/minute: No dosage adjustment nec-
Pharyngitis and/or tonsillitis: Treatment of pharyngi-
essary.
tis and/or tonsillitis caused by Streptococcus pyo-
CrCl 25 to 50 mL/minute: 500 mg every 12 hours.
genes (group A beta-hemolytic streptococci).
CrCl 10 to 25 mL/minute: 500 mg every 24 hours.
Skin and skin structure infections: Treatment of skin
CrCl <10 mL/minute: 500 mg every 36 hours.
and skin structure infections caused by staphylococci
and/or streptococci. Hepatic Impairment: Adult There are no dosage
Urinary tract infection: Treatment of urinary tract adjustments provided in the manufacturer’s labeling.
infections caused by Escherichia coli, Proteus mirabi- Pediatric
lis, and Klebsiella species. General dosing, susceptible infection: Mild to
Local Anesthetic/Vasoconstrictor Precautions moderate infection: Infants, Children, and Adoles-
No information available to require special precautions cents: Oral: 15 mg/kg/dose twice daily; maximum
Effects on Dental Treatment No significant effects or daily dose: 2,000 mg/day (Red Book [AAP 2015])
complications reported Impetigo: Children and Adolescents: Oral:
Effects on Bleeding No information available to 30 mg/kg/day in a single dose or divided every 12
require special precautions hours; maximum daily dose: 1,000 mg/day
Adverse Reactions Pharyngitis/tonsillitis: Children and Adolescents:
1% to 10%: Gastrointestinal: Diarrhea Oral: 30 mg/kg/day in a single dose or divided
<1%: postmarketing, and/or case reports: Abdominal every 12 hours for 10 days; maximum daily dose:
pain, agranulocytosis, anaphylaxis, angioedema, 1,000 mg/day
arthralgia, cholestasis, Clostridioides (formerly Clostri- Skin and skin structure infections: Children and
dium) difficile-associated diarrhea, dyspepsia, eryth- Adolescents: Oral: 15 mg/kg/dose every 12 hours;
ema multiforme, erythematous rash, fever, genital maximum daily dose: 1,000 mg/day
264
CEFAZOLIN
Urinary tract infections: Children and Adolescents: dosage forms containing benzyl alcohol derivative with
Oral: 15 mg/kg/dose every 12 hours; maximum caution in neonates. Some dosage forms may contain
daily dose: 2,000 mg/day propylene glycol; large amounts are potentially toxic
Renal Impairment: Pediatric and have been associated with hyperosmolality, lactic
Infants, Children, and Adolescents: There are no acidosis, seizures, and respiratory depression; use
dosage adjustments provided in the manufacturer's caution (AAP 1997; Zar 2007). See manufacturer’s
labeling for this age group; however, the following labeling.
have been used by some clinicians (Aronoff 2007): Warnings: Additional Pediatric Considerations
Dosing based on a usual dose of 30 mg/kg/day in Some dosage forms may contain propylene glycol; in
divided doses every 12 hours: neonates large amounts of propylene glycol delivered
CrCl ≥30 mL/minute/1.73 m2: No dosage adjust- orally, intravenously (eg, >3,000 mg/day), or topically
ment necessary have been associated with potentially fatal toxicities
CrCl 10 to 29 mL/minute/1.73 m2: 15 mg/kg/dose which can include metabolic acidosis, seizures, renal
every 24 hours failure, and CNS depression; toxicities have also been
CrCl <10 mL/minute/1.73 m2: 15 mg/kg/dose every reported in children and adults including hyperosmolal-
36 hours ity, lactic acidosis, seizures, and respiratory depression;
Hemodialysis, intermittent: 15 mg/kg/dose every 24 use caution (AAP 1997; Shehab 2009).
hours Drug Interactions
Peritoneal dialysis: 15 mg/kg/dose every 36 hours
Metabolism/Transport Effects None known.
age adjustments provided in the manufacturer's label-
Avoid concomitant use of Cefadroxil with any of the
ing.
following: BCG (Intravesical); Cholera Vaccine
Mechanism of Action Inhibits bacterial cell wall syn-
thesis by binding to one or more of the penicillin-binding Increased Effect/Toxicity
proteins (PBPs) which in turn inhibits the final trans- Cefadroxil may increase the levels/effects of: Vitamin
peptidation step of peptidoglycan synthesis in bacterial K Antagonists
cell walls, thus inhibiting cell wall biosynthesis. Bacteria The levels/effects of Cefadroxil may be increased by:
eventually lyse due to ongoing activity of cell wall Probenecid
autolytic enzymes (autolysins and murein hydrolases) Decreased Effect
while cell wall assembly is arrested. Cefadroxil may decrease the levels/effects of: BCG
Contraindications Hypersensitivity to cefadroxil, any (Intravesical); BCG Vaccine (Immunization); Cholera
component of the formulation, or other cephalosporins Vaccine; Lactobacillus and Estriol; Sodium Picosul-
Warnings/Precautions Use with caution in patients fate; Typhoid Vaccine
with renal impairment (CrCl <50 mL/minute/1.73 m2); Pharmacodynamics/Kinetics
dosage adjustment may be needed. Hypersensitivity Half-life Elimination 1 to 2 hours; 20 to 24 hours in
reactions, including anaphylaxis, may occur. If an aller- renal failure
gic reaction occurs, discontinue treatment and institute
Time to Peak
appropriate supportive measures. Use with caution in
Serum: Within 70 to 90 minutes
patients with a history of penicillin allergy. Use with
caution in patients with a history of gastrointestinal Pregnancy Risk Factor B
disease, particularly colitis. Prolonged use may result Pregnancy Considerations Adverse events have not
in fungal or bacterial superinfection, including C. diffi- been observed in animal reproduction studies. Cefa-
cile-associated diarrhea (CDAD) and pseudomembra- droxil crosses the placenta. Limited data is available
nous colitis; CDAD has been observed >2 months concerning the use of cefadroxil in pregnancy; however,
postantibiotic treatment. Only IM penicillin has been adverse fetal effects were not noted in a small clinical
shown to be effective in the prophylaxis of rheumatic trial.
fever. Cefadroxil is generally effective in the eradication Breastfeeding Considerations Very small amounts
of streptococci from the oropharynx; efficacy data for of cefadroxil are excreted in breast milk. The manufac-
cefadroxil in the prophylaxis of subsequent rheumatic turer recommends that caution be exercised when
fever episodes are not available. Potentially significant administering cefadroxil to nursing women. Nondose-
drug-drug interactions may exist, requiring dose or related effects could include modification of bowel flora.
frequency adjustment, additional monitoring, and/or Dosage Forms: US
selection of alternative therapy. Capsule, Oral:
Suspension may contain sulfur dioxide (sulfite); hyper- Generic: 500 mg
sensitivity reactions, including anaphylaxis and/or asth- Suspension Reconstituted, Oral:
matic exacerbations, may occur (may be life Generic: 250 mg/5 mL (50 mL, 100 mL); 500 mg/5 mL
threatening). (75 mL, 100 mL)
Tablet, Oral:
Dosage form specific issues: Some dosage forms may Generic: 1 g
contain sodium benzoate/benzoic acid; benzoic acid
(benzoate) is a metabolite of benzyl alcohol; large
amounts of benzyl alcohol (≥99 mg/kg/day) have been CeFAZolin (sef A zoe lin)
Related Information
sists of metabolic acidosis, respiratory distress, gasping Antibiotic Prophylaxis on page 1502
respirations, CNS dysfunction (including convulsions, Brand Names: Canada Cefazolin For Injection; Cefa-
intracranial hemorrhage), hypotension, and cardiovas- zolin For Injection, USP
cular collapse (AAP ["Inactive" 1997]; CDC 1982); some Generic Availability (US) Yes
data suggests that benzoate displaces bilirubin from Pharmacologic Category Antibiotic, Cephalosporin
protein binding sites (Ahlfors, 2001); avoid or use (First Generation)
265
CEFAZOLIN
Dental Use Alternative antibiotic for prevention of infec- Note: Intramuscular injections should be avoided in
tive endocarditis when parenteral administration is patients who are receiving anticoagulant therapy. In
needed. Individuals allergic to amoxicillin (penicillins) these circumstances, orally administered regimens
may receive cefazolin provided they have not had an should be given whenever possible. Intravenously
immediate, local, or systemic IgE-mediated anaphylac- administered antibiotics should be used for patients
tic allergic reaction to penicillin. who are unable to tolerate or absorb oral medica-
Use tions.
Biliary tract infections: Treatment of biliary tract infec- Note: American Heart Association (AHA) guidelines
tions due to Escherichia coli, various strains of strep- now recommend prophylaxis only in patients under-
tococci, Proteus mirabilis, Klebsiella species and going invasive procedures and in whom underlying
Staphylococcus aureus. cardiac conditions may predispose to a higher risk of
Bone and joint infections: Treatment of bone and joint adverse outcomes should infection occur. As of April
infections due to S. aureus. 2007, routine prophylaxis for GI/GU procedures is no
Endocarditis, treatment: Treatment of endocarditis longer recommended by the AHA.
due to S. aureus (penicillin-sensitive and penicillin- Dosing
resistant) and group A beta-hemolytic streptococci Adult & Geriatric
(S. pyogenes). Usual dosage range: IM, IV: 1 to 1.5 g every 8 hours,
Genital infections: Treatment of genital infections (ie, depending on severity of infection; maximum: 12 g
prostatitis, epididymitis) due to E. coli, P. mirabilis, and daily
Klebsiella species. Catheter-related bloodstream infections (off-label
Perioperative prophylaxis: To reduce the incidence of use): IV: 2 g every 8 hours (IDSA [Mermel 2009])
certain postoperative infections in patients undergoing Cholecystitis, mild-to-moderate: IV: 1 to 2 g every 8
surgical procedures. hours for 4 to 7 days (provided source controlled)
Respiratory tract infections: Treatment of respiratory Endocarditis, prophylaxis (off-label use): Dental
tract infections due to S. pneumoniae, Klebsiella spe- and upper respiratory procedures: IM, IV: 1 g 30
cies, Haemophilus influenzae, S. aureus (penicillin- to 60 minutes before procedure. Intramuscular injec-
sensitive and penicillin-resistant) and group A beta- tions should be avoided in patients who are receiving
hemolytic streptococci. anticoagulant therapy. In these circumstances, orally
Septicemia: Treatment of septicemia due to Strepto-
administered regimens should be given whenever
coccus pneumoniae, S. aureus (penicillin-sensitive
possible. Intravenously administered antibiotics
and penicillin-resistant), P. mirabilis, E. coli and Kleb-
should be used for patients who are unable to
siella species.
tolerate or absorb oral medications.
Note: American Heart Association (AHA) guidelines
and skin structure infections due to S. aureus (pen-
now recommend prophylaxis only in patients under-
icillin-sensitive and penicillin-resistant), group A beta-
hemolytic streptococci and other strains of strepto- going invasive procedures and in whom underlying
cocci. cardiac conditions may predispose to a higher risk
Urinary tract infections: Treatment of urinary tract of adverse outcomes should infection occur. As of
infections due to E. coli, P. mirabilis, Klebsiella species April 2007, routine prophylaxis for GI/GU proce-
and some strains of enterobacter. dures is no longer recommended by the AHA.
Local Anesthetic/Vasoconstrictor Precautions Endocarditis, treatment: IV:
No information available to require special precautions Manufacturer’s labeling: 1 to 1.5 g every 6 hours
Effects on Dental Treatment Key adverse event(s) Alternate dosing (AHA [Baddour 2015]): MSSA in
related to dental treatment: Oral candidiasis reported; penicillin-allergic (nonanaphylactoid) patients:
frequency not defined. Native valve: 2 g every 8 hours for 6 weeks
Effects on Bleeding May potentiate the anticoagulant Prosthetic valve: 2 g every 8 hours for a minimum
effects of vitamin K anticoagulants (ie, warfarin) due to of 6 weeks (in combination with rifampin for entire
alterations of gut flora. course of therapy and gentamicin for the first 2
Adverse Reactions Frequency not defined. weeks)
Cardiovascular: Localized phlebitis Group B streptococcus, maternal use (neonatal
Central nervous system: Seizure prophylaxis) (alternative agent) (off-label): IV:
Dermatologic: Pruritus, skin rash, Stevens-Johnson 2 g once, then 1 g every 8 hours until delivery
syndrome (CDC [Verani 2010])
Gastrointestinal: Abdominal cramps, anorexia, diar- Intra-abdominal infection, complicated, commun-
rhea, nausea, oral candidiasis, pseudomembranous ity-acquired, mild-to-moderate (in combination
colitis, vomiting with metronidazole): IV: 1 to 2 g every 8 hours for
Genitourinary: Vaginitis 4 to 7 days (provided source controlled)
Hepatic: Hepatitis, increased serum transaminases Moderate to severe infections: IV: 500 mg to 1 g
Hematologic: Eosinophilia, leukopenia, neutropenia, every 6 to 8 hours
thrombocythemia, thrombocytopenia Mild infection with gram-positive cocci: IV: 250 to
Hypersensitivity: Anaphylaxis 500 mg every 8 hours
Local: Pain at injection site Osteomyelitis, native vertebral (off-label dose):
Renal: Increased blood urea nitrogen, increased serum Staphylococci (oxacillin-susceptible): IV: 1 to
creatinine, renal failure 2 g every 8 hours for 6 weeks (IDSA [Berbari 2015])
Miscellaneous: Fever Perioperative prophylaxis:
Dental Usual Dosage Manufacturer’s labeling: IM, IV: 1 to 2 g initiated 30
Infective endocarditis prophylaxis (off-label use): IM, IV: to 60 minutes prior to surgery; may repeat after 2
Infants and Children: 50 mg/kg 30 to 60 minutes hours if procedure is lengthy with 500 mg to 1 g
before procedure; maximum dose: 1 g intraoperatively, followed by 500 mg to 1 g every 6
Adults: 1 g 30 to 60 minutes before procedure. to 8 hours for 24 hours postoperatively.
266
CEFAZOLIN
Guideline recommendations (off-label): IV: Note: For Prosthetic joint infection, Staphylococcal (oxacil-
most surgical procedures, joint clinical practice lin-susceptible): IV: 1 to 2 g every 8 hours for 2 to 6
guidelines from the American Society of Health- weeks (in combination with rifampin) followed by oral
System Pharmacists, Infectious Diseases Society antibiotic treatment and suppressive regimens
of America, Surgical Infection Society, and Society (Osmon 2013)
for Healthcare Epidemiology of America (ASHP/ Severe infection: IV: 1 to 1.5 g every 6 hours
IDSA/SIS/SHEA) recommend a dose of 2 g within Skin and soft tissue infection due to MSSA, includ-
60 minutes prior to surgical incision (for nonobese ing pyomyositis: IV: 1 g every 8 hours for 7 to 14
patients weighing <120 kg). For procedures requir- days; treat pyomyositis for 14 to 21 days (IDSA
ing anaerobic coverage (eg, appendectomy, small [Stevens 2014])
bowel surgery with intestinal obstruction, colon Skin and soft tissue necrotizing infection due to
procedures), combine cefazolin with metronidazole MSSA (off-label use): IV: 1 g every 8 hours; con-
as an alternative to a second-generation cephalo- tinue until further debridement is not necessary,
sporin with anaerobic activity (eg, cefoxitin or cefo- patient has clinically improved, and patient is afebrile
tetan). Cefazolin doses may be repeated for 48 to 72 hours (IDSA [Stevens 2014])
intraoperatively in 4 hours if procedure is lengthy Streptococcal skin infections: IV: 1 g every 8 hours
or if there is excessive blood loss (Bratzler 2013).
(IDSA [Stevens 2014])
For clean and clean-contaminated procedures,
Surgical site infection (trunk or extremity [away
continued prophylactic antibiotics beyond surgical
from axilla or perineum]) (off-label use): IV:
incision closure is not recommended, even in the
500 mg to 1 g every 8 hours (IDSA [Stevens 2014])
presence of a drain (CDC [Berríos-Torres 2017]).
UTI (uncomplicated): IM, IV: 1 g every 12 hours
Obesity: The ASHP/IDSA/SIS/SHEA guidelines rec-
ommend that for patients weighing ≥120 kg, a dose Renal Impairment: Adult
of 3 g within 60 minutes prior to surgical incision CrCl ≥55 mL/minute: No dosage adjustment neces-
should be administered (Bratzler 2013). Alterna- sary
tively, for patients with BMI >40 kg/m2, a single CrCl 35 to 54 mL/minute: Administer full dose in
2 g dose may be sufficient for common general intervals of ≥8 hours
surgical procedures lasting <5 hours; patients CrCl 11 to 34 mL/minute: Administer 50% of usual
enrolled in this multigroup study had a BMI up to dose every 12 hours
a group mean of 55.7 kg/m2 (Ho 2012). CrCl ≤10 mL/minute: Administer 50% of usual dose
Cardiothoracic surgery: IV: 1 g (see "Note") initiated every 18 to 24 hours
30 to 60 minutes prior to surgery (usually at the time Intermittent hemodialysis (IHD) (administer after
of anesthetic induction); repeat dose if the duration hemodialysis on dialysis days): Dialyzable (20%
of operation exceeds 3 hours (Hillis 2011). The to 50%): 500 mg to 1 g every 24 hours or use 1
ASHP/IDSA/SIS/SHEA guidelines recommend the to 2 g every 48 to 72 hours (Heintz 2009) or 15 to
use of 2 g (single dose) administered within 60 20 mg/kg (maximum dose: 2 g) after dialysis 3
minutes prior to surgical incision (Bratzler 2013). times weekly (Ahern 2003; Sowinski 2001) or 2 g
May either continue for ≤48 hours postoperatively after dialysis if next dialysis expected in 48 hours or
or administer as a single dose preoperatively (may 3 g after dialysis if next dialysis is expected in 72
be preferred due to reduced cost and potential for hours (Stryjewski 2007).
antimicrobial resistance) (Bratzler 2013; Bucknell Note: Dosing dependent on the assumption of 3
2000; Douglas 2011; Edwards 2006; Hillis 2011). times weekly, complete IHD sessions.
Note: For patients weighing >60 kg, the Society of Peritoneal dialysis (PD): IV: 500 mg every 12 hours
Thoracic Surgeons recommends a preoperative Continuous renal replacement therapy (CRRT)
dose of 2 g administered within 60 minutes of skin (Heintz 2009; Trotman 2005): Drug clearance is
incision. If the surgical incision remains open in highly dependent on the method of renal replace-
the operating room, follow with 1 g every 3 to 4 ment, filter type, and flow rate. Appropriate dosing
hours unless cardiopulmonary bypass is to be requires close monitoring of pharmacologic
discontinued within 4 hours then delay adminis- response, signs of adverse reactions due to drug
tration (Engelman 2007). accumulation, as well as drug concentrations in
Peritonitis, treatment (off-label route; Li 2010):
relation to target trough (if appropriate). The follow-
Intraperitoneal:
ing are general recommendations only (based on
Intermittent exchange: 15 mg/kg per exchange every
dialysate flow/ultrafiltration rates of 1 to 2 L/hour
24 hours in the long dwell (≥6 hours)
and minimal residual renal function) and should not
Continuous exchange: Loading dose: 500 mg per
supersede clinical judgment:
liter of dialysate. Maintenance: 125 mg per liter of
dialysate. CVVH: Loading dose of 2 g followed by 1 to 2 g
Note: If patient has residual renal function (eg, >100 every 12 hours
mL/day urine output), empirically increase each CVVHD/CVVHDF: Loading dose of 2 g followed by
dose by 25% either 1 g every 8 hours or 2 g every 12 hours.
Automated peritoneal dialysis: 20 mg/kg every 24 Note: Dosage of 1 g every 8 hours results in
hours in the long day dwell; Note: Guidelines similar steady-state concentrations as 2 g every
suggest nighttime levels of intraperitoneal cefazolin 12 hours and is more cost effective (Heintz 2009).
may fall below the MIC of most organisms and Hepatic Impairment: Adult There are no dosage
adding cefazolin to each exchange may be war- adjustments provided in the manufacturer's labeling.
ranted Obesity: Adult Refer to indication-specific dosing for
Pneumococcal pneumonia: IV: 500 mg every 12 obesity-related information (may not be available for
hours all indications).
267
CEFAZOLIN
Pediatric divided every 8 hours; maximum dose: 1,000 mg/

General dosing, susceptible infection (Bradley dose; continue therapy until surgical debridement
2019; Red Book [AAP 2018]): Infants, Children, no longer necessary, clinical improvement and afe-
and Adolescents: IM, IV: brile for 48 to 72 hours
Mild to moderate infections: 25 to 100 mg/kg/day Streptococcal, nonpurulent skin infection (cellulitis):
divided every 8 hours; maximum daily dose: 6 IV: 100 mg/kg/day divided every 8 hours; maximum
g/day dose: 1,000 mg/dose; duration of therapy at least 5
Severe infections (eg, bone/joint infections): 100 to days, but longer may be necessary in some cases
150 mg/kg/day divided every 6 to 8 hours; max- Surgical prophylaxis: Infants, Children, and Adoles-
imum daily dose: 12 g/day cents: IV: 30 mg/kg within 60 minutes prior to proce-
Endocarditis, bacterial: dure, may repeat in 4 hours for prolonged procedure
Prophylaxis for dental and upper respiratory proce- or excessive blood loss (eg, >1,500 mL in adults);
dures: Infants, Children, and Adolescents: IM, IV: maximum dose dependent upon patient weight:
50 mg/kg 30 to 60 minutes before procedure; max- Weight <120 kg: 2,000 mg/dose; weight ≥120 kg:
imum dose: 1,000 mg/dose (AHA [Wilson 2007]). 3,000 mg/dose (ASHP/IDSA [Bratzler 2013]; Red
Note: AHA guidelines (Baltimore 2015) limit the use Book [AAP 2018])
of prophylactic antibiotics to patients at the highest Renal Impairment: Pediatric
risk for infective endocarditis (IE) or adverse out- IM, IV:
comes (eg, prosthetic heart valves, patients with Infants >1 month, Children, and Adolescents: After
previous IE, unrepaired cyanotic congenital heart initial loading dose is administered, modify dose
disease, repaired congenital heart disease with based on the degree of renal impairment:
prosthetic material or device during first 6 months CrCl >70 mL/minute: No dosage adjustment
after procedure, repaired congenital heart disease required
with residual defects at the site or adjacent to site of CrCl 40 to 70 mL/minute: Administer 60% of the
prosthetic patch or device, and heart transplant usual daily dose divided every 12 hours
recipients with cardiac valvulopathy). CrCl 20 to 40 mL/minute: Administer 25% of the
Tr e a t m e n t : C h i l d r e n a n d A d o l e s c e n t s : I V: usual daily dose divided every 12 hours
100 mg/kg/day in divided doses every 8 hours; CrCl 5 to 20 mL/minute: Administer 10% of the
usual adult dose: 2,000 mg/dose; maximum daily usual daily dose given every 24 hours
dose: 12 g/day; treat for at least 4 weeks; longer Hemodialysis: 25 mg/kg/dose every 24 hours
durations may be necessary; may use with or with- (Aronoff 2007)
out gentamicin (AHA [Baltimore 2015]) Peritoneal dialysis: 25 mg/kg/dose every 24 hours
(Aronoff 2007)
Peritonitis (peritoneal dialysis) (ISPD [Warady
Continuous renal replacement therapy: 25 mg/kg/
2012]): Limited data available: Infants, Children,
dose every 8 hours (Aronoff 2007)
and Adolescents:
Prophylaxis:
Touch contamination of PD line: Intraperitoneal:
ing.
125 mg per liter
Invasive dental procedures: IV: 25 mg/kg adminis- Mechanism of Action Inhibits bacterial cell wall syn-
tered 30 to 60 minutes before procedure; max- thesis by binding to one or more of the penicillin-binding
imum dose: 1,000 mg/dose proteins (PBPs) which in turn inhibits the final trans-
Gastrointestinal or genitourinary procedures: IV: peptidation step of peptidoglycan synthesis in bacterial
25 mg/kg administered 60 minutes before proce- cell walls, thus inhibiting cell wall biosynthesis. Bacteria
dure; maximum dose: 2,000 mg/dose eventually lyse due to ongoing activity of cell wall
Treatment: Intraperitoneal: autolytic enzymes (autolysins and murein hydrolases)
Intermittent: 20 mg/kg every 24 hours in the long while cell wall assembly is arrested.
dwell Contraindications Hypersensitivity to cefazolin, other
Continuous: Loading dose: 500 mg per liter of cephalosporin antibiotics, penicillins, other beta-lac-
dialysate; maintenance: 125 mg per liter of dial- tams, or any component of the formulation.
ysate Warnings/Precautions Hypersensitivity reactions,
including anaphylaxis, may occur. If an allergic reaction
Pneumonia, community-acquired pneumonia
occurs, discontinue treatment and institute appropriate
(CAP), S. aureus, methicillin susceptible: Infants
supportive measures. Use with caution in patients with
>3 months, Children, and Adolescents: IV: 50 mg/kg/
a history of penicillin allergy. Use with caution in
dose every 8 hours (Bradley 2011); usual maximum
patients with renal impairment; dosage adjustment
dose for severe infections: 12 g/day (Red Book
required. Prolonged use may result in fungal or bacte-
[AAP 2018])
rial superinfection, including C. difficile-associated diar-
Skin and soft tissue infections, S. aureus, methi- rhea (CDAD) and pseudomembranous colitis; CDAD
cillin susceptible (mild to moderate): (IDSA [Ste- has been observed >2 months postantibiotic treatment.
vens 2014]): Infants, Children, and Adolescents: May be associated with increased INR, especially in
S. aureus, methicillin susceptible skin and soft tissue nutritionally-deficient patients, prolonged treatment,
infections including pyomyositis: IV: 50 mg/kg/day hepatic or renal disease. Use with caution in patients
divided every 8 hours; maximum dose: 1,000 mg/ with a history of seizure disorder; high levels, partic-
dose; higher doses may be required in severe ularly in the presence of renal impairment, may
cases; duration of therapy at least 5 days, but increase risk of seizures. Potentially significant drug-
longer may be necessary in some cases, eg, febrile drug interactions may exist, requiring dose or frequency
and neutropenic patients: 7 to 14 days; pyomyosi- adjustment, additional monitoring, and/or selection of
tis: 14 to 21 days alternative therapy.
S. aureus, methicillin susceptible necrotizing infec- Drug Interactions
tion of skin, fascia, or muscle: IV: 100 mg/kg/day Metabolism/Transport Effects None known.
268
CEFDINIR
Avoid Concomitant Use Solution Reconstituted, Injection:

Avoid concomitant use of CeFAZolin with any of the Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g
following: BCG (Intravesical); Cholera Vaccine (1 ea); 100 g (1 ea); 300 g (1 ea)
Increased Effect/Toxicity Solution Reconstituted, Injection [preservative free]:
CeFAZolin may increase the levels/effects of: Fosphe- Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea)
nytoin; Phenytoin; RifAMPin; Vitamin K Antagonists Solution Reconstituted, Intravenous:
Generic: 1 g (1 ea)
The levels/effects of CeFAZolin may be increased by: Solution Reconstituted, Intravenous [preservative
Probenecid free]:
Decreased Effect Generic: 1 g and Dextrose 4% (1 ea); 2 g and Dex-
CeFAZolin may decrease the levels/effects of: BCG trose 3% (1 ea)
(Intravesical); BCG Vaccine (Immunization); Cholera
Vaccine; Lactobacillus and Estriol; Sodium Picosul- Cefdinir (SEF di ner)
fate; Typhoid Vaccine
Dietary Considerations Some products may contain Pharmacologic Category Antibiotic, Cephalosporin
sodium. (Third Generation)
Pharmacodynamics/Kinetics Use
Half-life Elimination IM or IV: Neonates: 3 to 5 hours; Chronic obstructive pulmonary disease, exacerba-
Adults: 1.8 hours (IV); ~2 hours (IM) (prolonged with tion: Treatment of acute exacerbations of chronic
renal impairment) bronchitis in adults and adolescents caused by Hae-
Time to Peak Serum: IM: 0.5 to 2 hours; IV: Within 5 mophilus influenzae (including beta-lactamase-pro-
minutes ducing strains), Haemophilus parainfluenzae
(including beta-lactamase-producing strains), Strepto-
coccus pneumoniae (penicillin-susceptible strains
Pregnancy Considerations only), and Moraxella catarrhalis (including beta-lacta-
Cefazolin crosses the placenta. mase-producing strains)
Adverse events have not been reported in the fetus Otitis media, acute: Treatment of acute bacterial otitis
following administration of cefazolin prior to cesarean media in pediatric patients caused by H. influenzae
delivery. (including beta-lactamase-producing strains), S. pneu-
moniae (penicillin-susceptible strains only), and M.
Cefazolin is recommended for group B streptococcus catarrhalis (including beta-lactamase-producing
prophylaxis in pregnant patients with a nonanaphylactic strains)
penicillin allergy. It is also one of the antibiotics recom- Pneumonia, community-acquired: Treatment of com-
mended for prophylactic use prior to cesarean delivery munity-acquired pneumonia in adults and adolescents
and may be used in certain situations prior to vaginal caused by H. influenzae (including beta-lactamase-
delivery in women at high risk for endocarditis (ACOG producing strains), H. parainfluenzae (including beta-
199 2018; ACOG 485 2011; CDC [Verani 2010]). lactamase-producing strains), S. pneumoniae (penicil-
lin-susceptible strains only), and M. catarrhalis (includ-
Due to pregnancy-induced physiologic changes, some ing beta-lactamase-producing strains)
pharmacokinetic parameters of cefazolin may be Sinusitis, acute: Treatment of acute maxillary sinusitis
altered (Allegaert 2009; Elkomy 2014; Philipson in adults and adolescents caused by H. influenzae
1987). In addition to pregnancy, obesity has been found (including beta-lactamase-producing strains), S. pneu-
to influence the pharmacokinetics of cefazolin (Pevzner moniae (penicillin-susceptible strains only), and M.
2011; Stitely 2013; Young 2015). Dose adjustments catarrhalis (including beta-lactamase-producing
may be required in pregnant women who are obese strains). Note: Limitations of use: According to the
(ACOG 199 2018). IDSA guidelines for acute bacterial rhinosinusitis, cef-
Breastfeeding Considerations dinir is no longer recommended as monotherapy for
Cefazolin is present in breast milk. initial empiric treatment (IDSA [Chow 2012]).
Based on limited information, the relative infant dose Skin and skin structure infections, uncomplicated:
(RID) of cefazolin is <1% following a single maternal Treatment of uncomplicated skin and skin structure
dose of 2 g (Yoshioka 1979). infections in adults, adolescents, and pediatric
In general, breastfeeding is considered acceptable patients caused by Staphylococcus aureus (including
beta-lactamase-producing strains) and Streptococcus
when the RID of a medication is <10% (Anderson
pyogenes
2016; Ito 2000).
Streptococcal pharyngitis (group A): Treatment of
The RID of cefazolin was calculated using a milk
pharyngitis/tonsillitis in adults, adolescents, and pedia-
concentration of 1.51 mcg/mL, providing an estimated tric patients caused by S. pyogenes
daily infant dose via breast milk of 0.2265 mcg/kg/day. Local Anesthetic/Vasoconstrictor Precautions
This milk concentration was obtained 3 hours follow- No information available to require special precautions
ing maternal administration cefazolin 2 g IV to 20 Effects on Dental Treatment No significant effects or
postpartum women (Yoshioka 1979). complications reported
The manufacturer recommends that caution be exer- Effects on Bleeding No information available to
cised when administering cefazolin to breastfeeding require special precautions
women. In general, antibiotics that are present in Adverse Reactions
breast milk may cause nondose-related modification >10%: Gastrointestinal: Diarrhea (8% to 15%)
of bowel flora (WHO 2002). 1% to 10%:
Dosage Forms: US Central nervous system: Headache (2%)
Solution, Intravenous [preservative free]: Dermatologic: Skin rash (≤3%)
Generic: 1 g/50 mL in Dextrose 4% (50 mL); 2 g/100 Endocrine & metabolic: Decreased serum bicarbonate
mL in Dextrose 4% (100 mL) (≤1%), glycosuria (≤1%), hyperglycemia (≤1%),
269
CEFDINIR
hyperphosphatemia (≤1%), increased gamma-glu- Pharmacologic Category Antibiotic, Cephalosporin

tamyl transferase (≤1%), increased lactate dehydro- (Third Generation)
genase (≤1%) Use Treatment of acute bacterial exacerbation of chronic
Gastrointestinal: Nausea (≤3%), abdominal pain bronchitis or community-acquired pneumonia (due to
(≤1%), vomiting (≤1%) susceptible organisms including Haemophilus influen-
Genitourinary: Vulvovaginal candidiasis (≤4%), urine zae, Haemophilus parainfluenzae, Streptococcus pneu-
abnormality (increased leukocytes: ≤2%), proteinuria moniae-penicillin susceptible only, Moraxella
(1% to 2%), occult blood in urine (≤1%), vagini- catarrhalis); pharyngitis or tonsillitis (Streptococcus
tis (≤1%) pyogenes); and uncomplicated skin and skin-structure
Hematologic & oncologic: Lymphocytosis (≤2%), eosi- infections (Staphylococcus aureus - not MRSA, Strep-
nophilia (1%), lymphocytopenia (1%), abnormal neu- tococcus pyogenes)
trophils (functional disorder of polymorphonuclear Local Anesthetic/Vasoconstrictor Precautions
neutrophils: ≤1%), thrombocythemia (≤1%), change No information available to require special precautions
in WBC count (≤1%)
Hepatic: Increased serum alkaline phosphatase
(≤1%), increased serum ALT (≤1%)
Renal: Increased urine pH (≤1%), increased urine
specific gravity (≤1%)
<1%, postmarketing, and/or case reports: Abnormal Adverse Reactions
stools, anaphylaxis, anorexia, asthma, blood coagu- >10%: Gastrointestinal: Diarrhea (11% to 15%)
lation disorder, bloody diarrhea, candidiasis, cardiac 1% to 10%:
failure, chest pain, cholestasis, conjunctivitis, consti- Central nervous system: Headache (2% to 3%)
pation, cutaneous candidiasis, decreased hemoglo- Endocrine & metabolic: Increased serum glucose (1%
bin, decreased urine specific gravity, disseminated to 2%)
intravascular coagulation, dizziness, drowsiness, dys- Gastrointestinal: Nausea (4% to 6%), abdominal pain
pepsia, enterocolitis (acute), eosinophilic pneumonitis, (2%), dyspepsia (1% to 2%), vomiting (1%)
erythema multiforme, erythema nodosum, exfoliative Genitourinary: Vulvovaginal candidiasis (3% to 6%),
dermatitis, facial edema, fever, flatulence, fulminant hematuria (3%), urine abnormality (increased leuko-
hepatitis, granulocytopenia, hemolytic anemia, hemor- cytes: 2%)
rhagic colitis, hemorrhagic diathesis, hepatic failure, Hematologic & oncologic: Decreased hematocrit (2%)
hepatitis (acute), hyperkalemia, hyperkinesia, hyper- <1%, postmarketing, and/or case reports: Abnormal
sensitivity angiitis, hypertension, hypocalcemia, hypo- dreams, acute renal failure, decreased serum albu-
phosphatemia, immune thrombocytopenia, increased min, anorexia, arthralgia, asthma, change in WBC
amylase, increased blood urea nitrogen, increased count (decrease or increase), coagulation time
monocytes, increased serum AST, increased serum increased, constipation, decreased hemoglobin,
bilirubin, insomnia, interstitial pneumonitis (idiopathic), decreased neutrophils, decreased serum calcium,
intestinal obstruction, involuntary body movements, decreased serum sodium, diaphoresis, dizziness,
jaundice, laryngeal edema, leukopenia, leukorrhea, drowsiness, dysgeusia, eosinophilic pneumonitis,
loss of consciousness, maculopapular rash, melena, eosinophilia, eructation, erythema multiforme, facial
myocardial infarction, pancytopenia, peptic ulcer, edema, fever, flatulence, fungal infection, gastritis,
pneumonia (drug-induced), pruritus, pseudomembra- gastrointestinal disease, hyperglycemia, hypersensi-
nous colitis, renal disease, renal failure (acute), respi- tivity reaction, hypochloremia, hypophosphatemia,
ratory failure (acute), rhabdomyolysis, serum increased appetite, increased blood urea nitrogen,
sickness, shock, Stevens-Johnson syndrome, stoma- increased serum ALT, increased serum AST,
titis, thrombocytopenia, toxic epidermal necrolysis, increased serum cholesterol, increased serum potas-
upper gastrointestinal hemorrhage, weakness, xero- sium, increased thirst, insomnia, interstitial pneumo-
stomia nitis, leukopenia, leukorrhea, lymphocytosis, myalgia,
Mechanism of Action Inhibits bacterial cell wall syn- nervousness, oral candidiasis, oral mucosa ulcer,
thesis by binding to one or more of the penicillin-binding pain, peripheral edema, pharyngitis, positive direct
proteins (PBPs) which in turn inhibits the final trans- Coombs test, pseudomembranous colitis, proteinuria,
peptidation step of peptidoglycan synthesis in bacterial pruritus, rhinitis, sinusitis, skin rash, Stevens-Johnson
cell walls, thus inhibiting cell wall biosynthesis. Bacteria syndrome, stomatitis, thrombocythemia, thrombocyto-
eventually lyse due to ongoing activity of cell wall penia, toxic epidermal necrolysis, urinary frequency,
autolytic enzymes (autolysins and murein hydrolases) urticaria, vaginitis, weakness, weight loss, xerostomia
while cell wall assembly is arrested. Mechanism of Action Inhibits bacterial cell wall syn-
Pharmacodynamics/Kinetics thesis by binding to one or more of the penicillin-binding
Half-life Elimination 1.7 (± 0.6) hours with normal proteins (PBPs) which in turn inhibits the final trans-
renal function peptidation step of peptidoglycan synthesis in bacterial
Time to Peak 2 to 4 hours cell walls, thus inhibiting cell wall biosynthesis. Bacteria
Pregnancy Risk Factor B eventually lyse due to ongoing activity of cell wall
Pregnancy Considerations Teratogenic events have autolytic enzymes (autolysins and murein hydrolases)
not been observed in animal reproduction studies. An while cell wall assembly is arrested.
increase in most types of birth defects was not found Pharmacodynamics/Kinetics
following first trimester exposure to cephalosporins. Half-life Elimination 1.6 ± 0.4 hours; increased with
moderate (2.7 hours) and severe (4.7 hours) renal
Cefditoren (sef de TOR en) impairment
Time to Peak 1.5 to 3 hours
Related Information Pregnancy Risk Factor B
Bacterial Infections on page 1525 Pregnancy Considerations Adverse events have not
Brand Names: US Spectracef been observed in animal reproduction studies. An
270
CEFIXIME
increase in most types of birth defects was not found Mechanism of Action Inhibits bacterial cell wall syn-
following first trimester exposure to cephalosporins. thesis by binding to one or more of the penicillin-binding
proteins (PBPs) which in turn inhibits the final trans-
Cefepime (SEF e pim)
peptidation step of peptidoglycan synthesis in bacterial
cell walls, thus inhibiting cell wall biosynthesis. Bacteria
Brand Names: US Maxipime eventually lyse due to ongoing activity of cell wall
Brand Names: Canada Maxipime autolytic enzymes (autolysis and murein hydrolases)
Pharmacologic Category Antibiotic, Cephalosporin while cell wall assembly is arrested.
(Fourth Generation) Pharmacodynamics/Kinetics
Use Half-life Elimination
Intraabdominal infections: Treatment, in combination Neonates: 4 to 5 hours (Lima-Rogel 2008)
with metronidazole, of complicated intraabdominal Children 2 months to 6 years: 1.77 to 1.96 hours
infections caused by Escherichia coli, viridans group Adults: 2 hours
streptococci, Pseudomonas aeruginosa, Klebsiella Hemodialysis: 13.5 hours
pneumoniae, Enterobacter species, or Bacteroides Continuous peritoneal dialysis: 19 hours
fragilis Time to Peak IM: 1 to 2 hours; IV: 0.5 hours
Neutropenic fever: Empiric treatment of febrile neu- Pregnancy Risk Factor B
tropenic patients Pregnancy Considerations Adverse events were not
Pneumonia (moderate to severe): Treatment of mod- observed in animal reproduction studies. Cefepime
erate to severe pneumonia caused by Streptococcus crosses the placenta.
pneumoniae, including cases associated with concur-
rent bacteremia, P. aeruginosa, K. pneumoniae, or
Enterobacter species
Cefixime (sef IKS eem)
Skin and soft tissue infections: Treatment of moder- Related Information

ate to severe skin and soft tissue infections caused by Sexually-Transmitted Diseases on page 1494
Staphylococcus aureus (methicillin-susceptible iso- Brand Names: US Suprax
lates only) or Streptococcus pyogenes
Brand Names: Canada Auro-Cefixime; Suprax
Urinary tract infections, including pyelonephritis:
Treatment of urinary tract infections, including pyelo-
Pharmacologic Category Antibiotic, Cephalosporin
nephritis, caused by E. coli, K. pneumoniae, or Pro- (Third Generation)
teus mirabilis, including cases associated with Use
concurrent bacteremia with these microorganisms Treatment of uncomplicated urinary tract infections (due
Local Anesthetic/Vasoconstrictor Precautions to Escherichia coli and Proteus mirabilis), otitis media
No information available to require special precautions (due to Haemophilus influenzae, Moraxella catarrha-
Effects on Dental Treatment Key adverse event(s) lis, and Streptococcus pyogenes), pharyngitis and
related to dental treatment: Rare occurrence of oral tonsillitis (due to Streptococcus pyogenes), acute
candidiasis. exacerbations of chronic bronchitis (due to Strepto-
coccus pneumoniae and Haemophilus influenzae);
uncomplicated cervical/urethral gonorrhea (due to N.
gonorrhoeae [penicillinase- and nonpenicillinase-pro-
Adverse Reactions
ducing])
>10%: Hematologic & oncologic: Positive direct
Note: Due to concerns of resistance, the CDC no
Coombs test (without hemolysis; 16%)
longer recommends use of cefixime as a first-line
1% to 10%:
regimen in the treatment of uncomplicated gonorrhea
Cardiovascular: Localized phlebitis (1%)
in the US; ceftriaxone is the preferred cephalosporin in
Central nervous system: Headache (≤1%)
combination with azithromycin (CDC 2012; CDC
Dermatologic: Skin rash (1% to 4%), pruritus (≤1%)
[Workowski 2015]).
Endocrine & metabolic: Hypophosphatemia (3%)
Gastrointestinal: Diarrhea (≤3%), nausea (≤2%), vom- Local Anesthetic/Vasoconstrictor Precautions
iting (≤1%) No information available to require special precautions
Hematologic & oncologic: Eosinophilia (2%) Effects on Dental Treatment No significant effects or
Hepatic: Increased serum ALT (3%), abnormal partial complications reported
thromboplastin time (2%), increased serum AST Effects on Bleeding No information available to
(2%), abnormal prothrombin time (1%) require special precautions
Hypersensitivity: Hypersensitivity (in patients with a Adverse Reactions
history of penicillin allergy: ≤10%) >10%: Gastrointestinal: Diarrhea (16%)
Miscellaneous: Fever (≤1%) 2% to 10%: Gastrointestinal: Abdominal pain, nausea,
<1%, postmarketing, and/or case reports: Agranulocy- dyspepsia, flatulence, loose stools
tosis, anaphylactic shock, anaphylaxis, anemia, apha- <2%: Acute renal failure, anaphylactoid reaction, ana-
s i a , b r a i n d i s e a s e , C l o s tr i d i o i d e s ( fo r m e r ly phylaxis, angioedema, candidiasis, dizziness, drug
Clostridium) difficile-associated diarrhea, colitis, fever, eosinophilia, erythema multiforme, facial
coma, confusion, decreased hematocrit, erythema, edema, fever, headache, hepatitis, hyperbilirubinemia,
hallucination, hypercalcemia, hyperkalemia, hyper- increased blood urea nitrogen, increased serum crea-
phosphatemia, hypocalcemia, increased blood urea tinine, increased serum transaminases, jaundice, leu-
nitrogen, increased serum alkaline phosphatase, kopenia, neutropenia, prolonged prothrombin time,
increased serum bilirubin, increased serum creatinine, pruritus, pseudomembranous colitis, seizure, serum
leukopenia, local inflammation, local pain, myoclonus, sickness-like reaction, skin rash, Stevens-Johnson
neurotoxicity, neutropenia, oral candidiasis, pseudo- syndrome, thrombocytopenia, toxic epidermal necrol-
membranous colitis, seizure, status epilepticus (non- ysis, urticaria, vaginitis, vomiting
convulsive), stupor, thrombocytopenia, urticaria, Mechanism of Action Inhibits bacterial cell wall syn-
vaginitis thesis by binding to one or more of the penicillin-binding
271
CEFIXIME
proteins (PBPs); which in turn inhibits the final trans- Streptococcus species, E. coli, Klebsiella species,
peptidation step of peptidoglycan synthesis in bacterial Bacteroides species, and anaerobic cocci (including
cell walls, thus inhibiting cell wall biosynthesis. Bacteria Peptostreptococcus species and Peptococcus spe-
eventually lyse due to ongoing activity of cell wall cies), P. mirabilis, and Clostridium species.
autolytic enzymes (autolysins and murein hydrolases) Lower respiratory tract infections: Treatment of
while cell wall assembly is arrested. lower respiratory tract infections, including pneumo-
Pharmacodynamics/Kinetics nia, caused by S. pneumoniae, S. pyogenes (group A
Half-life Elimination Normal renal function: 3 to 4 streptococci) and other streptococci (excluding enter-
hours; Moderate impairment (CrCl 20 to 40 mL/ ococci, [eg, Enterococcus faecalis]), S. aureus (pen-
minute): 6.4 hours; Renal failure: Up to 11.5 hours icillinase and nonpenicillinase producing), E. coli,
Time to Peak Serum: Suspension: 2 to 6 hours; Klebsiella species, H. influenzae (including ampicil-
Capsule: 3 to 8 hours; Delayed with food lin-resistant strains), H. parainfluenzae, P. mirabilis,
Pregnancy Risk Factor B S. marcescens, Enterobacter species, and indole-
Pregnancy Considerations Adverse events were not positive Proteus and Pseudomonas species (including
observed in animal reproduction studies. P. aeruginosa).
Cefixime crosses the placenta and can be detected in and skin structure infections caused by S. aureus
the amniotic fluid (Ozyüncü 2010). (penicillinase and nonpenicillinase producing), S. epi-
dermidis, S. pyogenes (group A streptococci) and
Cefotaxime (sef oh TAKS eem) other streptococci, Enterococcus species, Acineto-
bacter species, E. coli, Citrobacter species (including
Brand Names: US Claforan in D5W [DSC]; Claforan Citrobacter freundii), Enterobacter species, Klebsiella
[DSC] species, P. mirabilis, P. vulgaris, M. morganii, P.
Brand Names: Canada Cefotaxime Sodium For Injec- rettgeri, Pseudomonas species, S. marcescens, Bac-
tion; Claforan teroides species, and anaerobic cocci (including Pep-
Pharmacologic Category Antibiotic, Cephalosporin tostreptococcus species and Peptococcus species).
(Third Generation) Surgical prophylaxis: Reduce the incidence of certain
Use infections in patients undergoing surgical procedures
Bacteremia/Septicemia: Treatment of bacteremia/ (eg, abdominal or vaginal hysterectomy, GI and GU
septicemia caused by Escherichia coli, Klebsiella spe- tract surgery) that may be classified as contaminated
cies, and Serratia marcescens, Staphylococcus aur- or potentially contaminated; reduce the incidence of
eus and Streptococcus species (including certain postoperative infections in patients undergoing
Streptococcus pneumoniae). cesarean section.
Bone or joint infections: Treatment of bone or joint Local Anesthetic/Vasoconstrictor Precautions
infections caused by S. aureus (penicillinase and non- No information available to require special precautions
penicillinase producing strains), Streptococcus spe- Effects on Dental Treatment No significant effects or
cies (including Streptococcus pyogenes), complications reported
Pseudomonas species (including Pseudomonas aer- Effects on Bleeding No information available to
uginosa), and Proteus mirabilis. require special precautions
CNS infections: Treatment of CNS infections (eg, Adverse Reactions
meningitis, ventriculitis) caused by Neisseria meningi- 1% to 10%:
tidis, Haemophilus influenzae, S. pneumoniae, Kleb- Dermatologic: Pruritus (≤2%), skin rash (≤2%)
siella pneumoniae, and E. coli. Gastrointestinal: Colitis (≤1%), diarrhea (≤1%), nau-
Genitourinary infections: Treatment of genitourinary sea (≤1%), vomiting (≤1%)
infections, including urinary tract infections (UTIs), Hematologic & oncologic: Eosinophilia (≤2%)
caused by Enterococcus species, Staphylococcus Local: Induration at injection site (IM ≤4%), inflamma-
epidermidis, S. aureus (penicillinase and nonpenicilli- tion at injection site (IV ≤4%), pain at injection site
nase producing), Citrobacter species, Enterobacter (IM ≤4%), tenderness at injection site (IM ≤4%)
species, E. coli, Klebsiella species, P. mirabilis, Pro- Miscellaneous: Fever (≤2%)
teus vulgaris, Providencia stuartii, Morganella morga- <1%, postmarketing and/or case reports: Acute gener-
nii, Providencia rettgeri, S. marcescens, and alized exanthematous pustulosis, acute renal failure,
Pseudomonas species (including P. aeruginosa). Also, agranulocytosis, anaphylaxis, bone marrow failure,
uncomplicated gonorrhea (cervical/urethral and rectal) brain disease, candidiasis, cardiac arrhythmia (after
caused by Neisseria gonorrhoeae, including penicilli- rapid IV injection via central catheter), cholestasis,
nase-producing strains. Note: CDC STD guidelines do Clostridioides (formerly Clostridium) difficile-associ-
not recommend cefotaxime as a treatment option for ated diarrhea, dizziness, erythema multiforme, gran-
uncomplicated gonorrhea; ceftriaxone is the preferred ulocytopenia, headache, hemolytic anemia, hepatitis,
cephalosporin (CDC [Workowski 2015]). increased blood urea nitrogen, increased gamma-glu-
Gynecologic infections: Treatment of gynecologic tamyl transferase, increased lactate dehydrogenase,
infections, including pelvic inflammatory disease, increased serum alkaline phosphatase, increased
endometritis, and pelvic cellulitis, caused by S. epi- serum ALT, increased serum AST, increased serum
dermidis, Streptococcus species, Enterococcus spe- bilirubin, increased serum creatinine, injection site
cies, Enterobacter species, Klebsiella species, E. coli, phlebitis, interstitial nephritis, jaundice, leukopenia,
P. mirabilis, Bacteroides species (including Bacter- local irritation, neutropenia, pancytopenia, positive
oides fragilis), Clostridium species, and anaerobic direct Coombs test, pseudomembranous colitis, Ste-
cocci (including Peptostreptococcus and Peptococcus vens-Johnson syndrome, thrombocytopenia, toxic epi-
species) and Fusobacterium species (including Fuso- dermal necrolysis, urticaria, vaginitis
bacterium nucleatum). Mechanism of Action Inhibits bacterial cell wall syn-
Intra-abdominal infections: Treatment of intra- thesis by binding to one or more of the penicillin-binding
abdominal infections, including peritonitis caused by proteins (PBPs) which in turn inhibits the final
272
CEFOXITIN
transpeptidation step of peptidoglycan synthesis in patients with other serious infections (often adminis-
bacterial cell walls, thus inhibiting cell wall biosynthesis. tered with concomitant aminoglycosides).
Bacteria eventually lyse due to ongoing activity of cell Skin and skin structure infections: Treatment of skin
wall autolytic enzymes (autolysins and murein hydro- and skin structure infections due to S. aureus (pen-
lases) while cell wall assembly is arrested. Cefotaxime icillinase- and non-penicillinase-producing strains),
has activity in the presence of some beta-lactamases, Staphylococcus epidermidis, Streptococcus pyo-
both penicillinases and cephalosporinases, of gram- genes, Streptococcus spp. (excluding enterococci),
negative and gram-positive bacteria. Enterococcus spe- E. coli, K. pneumoniae, Peptococcus niger, Peptos-
cies may be intrinsically resistant to cefotaxime. Most treptococcus spp.
extended-spectrum beta-lactamase (ESBL)-producing Surgical (perioperative) prophylaxis: Preoperative
and carbapenemase-producing isolates are resistant
administration in surgical procedures that are classi-
to cefotaxime.
fied as clean contaminated or potentially contaminated
(eg, cesarean section, abdominal or vaginal hysterec-
Cefotaxime: Infants ≤1500 g: 4.6 hours; Infants tomy, transurethral surgery, biliary tract surgery, GI
>1500 g: 3.4 hours; Children: 1.5 hours; Adults: 1 surgery).
to 1.5 hours; prolonged with renal and/or hepatic Urinary tract infections: Treatment of urinary tract
impairment infections caused by E. coli, Klebsiella spp. (including
Desacetylcefotaxime: 1.3 to 1.9 hours; prolonged with K. pneumoniae), P. mirabilis and Proteus spp. (which
renal impairment (Ings 1982) may include the organisms now called Proteus vulga-
Time to Peak Serum: IM: Within 30 minutes ris, Providencia rettgeri, and Morganella morganii).
Pregnancy Risk Factor B Local Anesthetic/Vasoconstrictor Precautions
Pregnancy Considerations Adverse events have not No information available to require special precautions
been observed in animal reproduction studies. Cefotax- Effects on Dental Treatment No significant effects or
ime crosses the human placenta and can be found in complications reported
fetal tissue. An increase in most types of birth defects Effects on Bleeding May potentiate the anticoagulant
was not found following first trimester exposure to effects of vitamin K anticoagulants (ie, warfarin) due to
cephalosporins. During pregnancy, peak cefotaxime alterations of gut flora. Cefotetan may have additional
serum concentrations are decreased and the serum hypoprothrombinemic activity.
half-life is shorter. Cefotaxime is approved for use in Adverse Reactions
women undergoing cesarean section (consult current 1% to 10%:
guidelines for appropriate use). Gastrointestinal: Diarrhea (1%)
Hepatic: Increased serum transaminases (1%)
CefoTEtan (SEF oh tee tan) Hypersensitivity: Hypersensitivity reaction (1%)
<1%, postmarketing, and/or case reports: Agranulocy-
Brand Names: US Cefotan tosis, anaphylaxis, eosinophilia, fever, hemolytic ane-
Pharmacologic Category Antibiotic, Cephalosporin mia, hemorrhage, increased blood urea nitrogen,
(Second Generation) increased serum creatinine, leukopenia, nausea,
Use nephrotoxicity, phlebitis, prolonged prothrombin time,
Bone and joint infections: Treatment of bone and joint pruritus, pseudomembranous colitis, skin rash, throm-
infections caused by Staphylococcus aureus. bocythemia, thrombocytopenia, urticaria, vomiting
Gynecologic infections: Treatment of gynecologic
infections caused by S. aureus, (including penicilli-
nase- and non-penicillinase-producing strains), Staph- thesis by binding to one or more of the penicillin-binding
ylococcus epidermidis, Streptococcus spp. (excluding proteins (PBPs) which in turn inhibits the final trans-
enterococci), Streptococcus agalactiae, Escherichia peptidation step of peptidoglycan synthesis in bacterial
coli, Proteus mirabilis, Neisseria gonorrhoeae, Bacter- cell walls, thus inhibiting cell wall biosynthesis. Bacteria
oides spp. (excluding Bacteroides distasonis, Bacter- eventually lyse due to ongoing activity of cell wall
oides ovatus, Bacteroides thetaiotaomicron), autolytic enzymes (autolysins and murein hydrolases)
Fusobacterium spp., and gram-positive anaerobic while cell wall assembly is arrested.
cocci (including Peptococcus and Peptostreptococcus Pharmacodynamics/Kinetics
spp.). Half-life Elimination 3 to 4.6 hours, prolonged in
Limitations of use: Cefotetan has no activity against patients with moderately impaired renal function (up
Chlamydia (Chlamydophila) trachomatis. When to 10 hours)
treating pelvic inflammatory disease, add appropriate Time to Peak Serum: IM: 1 to 3 hours
antichlamydial coverage. Pregnancy Risk Factor B
Intra-abdominal infections: Treatment of intra- Pregnancy Considerations Adverse events have not
abdominal infections caused by E. coli, Klebsiella been observed in animal reproduction studies. Cefote-
spp. (including K. pneumoniae), Streptococcus spp. tan crosses the placenta and produces therapeutic
(excluding enterococci) and Clostridium spp.
concentrations in the amniotic fluid and cord serum.
Lower respiratory tract infections: Treatment of
Cefotetan is one of the antibiotics recommended for
lower respiratory tract infections caused by Strepto-
use with cesarean delivery.
coccus pneumoniae, S. aureus (penicillinase- and
non-penicillinase-producing strains), Haemophilus
influenzae (including ampicillin-resistant strains), CefOXitin (se FOKS i tin)
Klebsiella spp. (including K. pneumoniae), E. coli, P.
mirabilis, and Serratia marcescens. Brand Names: Canada Cefoxitin For Injection
Serious infections: Treatment of confirmed or sus- Pharmacologic Category Antibiotic, Cephalosporin
pected gram-positive or gram-negative sepsis or in (Second Generation)
273
CEFOXITIN
Use proteins (PBPs) which in turn inhibits the final trans-

Bone and joint infections: Treatment of bone and joint peptidation step of peptidoglycan synthesis in bacterial
infections caused by Staphylococcus aureus (includ- cell walls, thus inhibiting cell wall biosynthesis. Bacteria
ing penicillinase-producing strains). eventually lyse due to ongoing activity of cell wall
Gynecological infections: Treatment of endometritis, autolytic enzymes (autolysins and murein hydrolases)
pelvic cellulitis, and pelvic inflammatory disease while cell wall assembly is arrested.
caused by Escherichia coli, Neisseria gonorrhoeae Pharmacodynamics/Kinetics
(including penicillinase-producing strains), Bacter- Half-life Elimination Neonates and Infants (PNA:
oides species including Bacteroides fragilis, Clostri- 10-53 days): 1.4 hours (Regazzi 1983); Adults:
dium species, P. niger, Peptostreptococcus species, 41-59 minutes; prolonged with renal impairment
and Streptococcus agalactiae. Time to Peak Serum: IM: Within 20-30 minutes
Intra-abdominal infections: Treatment of peritonitis Pregnancy Considerations Adverse events have not
and intra-abdominal infections or abscess, caused been observed in animal reproduction studies. Cefoxitin
by E. coli, Klebsiella species, Bacteroides species crosses the placenta and reaches the cord serum and
(including B. fragilis), and Clostridium species. amniotic fluid.
Peak serum concentrations of cefoxitin during preg-
pneumonia and lung abscess, caused by Streptococ-
nancy may be similar to or decreased compared to
cus pneumoniae, other streptococci (excluding enter-
nonpregnant values. Maternal half-life may be shorter
oco cci; eg, Enteroco ccus faeca lis [fo rme rly
at term. Pregnancy-induced hypertension increases
Streptococcus faecalis]), S. aureus (including penicil-
trough concentrations in the immediate postpartum
linase-producing strains), E. coli, Klebsiella species,
period. Cefoxitin is one of the antibiotics recommended
Haemophilus influenzae, and Bacteroides species.
for prophylactic use prior to cesarean delivery.
Perioperative prophylaxis: Prophylaxis of infection in
patients undergoing uncontaminated GI surgery,
abdominal or vaginal hysterectomy, or cesarean Cefpodoxime (sef pode OKS eem)
section.
Septicemia: Treatment of septicemia caused by S. Pharmacologic Category Antibiotic, Cephalosporin
pneumoniae, S. aureus (including penicillinase-pro- (Third Generation)
ducing strains), E. coli, Klebsiella species, and Bacter- Use
oides species including B. fragilis. Chronic bronchitis, acute bacterial exacerbation:
Skin and skin structure infections: Treatment of skin Treatment of acute bacterial exacerbation of chronic
and skin structure infections caused by S. aureus bronchitis caused by Streptococcus pneumoniae,
(including penicillinase-producing strains), Staphylo- Haemophilus influenzae (non-beta-lactamase-produc-
coccus epidermidis, Streptococcus pyogenes and ing strains only), or Moraxella catarrhalis.
other streptococci (excluding enterococci [eg, E. fae- Cystitis, acute uncomplicated: Treatment of acute
calis] [formerly S. faecalis]), E. coli, Proteus mirabilis, uncomplicated cystitis caused by Escherichia coli,
Klebsiella species, Bacteroides species including B. Klebsiella pneumoniae, Proteus mirabilis, or Staph-
fragilis, Clostridium species, P. niger, and Peptostrep- ylococcus saprophyticus.
tococcus species. Gonorrhea:
Urinary tract infections: Treatment of UTIs caused by Acute, uncomplicated anorectal infections in women:
E. coli, Klebsiella species, P. mirabilis, Morganella Treatment of acute, uncomplicated anorectal infec-
morganii, Proteus vulgaris, and Providencia species tions in women due to N. gonorrhoeae (including
(including Providencia rettgeri). penicillinase-producing strains). Note: Due to issues
of resistance, cefpodoxime is no longer recom-
Limitations of use: Cefoxitin does not have activity mended for the treatment of acute, uncomplicated
against Chlamydia trachomatis. When cefoxitin is anorectal infections in women.
used to treat pelvic inflammatory disease, add appro- Acute, uncomplicated urethral and cervical: Treatment
priate antichlamydial coverage. of acute, uncomplicated urethral and cervical gonor-
Local Anesthetic/Vasoconstrictor Precautions rhea caused by Neisseria gonorrhoeae (including
No information available to require special precautions penicillinase-producing strains). Note: Due to issues
Effects on Dental Treatment No significant effects or of resistance, cefpodoxime is no longer recom-
complications reported mended for the treatment of acute, uncomplicated
Effects on Bleeding May potentiate the anticoagulant urethral and cervical gonorrhea.
effects of vitamin K anticoagulants (ie, warfarin) due to Otitis media, acute: Treatment of acute otitis media
alterations of gut flora. caused by S. pneumoniae, (excluding penicillin-resist-
Adverse Reactions ant strains), Streptococcus pyogenes, H. influenzae
1% to 10%: Gastrointestinal: Diarrhea (including beta-lactamase-producing strains), or M.
<1%: Anaphylaxis, angioedema, bone marrow depres- catarrhalis (including beta-lactamase producing
sion, dyspnea, eosinophilia, exacerbation of myasthe- strains).
nia gravis, exfoliative dermatitis, fever, hemolytic Pharyngitis or tonsillitis: Treatment of pharyngitis or
anemia, hypotension, increased blood urea nitrogen, tonsillitis caused by S. pyogenes.
increased serum creatinine, increased serum trans- Pneumonia, community-acquired: Treatment of com-
aminases, interstitial nephritis, jaundice, leukopenia, munity-acquired pneumonia caused by S. pneumo-
nausea, nephrotoxicity (increased; with aminoglyco- niae or H. influenzae (including beta-lactamase-
sides), phlebitis, prolonged prothrombin time, pruritus, producing strains).
pseudomembranous colitis, skin rash, thrombocytope- Rhinosinusitis, acute bacterial: Treatment of acute
nia, thrombophlebitis, toxic epidermal necrolysis, urti- bacterial rhinosinusitis caused by H. influenzae
caria, vomiting (including beta-lactamase producing strains), S. pneu-
Mechanism of Action Inhibits bacterial cell wall syn- moniae, and M. catarrhalis. Note: According to the
thesis by binding to one or more of the penicillin-binding Infectious Diseases Society of America (IDSA)
274
CEFTAROLINE FOSAMIL
guidelines for acute bacterial rhinosinusitis, cefpodox- Pharyngitis/tonsillitis: Treatment of mild to moderate
ime is recommended in combination with clindamycin pharyngitis/tonsillitis caused by Streptococcus pyo-
due to concern for pneumococcal resistance. genes.
Skin and skin structure infections, uncomplicated: Limitations of use: Cefprozil is generally effective in
Treatment of uncomplicated skin and skin structure the eradication of S. pyogenes from the nasophar-
infections caused by S. aureus (including penicilli- ynx; however, substantial data establishing the effi-
nase-producing strains) or S. pyogenes. cacy of cefprozil in the subsequent prevention of
Local Anesthetic/Vasoconstrictor Precautions rheumatic fever are not available at present.
No information available to require special precautions Skin and skin-structure infections, uncomplicated:
Effects on Dental Treatment No significant effects or Treatment of mild to moderate uncomplicated skin and
complications reported skin-structure infections caused by Staphylococcus
Effects on Bleeding No information available to aureus (including penicillinase-producing strains) and
require special precautions S. pyogenes.
Adverse Reactions Local Anesthetic/Vasoconstrictor Precautions
>10%: No information available to require special precautions
Dermatologic: Diaper rash (12%) Effects on Dental Treatment No significant effects or
Gastrointestinal: Diarrhea (infants and toddlers 15%) complications reported
1% to 10%: Effects on Bleeding No information available to
Central nervous system: Headache (1%) require special precautions
Dermatologic: Skin rash (1%) Adverse Reactions
Gastrointestinal: Diarrhea (7%), nausea (4%), Frequency not always defined.
abdominal pain (2%), vomiting (1% to 2%) 1% to 10%:
Genitourinary: Vaginal infection (3%) Central nervous system: Dizziness (1%)
<1%: Anaphylaxis, anxiety, chest pain, cough, Dermatologic: Diaper rash (2%), genital pruritus (2%)
decreased appetite, dizziness, dysgeusia, epistaxis, Gastrointestinal: Nausea (4%), diarrhea (3%),
eye pruritus, fatigue, fever, flatulence, flushing, fungal abdominal pain (1%), vomiting (1%)
skin infection, hypotension, insomnia, malaise, night- Genitourinary: Vaginitis
mares, pruritus, pseudomembranous colitis, purpuric Hepatic: Increased serum transaminases (2%)
nephritis, tinnitus, vulvovaginal candidiasis, weak- Infection: Superinfection
ness, xerostomia <1%, postmarketing, and/or case reports: Anaphylaxis,
Mechanism of Action Inhibits bacterial cell wall syn- angioedema, arthralgia, cholestatic jaundice, confu-
thesis by binding to one or more of the penicillin-binding sion, drowsiness, eosinophilia, erythema multiforme,
proteins (PBPs) which in turn inhibits the final trans- fever, headache, hyperactivity, increased blood urea
peptidation step of peptidoglycan synthesis in bacterial nitrogen, increased serum creatinine, insomnia, leu-
cell walls, thus inhibiting cell wall biosynthesis. Bacteria kopenia, pseudomembranous colitis, serum sickness,
eventually lyse due to ongoing activity of cell wall skin rash, Stevens-Johnson syndrome, thrombocyto-
autolytic enzymes (autolysins and murein hydrolases) penia, urticaria
while cell wall assembly is arrested. Mechanism of Action Inhibits bacterial cell wall syn-
Pharmacodynamics/Kinetics thesis by binding to one or more of the penicillin-binding
Half-life Elimination ~2 to 3 hours; prolonged with proteins (PBPs) which in turn inhibits the final trans-
renal impairment (~10 hours for CrCl <30 mL/minute) peptidation step of peptidoglycan synthesis in bacterial
Time to Peak Tablets: Within 2 to 3 hours; Oral cell walls, thus inhibiting cell wall biosynthesis. Bacteria
suspension: Slower in presence of food, 48% increase eventually lyse due to ongoing activity of cell wall
in Tmax autolytic enzymes (autolysins and murein hydrolases)
Pregnancy Risk Factor B while cell wall assembly is arrested.
Pregnancy Considerations Pharmacodynamics/Kinetics
Adverse events were not observed in animal reproduc- Half-life Elimination
tion studies. Infants and Children (6 months to 12 years): 1.5 hours
Adults:
Normal renal function: 1.3 hours
Cefprozil (sef PROE zil)
Renal impairment: 5.2 hours
Related Information Renal failure: 5.9 hours
Hepatic impairment: 2 hours
Antibiotic Prophylaxis on page 1502
Brand Names: Canada Apo-Cefprozil; Auro-Cefprozil; Time to Peak Serum: Fasting: 1.5 hours
Ava-Cefprozil; Cefzil; RAN-Cefprozil; Sandoz-Cefprozil Pregnancy Risk Factor B
Pharmacologic Category Antibiotic, Cephalosporin Pregnancy Considerations Adverse events were not
(Second Generation) observed in animal reproduction studies.
Use
Acute bacterial exacerbation of chronic bronchitis: Ceftaroline Fosamil (sef TAR oh leen FOS a mil)
Treatment of mild to moderate acute bacterial exacer-
bations of chronic bronchitis caused by S. pneumo- Brand Names: US Teflaro
niae, H. influenzae (including beta-lactamase– Pharmacologic Category Antibiotic, Cephalosporin
producing strains), and M. catarrhalis (including (Fifth Generation)
beta-lactamase–producing strains). Use
Otitis media: Treatment of mild to moderate otitis Pneumonia, community-acquired: Treatment of com-
media caused by S. pneumoniae, Haemophilus influ- munity-acquired bacterial pneumonia in adults and
enzae (including beta-lactamase–producing strains), pediatric patients 2 months of age and older caused
and Moraxella (Branhamella) catarrhalis (including by Streptococcus pneumoniae (including cases with
beta-lactamase–producing strains). concurrent bacteremia), Staphylococcus aureus
275
CEFTAROLINE FOSAMIL
(methicillin-susceptible isolates only), Haemophilus

influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, CefTAZidime (SEF tay zi deem)
and Escherichia coli.
Skin and skin structure infections: Treatment of Brand Names: US Fortaz; Fortaz in D5W [DSC];
acute bacterial skin and skin structure infections in Tazicef
adults and pediatric patients 2 months of age and Brand Names: Canada Fortaz
older caused by Staphylococcus aureus (including Pharmacologic Category Antibiotic, Cephalosporin
methicillin-susceptible and methicillin-resistant iso- (Third Generation)
lates), Streptococcus pyogenes, Streptococcus aga- Use
lactiae, Escherichia coli, Klebsiella pneumoniae, and Bacterial septicemia: Treatment of septicemia caused
Klebsiella oxytoca. by Pseudomonas aeruginosa, Klebsiella spp., Haemo-
Local Anesthetic/Vasoconstrictor Precautions philus influenzae, Escherichia coli, Serratia spp.,
No information available to require special precautions Streptococcus pneumoniae, and Staphylococcus aur-
Effects on Dental Treatment No significant effects or eus (methicillin-susceptible strains).
complications reported Bone and joint infections: Treatment of bone and joint
Effects on Bleeding No information available to infections caused by Pseudomonas aeruginosa, Kleb-
require special precautions siella spp., Enterobacter spp., and Staphylococcus
aureus (methicillin-susceptible strains).
Adverse Reactions The following reactions occurred
CNS infections: Treatment of meningitis caused by
in all indicated populations unless otherwise specified.
Haemophilus influenzae and Neisseria meningitidis.
>10%: Hematologic & oncologic: Positive direct
Ceftazidime has also been used successfully in cases
Coombs test (infants, children, and adolescents:
of meningitis due to Pseudomonas aeruginosa and
18%; adults: 10% to 11%; no evidence of hemolysis
Streptococcus pneumoniae.
in any treatment group)
Empiric therapy in the immunocompromised
1% to 10%:
patient: Empiric treatment of infections in immuno-
Cardiovascular: Bradycardia (adults: <2%), palpita- compromised patients.
tions (adults: <2%), phlebitis (adults: 2%) Gynecologic infections: Treatment of endometritis,
Central nervous system: Insomnia (adults: 3% to 4%), pelvic cellulitis, and other infections of the female
headache (infants, children, and adolescents: <3%), genital tract caused by Escherichia coli.
dizziness (adults: <2%), seizure (adults: <2%) Intra-abdominal infections: Treatment of peritonitis
Dermatologic: Skin rash (3% to 7%), pruritus (infants, caused by Escherichia coli, Klebsiella spp., and
ch ild ren, an d ad ole sce nts : <3 %), urti caria Staphylococcus aureus (methicillin-susceptible
(adults: <2%) strains) and polymicrobial intra-abdominal infections
Endocrine & metabolic: Hypokalemia (adults: 2%), caused by aerobic and anaerobic organisms and
hyperglycemia (adults: <2%), hyperkalemia some Bacteroides spp. (many strains of Bacteroides
(adults: <2%) fragilis are resistant).
Gastrointestinal: Diarrhea (5% to 8%), vomiting (2% to Lower respiratory tract infections: Treatment of
5%), nausea (3% to 4%), constipation (adults: 2%), lower respiratory tract infections, including pneumo-
abdominal pain (adults: <2%), pseudomembranous nia, caused by Pseudomonas aeruginosa and other
colitis (adults: <2%) Pseudomonas spp.; Haemophilus influenzae, includ-
Hematologic & oncologic: Anemia (adults: <2%), eosi- ing ampicillin-resistant strains; Klebsiella spp.; Enter-
nophilia (adults: <2%), neutropenia (adults: <2%), obacter spp.; Proteus mirabilis; Escherichia coli;
thrombocytopenia (adults: <2%) Serratia spp.; Citrobacter spp.; Streptococcus pneu-
Hepatic: Increased serum ALT (infants, children, and moniae; and Staphylococcus aureus (methicillin-sus-
adolescents: <3%), increased serum AST (infants, ceptible strains).
children, and adolescents: <3%), increased serum Skin and skin-structure infections: Treatment of skin
transaminases (adults: 2%), hepatitis (adults: <2%) and skin-structure infections caused by Pseudomonas
Hypersensitivity: Anaphylaxis (adults: <2%), hyper- aeruginosa; Klebsiella spp.; Escherichia coli; Proteus
sensitivity (adults: <2%) spp.; including Proteus mirabilis and indole-positive
Renal: Renal failure (adults: <2%) Proteus; Enterobacter spp.; Serratia spp.; Staphylo-
Miscellaneous: Fever (adults: <2% to 3%) coccus aureus (methicillin-susceptible strains); and
<1%, postmarketing, and/or case reports: Agranulocy- Streptococcus pyogenes (group A beta-hemolytic
tosis (adults), leukopenia (adults) streptococci).
Mechanism of Action Inhibits bacterial cell wall syn- Urinary tract infections (UTI): Treatment of compli-
thesis by binding to penicillin-binding proteins (PBPs) 1 cated and uncomplicated UTIs caused by Pseudomo-
through 3. This action blocks the final transpeptidation nas aeruginosa; Enterobacter spp.; Proteus spp.,
step of peptidoglycan synthesis in bacterial cell walls including Proteus mirabilis and indole-positive Pro-
and inhibits cell wall biosynthesis. Bacteria eventually teus; Klebsiella spp.; and Escherichia coli.
lyse due to ongoing activity of cell wall autolytic Local Anesthetic/Vasoconstrictor Precautions
enzymes (autolysis and murein hydrolases) while cell No information available to require special precautions
wall assembly is arrested. Ceftaroline has a strong Effects on Dental Treatment No significant effects or
affinity for PBP2a, a modified PBP in MRSA, and complications reported
PBP2x in S. pneumoniae, contributing to its spectrum Effects on Bleeding No information available to
of activity against these bacteria. require special precautions
Pharmacodynamics/Kinetics Adverse Reactions
Half-life Elimination 1.6 ± 0.38 hours (single dose); 1% to 10%:
2.66 ± 0.4 hours (multiple dose) Dermatologic: Pruritus (<2%), skin rash (<2%)
Time to Peak ~1 hour Endocrine & metabolic: Increased lactate dehydrogen-
Pregnancy Considerations Adverse events have ase (6%), increased gamma-glutamyl transfer-
been observed in some animal reproduction studies. ase (5%)
276
CEFTIBUTEN
Gastrointestinal: Diarrhea (1%) pneumonia in adult patients caused by ceftazidime/

Hematologic & oncologic: Eosinophilia (8%), positive avibactam-susceptible K. pneumoniae, E. cloacae, E.
direct Coombs test (4%; without hemolysis), throm- coli, Serratia marcescens, P. mirabilis, P. aeruginosa,
bocythemia (2%) and Haemophilus influenzae.
Hepatic: Increased serum ALT (7%), increased serum Urinary tract infections, complicated (including
AST (6%), increased serum alkaline phospha- pyelonephritis): Treatment of complicated urinary
tase (4%) tract infections (cUTI) (including pyelonephritis) in
Hypersensitivity: Hypersensitivity reactions (2%) adult and pediatric patients ≥3 months of age, caused
Local: Inflammation at injection site (1%), injection site by C. freundii complex, E. cloacae, E. coli, K. pneumo-
phlebitis (1%) niae, P. mirabilis, and P. aeruginosa.
Miscellaneous: Fever (<2%) Local Anesthetic/Vasoconstrictor Precautions
Frequency not defined: No information available to require special precautions
Central nervous system: Seizure Effects on Dental Treatment No significant effects or
Hematologic & oncologic: Agranulocytosis, leukope- complications reported
nia, lymphocytosis, neutropenia, thrombocytopenia
Renal: Increased blood urea nitrogen, increased
serum creatinine
<1%, postmarketing, and/or case reports: Abdominal Adverse Reactions Also see ceftazidime monograph.
pain, anaphylaxis (severe in rare instances, including >10%: Hematologic & oncologic: Positive direct coombs
cardiopulmonary arrest), angioedema, candidiasis, test (3% to 21%; no hemolytic anemia reactions
Clostridioides (formerly Clostridium) difficile-associ- reported)
ated diarrhea, dizziness, erythema multiforme, head- 1% to 10%:
ache, hemolytic anemia, hyperbilirubinemia, jaundice, Dermatologic: Pruritus (2%)
nausea, pain at injection site, paresthesia, renal insuf- Gastrointestinal: Vomiting (≥5%), diarrhea (3%), nau-
ficiency, Stevens-Johnson syndrome, toxic epidermal sea (3%), constipation (2%), upper abdominal
necrolysis, urticaria, vaginitis, vomiting pain (1%)
Mechanism of Action Inhibits bacterial cell wall syn- <1%, postmarketing, and/or case reports: Acute renal
thesis by binding to one or more of the penicillin-binding failure, anxiety, candidiasis, Clostridioides (formerly
proteins (PBPs), which in turn inhibits the final trans- Clostridium) difficile-associated diarrhea, dysgeusia,
peptidation step of peptidoglycan synthesis in bacterial hypokalemia, increased gamma-glutamyl transferase,
cell walls, thus inhibiting cell wall biosynthesis. Bacteria increased serum ALT, increased serum AST, injection
eventually lyse due to ongoing activity of cell wall site phlebitis, leukopenia, maculopapular rash, neph-
autolytic enzymes (autolysins and murein hydrolases) rolithiasis, renal insufficiency, skin rash, thrombocyto-
while cell wall assembly is arrested. penia, thrombocythemia, urticaria
Pharmacodynamics/Kinetics Mechanism of Action
Half-life Elimination 1 to 2 hours, prolonged with Ceftazidime inhibits bacterial cell wall synthesis by
renal impairment binding to one or more of the penicillin-binding pro-
Time to Peak Serum: IM: ~1 hour teins (PBPs) which in turn inhibits the final trans-
peptidation step of peptidoglycan synthesis in
bacterial cell walls, thus inhibiting cell wall biosyn-
Pregnancy Considerations Adverse events have not thesis. Bacteria eventually lyse due to ongoing activity
been observed in animal reproduction studies. Ceftazi- of cell wall autolytic enzymes (autolysins and murein
dime crosses the placenta and reaches the cord serum hydrolases) while cell wall assembly is arrested.
and amniotic fluid. An increase in most types of birth Avibactam inactivates some beta-lactamases and pro-
defects was not found following first trimester exposure tects ceftazidime from degradation.
to cephalosporins. Maternal peak serum concentration Pharmacodynamics/Kinetics
is unchanged in the first trimester. After the first trimes- Half-life Elimination Ceftazidime: 2.76 hours; Avi-
ter, serum concentrations decrease by approximately bactam: 2.71 hours
50% of those in nonpregnant patients. Renal clearance
is increased during pregnancy.
been observed in animal reproduction studies con-
ducted with ceftazidime; adverse events have been
observed in some animal reproduction studies con-
Ceftazidime and Avibactam ducted with avibactam.
(SEF tay zi deem & a vi BAK tam)
Brand Names: US Avycaz Ceftibuten (sef TYE byoo ten)

Pharmacologic Category Cephalosporin Combina-
tion Related Information
Use Bacterial Infections on page 1525
Intra-abdominal infections, complicated: Treatment Brand Names: US Cedax [DSC]
of complicated intra-abdominal infections (cIAI) in Pharmacologic Category Antibiotic, Cephalosporin
adult and pediatric patients ≥3 months of age, in (Third Generation)
combination with metronidazole, caused by Citro- Use
bacter freundii complex, Enterobacter cloacae, Acute bacterial exacerbations of chronic bronchi-
Escherichia coli, Klebsiella oxytoca, Klebsiella pneu- tis: Treatment of mild to moderate acute bacterial
moniae, Proteus mirabilis, and Pseudomonas aerugi- exacerbations of chronic bronchitis due to Haemophi-
nosa. lus influenzae (including beta-lactamase-producing
Pneumonia, hospital-acquired and ventilator-asso- strains), Moraxella catarrhalis (including beta-lacta-
ciated: Treatment of hospital-acquired bacterial pneu- mase-producing strains), or Streptococcus pneumo-
monia and ventilator-associated (HAP/VAP) bacterial niae (penicillin-susceptible strains only).
277
CEFTIBUTEN
Limitations of use: In acute bacterial exacerbations of Product Availability All ceftibuten formulations (brand
chronic bronchitis clinical trials where M. catarrhalis and generic) have been discontinued in the US for more
was isolated from infected sputum at baseline, cefti- than 1 year.
buten clinical efficacy was 22% less than control.
Acute bacterial otitis media: Treatment of mild to
moderate acute bacterial otitis media due to H. influ- Ceftolozane and Tazobactam
(sef TOL oh zane & taz oh BAK tam)
enzae (including beta-lactamase-producing strains),
M. catarrhalis (including beta-lactamase-producing Brand Names: US Zerbaxa
strains), or Streptococcus pyogenes. Brand Names: Canada Zerbaxa
Limitations of use: Although ceftibuten used empiri- Pharmacologic Category Cephalosporin Combina-
cally was equivalent to comparators in the treatment tion
of clinically and/or microbiologically documented Use
acute otitis media, the efficacy against S. pneumo- Intra-abdominal infections: Treatment of complicated
niae was 23% less than control. Therefore, cefti- intra-abdominal infections in adults, in combination
buten should be given empirically only when with metronidazole, caused by Enterobacter cloacae,
adequate antimicrobial coverage against S. pneumo- Escherichia coli, Klebsiella oxytoca, K. pneumoniae,
niae has been previously administered. Proteus mirabilis, Pseudomonas aeruginosa, Bacter-
Pharyngitis/tonsillitis: Treatment of mild to moderate oides fragilis, Streptococcus anginosus, Streptococ-
pharyngitis and tonsillitis due to S. pyogenes. cus constellatus, and Streptococcus salivarius.
Local Anesthetic/Vasoconstrictor Precautions Urinary tract infections: Treatment of complicated
No information available to require special precautions urinary tract infections, including pyelonephritis, in
Effects on Dental Treatment No significant effects or adults caused by Escherichia coli, Klebsiella pneumo-
complications reported niae, Proteus mirabilis, and Pseudomonas aeru-
Effects on Bleeding No information available to ginosa.
1% to 10%: Effects on Dental Treatment No significant effects or
Central nervous system: Headache (≤3%), dizzi- complications reported
ness (≤1%) Effects on Bleeding No information available to
Gastrointestinal: Nausea (≤4%), diarrhea (3% to 4%), require special precautions
dyspepsia (≤2%), loose stools (≤2%), abdominal Adverse Reactions
pain (1% to 2%), vomiting (1% to 2%) 1% to 10%:
Hematologic & oncologic: Eosinophilia (3%), Cardiovascular: Hypotension (≤2%), atrial fibrilla-
decreased hemoglobin (1% to 2%), change in plate- tion (≤1%)
let count (increase: ≤1%) Central nervous system: Headache (3% to 6%),
Hepatic: Increased serum ALT (≤1%), increased insomnia (complicated intra-abdominal infections:
serum bilirubin (≤1%) 4%; complicated UTIs: 1%), anxiety (≤2%), dizziness
Renal: Increased blood urea nitrogen (2% to 4%) (≤1%)
<1%, postmarketing, and/or case reports: Agitation, Dermatologic: Skin rash (≤2%)
anorexia, aphasia, candidiasis, constipation, dehydra- Endocrine: Hypokalemia (complicated intra-abdominal
tion, diaper rash, drowsiness, dysgeusia, dyspnea, infections: 3%; complicated UTIs: <1%)
dysuria, eructation, fatigue, fever, flatulence, hematu- Gastrointestinal: Nausea (3% to 8%), diarrhea (com-
ria, hyperkinesia, increased serum alkaline phospha- plicated intra-abdominal infections: 6%; complicated
tase, increased serum AST, increased serum UTIs: 2%), constipation (2% to 4%), vomiting (com-
creatinine, insomnia, irritability, jaundice, leukopenia, plicated intra-abdominal infections: 3%, complicated
melena, nasal congestion, paresthesia, pruritus, pseu- UTIs: 1%), abdominal pain (≤1%)
domembranous colitis, psychosis, rigors, serum sick- Hematologic & oncologic: Anemia (≤2%), thrombocy-
ness, skin rash, Stevens-Johnson syndrome, stridor, themia (≤2%)
thrombocytopenia, toxic epidermal necrolysis, urtica- Hepatic: Increased serum ALT (2%), increased serum
ria, vaginitis, xerostomia AST (1% to 2%)
Mechanism of Action Inhibits bacterial cell wall syn- Miscellaneous: Fever (complicated intra-abdominal
thesis by binding to one or more of the penicillin-binding infections: 6%; complicated UTIs: 2%)
proteins (PBPs) which in turn inhibits the final trans- <1%, postmarketing, and/or case reports: Abdominal
peptidation step of peptidoglycan synthesis in bacterial distention, angina pectoris, candidiasis, Clostridioides
cell walls, thus inhibiting cell wall biosynthesis. Bacteria (formerly Clostridium) difficile-associated diarrhea,
eventually lyse due to ongoing activity of cell wall dyspepsia, dyspnea, flatulence, fungal urinary tract
autolytic enzymes (autolysins and murein hydrolases) infection, gastritis, hyperglycemia, hypomagnesemia,
while cell wall assembly is arrested. hypophosphatemia, increased gamma-glutamyl trans-
Pharmacodynamics/Kinetics ferase, increased serum alkaline phosphatase, infu-
Half-life Elimination Children: 2 hours; Adults: 2.4 sion site reaction, nonhemorrhagic stroke,
hours; CrCl 30 to 49 mL/minute: 7.1 hours; CrCl 5 to oropharyngeal candidiasis, paralytic ileus, positive
29 mL/minute: 13.4 hours; CrCl <5 mL/minute: 22.3 direct Coombs test, renal failure, renal insufficiency,
hours tachycardia, urticaria, venous thrombosis, vulvovagi-
Time to Peak 2 to 2.6 hours nal candidiasis
Pregnancy Risk Factor B Mechanism of Action Ceftolozane inhibits bacterial
Pregnancy Considerations Adverse events have not cell wall synthesis by binding to one or more of the
been observed in animal reproduction studies. An penicillin-binding proteins (PBPs); which in turn inhibits
increase in most types of birth defects was not found the final transpeptidation step of peptidoglycan syn-
following first trimester exposure to cephalosporins thesis in bacterial cell walls, thus inhibiting cell wall
(Crider 2009). biosynthesis. Ceftolozane is an inhibitor of PBPs of
278
CEFTRIAXONE
Pseudomonas aeruginosa (eg, PBP1b, PBP1c, and Surgical prophylaxis: Reduce the incidence of post-
PBP3) and Escherichia coli (eg, PBP3). Tazobactam operative infections in patients undergoing surgical
irreversibly inhibits many beta-lactamases (eg, certain procedures classified as contaminated or potentially
penicillinases and cephalosporinases), and can cova- contaminated (eg, vaginal or abdominal hysterectomy
lently bind to some plasmid-mediated and chromosomal or cholecystectomy for chronic calculous cholecystitis
bacterial beta-lactamases. in high-risk patients, such as those older than 70
Pharmacodynamics/Kinetics years, with acute cholecystitis not requiring therapeu-
Half-life Elimination Ceftolozane: ~3 hours; Tazo- tic antimicrobials, obstructive jaundice, or common
bactam: ~1 hour duct bile stones) and in surgical patients for whom
Time to Peak Plasma: Immediately following comple- infection at the operative site would present serious
tion of 60-minute infusion risk (eg, during coronary artery bypass surgery).
Pregnancy Risk Factor B Uncomplicated gonorrhea (cervical/urethral and
rectal): Caused by N. gonorrhoeae, including both
penicillinase- and nonpenicillinase-producing strains,
observed in some animal reproduction studies. Tazo-
and pharyngeal gonorrhea caused by nonpenicilli-
bactam crosses the placenta (Bourget, 1998).
nase-producing strains of N. gonorrhoeae.
Urinary tract infections (complicated and uncompli-
CefTRIAXone (sef trye AKS one) cated): Caused by E. coli, P. mirabilis, Proteus vulga-
ris, M. morganii, or K. pneumoniae.
Related Information Local Anesthetic/Vasoconstrictor Precautions
Antibiotic Prophylaxis on page 1502 No information available to require special precautions
Sexually-Transmitted Diseases on page 1494 Effects on Dental Treatment No significant effects or
Brand Names: Canada Ceftriaxone for Injection; Cef- complications reported
triaxone for Injection USP; Ceftriaxone Sodium for Effects on Bleeding May potentiate the anticoagulant
Injection; Ceftriaxone Sodium for Injection BP effects of vitamin K anticoagulants (ie, warfarin) due to
Pharmacologic Category Antibiotic, Cephalosporin alterations of gut flora.
(Third Generation) Adverse Reactions
Use >10%:
Acute bacterial otitis media: Caused by Streptococ- Dermatologic: Skin tightness (IM: ≤5% to ≤17%; local)
cus pneumoniae, Haemophilus influenzae (including Local: Induration at injection site (≤5% to ≤17%;
beta-lactamase-producing strains), or Moraxella catar- incidence higher with IM), warm sensation at injec-
rhalis (including beta-lactamase-producing strains). tion site (IM: ≤5% to ≤17%)
Bacterial septicemia: Caused by Staphylococcus aur- 1% to 10%:
eus, S. pneumoniae, Escherichia coli, H. influenzae, Dermatologic: Skin rash (2%)
or Klebsiella pneumoniae. Gastrointestinal: Diarrhea (3%)
Bone and joint infections: Caused by S. aureus, S. Hematologic & oncologic: Eosinophilia (6%), thrombo-
pneumoniae, E. coli, Proteus mirabilis, K. pneumo- cythemia (5%), leukopenia (2%)
niae, or Enterobacter spp. Hepatic: Increased serum transaminases (3%)
Intra-abdominal infections: Caused by E. coli, K. Local: Pain at injection site (≤1%), tenderness at
pneumoniae, Bacteroides fragilis, Clostridium spp., injection site (≤1%)
or Peptostreptococcus spp. Renal: Increased blood urea nitrogen (1%)
Lower respiratory tract infections: Caused by S. <1%, postmarketing and/or case reports: Abdominal
pain, acute generalized exanthematous pustulosis,
pneumoniae, S. aureus, H. influenzae, Haemophilus
acute renal failure (post-renal), agranulocytosis, aller-
parainfluenzae, K. pneumoniae, E. coli, Enterobacter
gic dermatitis, anaphylactoid reaction, anaphylaxis,
aerogenes, P. mirabilis, or Serratia marcescens.
anemia, basophilia, blood coagulation disorder, bron-
Meningitis, bacterial: Caused by H. influenzae, Neis-
chospasm, candidiasis, casts in urine, chills, choledo-
seria meningitidis, or S. pneumoniae. Ceftriaxone has
cholithiasis, cholelithiasis, Clostridioides (formerly
also been used successfully in a limited number of
Clostridium) difficile-associated diarrhea, colitis,
cases of meningitis and shunt infection caused by decreased prothrombin time, diaphoresis, dizziness,
Staphylococcus epidermidis and E. coli (efficacy for dysgeusia, dyspepsia, edema, epistaxis, erythema
these 2 organisms in this organ system was studied in multiforme, fever, flatulence, flushing, gallbladder
fewer than 10 infections). sludge, glossitis, glycosuria, granulocytopenia, head-
Pelvic inflammatory disease: Caused by N. gonor- ache, hematuria, hemolytic anemia, hypersensitivity
rhoeae. Ceftriaxone, like other cephalosporins, has no pneumonitis, increased monocytes, increased serum
activity against Chlamydia trachomatis. Therefore, alkaline phosphatase, increased serum bilirubin,
when cephalosporins are used in the treatment of increased serum creatinine, jaundice, kernicterus, leu-
patients with pelvic inflammatory disease and C. tra- kocytosis, lymphocytopenia, lymphocytosis, nausea,
chomatis is one of the suspected pathogens, appro- nephrolithiasis, neutropenia, oliguria, palpitations,
priate antichlamydial coverage should be added. pancreatitis, phlebitis, prolonged prothrombin time,
Skin and skin structure infections: Caused by S. pruritus, pseudomembranous colitis, seizure, serum
aureus, S. epidermidis, Streptococcus pyogenes, vir- sickness, Stevens-Johnson syndrome, stomatitis,
idans group streptococci, E. coli, Enterobacter cloa- thrombocytopenia, toxic epidermal necrolysis, ureteral
cae, Klebsiella oxytoca, K. pneumoniae, P. mirabilis, obstruction, urogenital fungal infection, urolithiasis,
Morganella morganii (efficacy for this organism in this urticaria, vaginitis, vomiting
organ system was studied in fewer than 10 infections), Mechanism of Action Inhibits bacterial cell wall syn-
Pseudomonas aeruginosa, S. marcescens, Acineto- thesis by binding to one or more of the penicillin-binding
bacter calcoaceticus, or B. fragilis (efficacy for this proteins (PBPs) which in turn inhibits the final trans-
organism in this organ system was studied in fewer peptidation step of peptidoglycan synthesis in bacterial
than 10 infections), or Peptostreptococcus spp. cell walls, thus inhibiting cell wall biosynthesis. Bacteria
279
CEFTRIAXONE
eventually lyse due to ongoing activity of cell wall Pharyngitis/tonsillitis (tablets and oral suspension
autolytic enzymes (autolysins and murein hydrolases) only): Treatment of mild to moderate pharyngitis/
while cell wall assembly is arrested. tonsillitis caused by S. pyogenes in adults and pedia-
Pharmacodynamics/Kinetics tric patients ≥3 months of age.
Half-life Elimination Limitations of use: Efficacy in the prevention of rheu-
Neonates (Martin 1984): 1 to 4 days: 16 hours; 9 to 30 matic fever has not been established in clinical trials.
days: 9 hours Efficacy in the treatment of penicillin-resistant strains
Infants and Children: 4 to 6.6 hours (Richards 1984) of S. pyogenes has not been demonstrated.
Adults: Normal renal and hepatic function: ~5 to 9 Septicemia (injection only): Treatment of septicemia
hours caused by S. aureus (penicillinase- and non-penicilli-
Adults: Renal impairment (mild-to-severe): ~12 to 16 nase-producing strains), S. pneumoniae, E. coli, H.
hours influenzae (including ampicillin-resistant strains), and
Time to Peak Serum: IM: 2 to 3 hours Klebsiella spp.
Pregnancy Risk Factor B Sinusitis, acute bacterial (tablets and oral suspen-
Pregnancy Considerations Adverse events have not sion only): Treatment of mild to moderate acute
been observed in animal reproduction studies. Ceftriax- bacterial maxillary sinusitis caused by S. pneumoniae
one crosses the placenta. Pregnancy was found to or H. influenzae (non-beta-lactamase-producing
influence the single dose pharmacokinetics of ceftriax- strains only).
one when administered prior to delivery (Popović 2007). Limitations of use: Effectiveness for sinus infections
The pharmacokinetics of ceftriaxone following multiple caused by beta-lactamase-producing H. influenzae
doses in the third trimester are similar to those of or M. catarrhalis in patients with acute bacterial
nonpregnant patients (Bourget Fernandez 1993). Cef- maxillary sinusitis has not been established. Note:
triaxone is recommended for use in pregnant women for According to the IDSA guidelines for acute bacterial
the treatment of gonococcal infections, Lyme disease, rhinosinusitis, cefuroxime is no longer recommended
and may be used in certain situations prior to vaginal as monotherapy for initial empiric treatment (IDSA
delivery in women at high risk for endocarditis (consult [Chow 2012]).
current guidelines) (ACOG 120, 2011; CDC [Workowski Skin and skin-structure infections (impetigo) (oral
2015]; Wormser 2006). suspension only): Treatment of pediatric patients 3
months to 12 years of age with skin or skin-structure
infections (impetigo) caused by S. aureus (including
Cefuroxime (se fyoor OKS eem)
beta-lactamase-producing strains) or S. pyogenes.
Related Information Skin and skin-structure infections (injection; tablets
Antibiotic Prophylaxis on page 1502 [uncomplicated infections only]): Treatment of
Bacterial Infections on page 1525 adults and pediatric patients >3 months of age with
Brand Names: US Ceftin [DSC]; Zinacef in Sterile skin and skin-structure infections (including impetigo)
Water [DSC]; Zinacef [DSC] caused by S. aureus (penicillinase- and non-penicilli-
Brand Names: Canada Ceftin nase-producing strains), S. pyogenes, E. coli, Kleb-
siella spp., and Enterobacter spp.
Pharmacologic Category Antibiotic, Cephalosporin
Surgical prophylaxis (injection only): Prophylaxis of
(Second Generation)
infection in patients undergoing surgical procedures
Use
that are classified as clean-contaminated or potentially
Bone and joint infections (injection only): Treatment
contaminated procedures.
of bone and joint infections caused by Staphylococcus
Urinary tract infections (tablets and injection only):
aureus (penicillinase- and non-penicillinase-producing
Treatment of adults and pediatric patients >3 months
strains).
of age with urinary tract infections caused by E. coli
Chronic obstructive pulmonary disease, acute
and Klebsiella spp.
exacerbation (tablets only): Treatment of mild to
moderate acute bacterial exacerbations of chronic Local Anesthetic/Vasoconstrictor Precautions
bronchitis in adults and adolescents ≥13 years of No information available to require special precautions
age caused by Streptococcus pneumoniae, Haemo- Effects on Dental Treatment No significant effects or
philus influenzae (beta-lactamase negative strains), or complications reported
Haemophilus parainfluenzae (beta-lactamase nega- Effects on Bleeding No information available to
tive strains). require special precautions
Lower respiratory tract infections (injection only): Adverse Reactions
Treatment of lower respiratory tract infections, includ- >10%: Gastrointestinal: Diarrhea (4% to 11%, duration
ing pneumonia, caused by S. pneumoniae, H. influen- dependent)
zae (including ampicillin-resistant strains), Klebsiella 1% to 10%:
spp., S. aureus (penicillinase- and non-penicillinase- Cardiovascular: Local thrombophlebitis (2%)
producing strains), Streptococcus pyogenes, and Dermatologic: Diaper rash (children 3%)
Escherichia coli. Endocrine & metabolic: Increased lactate dehydrogen-
Lyme disease (early) (tablets only): Treatment of ase (1%)
adults and adolescents ≥13 years of age with early Gastrointestinal: Nausea and vomiting (3% to 7%),
Lyme disease caused by Borrelia burgdorferi. unpleasant taste (children 5%)
Otitis media, acute (tablets and oral suspension Genitourinary: Vaginitis (≤5%)
only): Treatment of pediatric patients ≥3 months of Hematologic & oncologic: Decreased hematocrit
age with acute bacterial otitis media caused by S. (≤10%), decreased hemoglobin (≤10%), eosinophilia
pneumoniae, H. influenzae (including beta-lacta- (1% to 7%)
mase-producing strains), Moraxella catarrhalis Hepatic: Increased serum transaminases (2% to 4%),
(including beta-lactamase-producing strains), or S. increased serum alkaline phosphatase (2%)
pyogenes. Immunologic: Jarisch-Herxheimer reaction (6%)
280
CELECOXIB
<1%, postmarketing, and/or case reports (Limited to

important or life-threatening): Abdominal pain, ana- Celecoxib (se le KOKS ib)
phylaxis, angioedema, anorexia, arthralgia, brain dis-
Related Information
ease, candidiasis, chest pain, chest tightness, chills,
cholestasis, Clostridioides (formerly Clostridium) diffi-
cile-associated diarrhea, colitis, cough, decreased
on page 1484
creatinine clearance, dizziness, drowsiness, drug
Brand Names: US CeleBREX
fever, dyspepsia, dyspnea, dysuria, erythema, eryth-
Brand Names: Canada Celebrex
ema multiforme, fever, flatulence, gastrointestinal
hemorrhage, gastrointestinal infection, glossitis, head-
Pharmacologic Category Analgesic, Nonopioid; Non-
ache, hearing loss, hemolytic anemia, hepatitis, hyper- steroidal Anti-inflammatory Drug (NSAID), COX-2
activity, hyperbilirubinemia, hypersensitivity, Selective
hypersensitivity angiitis, increased blood urea nitro- Dental Use Management of acute dental pain
gen, increased liver enzymes, increased serum crea- Use
tinine, increased thirst, interstitial nephritis, irritability, Acute pain: Management of acute pain.
jaundice, joint swelling, leukopenia, muscle cramps, Ankylosing spondylitis: Relief of the signs/symptoms
muscle rigidity, muscle spasm (neck), neutropenia, of ankylosing spondylitis.
oral mucosa ulcer, pancytopenia, positive direct Juvenile idiopathic arthritis: Relief of the signs/symp-
Coombs test, prolonged prothrombin time, pruritus, toms of juvenile idiopathic arthritis (JIA) in patients 2
pseudomembranous colitis, renal insufficiency, renal years and older.
pain, seizure, serum sickness-like reaction, sialorrhea, Osteoarthritis: Relief of the signs/symptoms of osteo-
sinusitis, skin rash, Stevens-Johnson syndrome, arthritis.
stomach cramps, tachycardia, thrombocytopenia Primary dysmenorrhea: Treatment of primary dysme-
(rare), toxic epidermal necrolysis, trismus, upper res- norrhea.
Rheumatoid arthritis: Relief of the signs/symptoms of
piratory tract infection, urethral bleeding, urethral pain,
rheumatoid arthritis.
urinary tract infection, urticaria, vaginal discharge,
vaginal irritation, viral infection, vulvovaginal candidia- No information available to require special precautions
sis, vulvovaginal pruritus Effects on Dental Treatment Key adverse event(s)
Mechanism of Action Inhibits bacterial cell wall syn- related to dental treatment: Stomatitis, abnormal taste,
thesis by binding to one or more of the penicillin-binding and xerostomia (normal salivary flow resumes upon
proteins (PBPs) which in turn inhibits the final trans- discontinuation).
peptidation step of peptidoglycan synthesis in bacterial Effects on Bleeding No effects on bleeding or platelet
cell walls, thus inhibiting cell wall biosynthesis. Bacteria function have been reported. See Dental Health Pro-
eventually lyse due to ongoing activity of cell wall fessional Considerations.
autolytic enzymes (autolysins and murein hydrolases) Adverse Reactions
while cell wall assembly is arrested. ≥2%:
Pharmacodynamics/Kinetics Cardiovascular: Peripheral edema (2%)
Half-life Elimination Gastrointestinal: Diarrhea (6%), dyspepsia (9%),
Premature neonates: abdominal pain (4%), flatulence (2%), gastroesopha-
PNA ≤3 days: Median: 5.8 hours (de Louvois 1982) geal reflux disease, vomiting
Hepatic: Increased liver enzymes (<3x ULN: ≤6%)
PNA ≥8 days: Median: 1.6 to 3.8 hours (de Lou-
Renal: Nephrolithiasis (3%)
vois 1982)
Children and Adolescents: 1.4 to 1.9 hours sinusitis (5%), pharyngitis (2%), rhinitis (2%),
Adults: ~1 to 2 hours; prolonged with renal impairment dyspnea
Time to Peak Serum: IM: ~15 to 60 minutes; IV: 2 to 3 Miscellaneous: Accidental injury (3%)
minutes; Oral: Children: ~3 to 4 hours; Adults: ~2 to 3 Frequency not defined:
hours Dermatologic: Acute generalized exanthematous pus-
Pregnancy Risk Factor B tulosis, exfoliative dermatitis
Pregnancy Considerations Gastrointestinal: Gastrointestinal perforation, gastro-
Adverse events were not observed in animal reproduc- intestinaI ulcer, GI inflammation, intestinal perfo-
tion studies. Cefuroxime crosses the placenta and ration
Hypersensitivity: Anaphylaxis
reaches the cord serum and amniotic fluid. Placental
Immunologic: DRESS syndrome
transfer is decreased in the presence of oligohydram-
Respiratory: Local alveolar osteitis (post oral surgery
nios. Several studies have failed to identify an patients)
increased teratogenic risk to the fetus following mater- <2%, postmarketing, and/or case reports: Acute renal
nal cefuroxime use. failure, ageusia, agranulocytosis, albuminuria, alope-
During pregnancy, mean plasma concentrations of cia, anaphylactoid reaction, anemia, angina pectoris,
angioedema, anorexia, anosmia, anxiety, aplastic
cefuroxime are 50% lower, the AUC is 25% lower, and
anemia, arthralgia, aseptic meningitis, ataxia, bronchi-
the plasma half-life is shorter than nonpregnant values.
tis, bronchospasm, bronchospasm (aggravated), cel-
At term, plasma half-life is similar to nonpregnant val- lulitis, cerebrovascular accident, chest pain,
ues and peak maternal concentrations after IM admin- cholelithiasis, colitis (with bleeding), constipation, con-
istration are slightly decreased. Pregnancy does not tact dermatitis, coronary artery disease, cough, cyst,
alter the volume of distribution. Cefuroxime is one of cyst (NOS), cystitis, deafness, decreased hemoglobin,
the antibiotics recommended for prophylactic use prior deep vein thrombosis, depression, dermatitis, diapho-
to cesarean delivery. resis, diverticulitis, drowsiness, dysphagia, dysuria,
281
CELECOXIB
ecchymoses, edema, epistaxis, eructation, erythema urine, dosage adjustment is not necessary (Davies
multiforme, erythematous rash, esophageal perfora- 2000). Based on unpublished data, AUC was ~40%
tion, esophagitis, exacerbation of hypertension, facial lower in patients with chronic renal insufficiency
edema, fatigue, fever, flu-like symptoms, gangrene of (GFR 35 to 60 mL/minute) compared with subjects
skin or other tissue, gastritis, gastroenteritis, gastro- with normal renal function due to a higher apparent
esophageal reflux disease, gastrointestinal hemor- clearance.
rhage, hematuria, hemorrhoids, hepatic failure, Severe impairment: Use is not recommended.
hepatic necrosis, hepatitis, hiatal hernia, hot flash, Advanced renal disease: Use is not recommended;
hypercholesterolemia, hyperglycemia, hypersensitivity however, if celecoxib treatment cannot be avoided,
exacerbation, hypersensitivity reaction, hypertonia, monitor renal function closely.
hypoesthesia, hypoglycemia, hypokalemia, hypona- Abnormal renal function tests (persistent or worsen-
tremia, increased appetite, increased blood urea nitro- ing): Discontinue use.
gen, increased creatine phosphokinase, increased Hepatic Impairment: Adult
nonprotein nitrogen, increased serum alkaline phos- Mild impairment (Child-Pugh class A): No dosage
phatase, interstitial nephritis, intestinal obstruction,
adjustment necessary; AUC increased ~40% in mild
intracranial hemorrhage, jaundice, laryngitis, leg
hepatic impairment compared with healthy subjects.
cramps, leukopenia, maculopapular rash, melena,
Moderate impairment (Child-Pugh class B): Reduce
migraine, myalgia, myocardial infarction, nervous-
dose by 50%.
ness, osteoarthritis, pain, palpitations, pancreatitis,
pancytopenia, paresthesia, peripheral pain, pneumo- Severe impairment (Child-Pugh class C): Use is not
nia, pruritus, pulmonary embolism, skin changes, skin recommended.
photosensitivity, Stevens-Johnson syndrome, stomati- Abnormal liver function tests (persistent or worsening):
tis, syncope, synovitis, tachycardia, tendonitis, tenes- Discontinue use.
mus, thrombocythemia, thrombocytopenia, Pediatric
thrombophlebitis, tinnitus, toxic epidermal necrolysis, Juvenile idiopathic arthritis (JIA): Note: Use the
urinary frequency, urticaria, vasculitis, ventricular fibril- lowest effective dose for the shortest duration of
lation, vertigo, weight gain, xeroderma, xerostomia time, consistent with individual patient goals.
Dental Usual Dosage Acute dental pain: Adults: Oral: Children ≥2 years and Adolescents:
400 mg, followed by an additional 200 mg if needed on ≥10 kg to ≤25 kg: Oral: 50 mg twice daily
day 1; maintenance dose: 200 mg twice daily as >25 kg: Oral: 100 mg twice daily
needed Dosing adjustment in poor metabolizers of
Dosing CYP2C9 substrates: Use with caution in patients
Adult Note: Use the lowest effective dose for the who are known or suspected poor metabolizers of
shortest duration of time, consistent with individual cytochrome P450 isoenzyme 2C9 substrates.
patient treatment goals. Due to an increased risk of Children ≥2 years and Adolescents: Consider alter-
cardiovascular events, use should generally be nate therapy in JIA patients who are poor metabo-
avoided in patients with established cardiovascular lizers; experience in adult patients suggests dosing
disease or risk factors for cardiovascular disease. adjustment.
Use should also be avoided in those with heart failure Renal Impairment: Pediatric Children ≥2 years and
(Chan 2018; Schmidt 2016). Adolescents:
Acute pain or primary dysmenorrhea: Oral: Initial Baseline:
dose: 400 mg, followed by an additional 200 mg if Mild or moderate impairment: There are no dosage
needed on day 1; maintenance dose: 200 mg twice adjustments provided in the manufacturer's label-
daily as needed ing; however, since <1% of the drug is excreted in
Ankylosing spondylitis: Oral: 200 mg once daily or the urine, dosage adjustment is not necessary
100 mg twice daily; if no effect after 6 weeks, may (Davies 2000). Based on unpublished data, AUC
increase to 400 mg/day. If no response following 6 was ~40% lower in adult patients with chronic renal
weeks of treatment with 400 mg/day, consider dis- insufficiency (GFR 35 to 60 mL/minute) compared
continuation and alternative treatment.
with subjects with normal renal function due to a
Gout, acute flare (alternative agent) (off-label use):
higher apparent clearance.
Oral: 200 mg twice daily; initiate within 24 to 48
Severe impairment: Use is not recommended.
hours of flare onset preferably; discontinue 2 to 3
Advanced renal disease: Use is not recommended;
days after resolution of clinical signs; usual duration:
however, if celecoxib treatment cannot be avoided,
5 to 7 days (ACR [Khanna 2012]; Becker 2018)
Osteoarthritis: Oral: 200 mg once daily or 100 mg monitor renal function closely.
twice daily During therapy: Abnormal renal function tests (persis-
Rheumatoid arthritis: Oral: 100 to 200 mg twice tent or worsening): Discontinue use.
daily Hepatic Impairment: Pediatric
Dosing adjustment in poor CYP2C9 metabolizers Children ≥2 years and Adolescents:
(ie, CYP2C9*3/*3): Reduce initial dose by 50%; Moderate hepatic impatient (Child-Pugh Class B):
consider alternative treatment in patients with JIA Reduce dose by 50%; monitor closely
who are poor CYP2C9 metabolizers. Severe hepatic impairment (Child-Pugh Class C):
Geriatric Initiate at the lowest recommended dose. Use is not recommended; has not been studied
The AUC in elderly patients (especially females and Mechanism of Action Inhibits prostaglandin synthe-
patients weighing <50 kg) may be increased by 50% sis by decreasing the activity of the enzyme, cyclo-
compared with younger subjects. oxygenase-2 (COX-2), which results in decreased
Renal Impairment: Adult formation of prostaglandin precursors; has antipyretic,
Mild or moderate impairment: There are no dosage analgesic, and anti-inflammatory properties. Celecoxib
adjustments provided in the manufacturer’s labeling; does not inhibit cyclooxygenase-1 (COX-1) at therapeu-
however, since <1% of the drug is excreted in the tic concentrations.
282
CELECOXIB
Contraindications gastrointestinal complications (eg, ulcer) occurs; con-

Hypersensitivity to celecoxib, sulfonamides, aspirin, comitant gastroprotective therapy (eg, proton pump
other NSAIDs, or any component of the formulation; inhibitors) is recommended (Bhatt 2008).
patients who have experienced asthma, urticaria, or
NSAIDs may cause serious skin adverse events includ-
allergic-type reactions after taking aspirin or other
NSAIDs; use in the setting of CABG surgery. ing exfoliative dermatitis, Stevens-Johnson syndrome
Note: Although the FDA approved product labeling (SJS), and toxic epidermal necrolysis (TEN); may occur
states this medication is contraindicated with other without warning and in patients without prior known
sulfonamide-containing drug classes, the scientific sulfa allergy. Anaphylactoid reactions may occur, even
basis of this statement has been challenged. See without prior exposure; patients with "aspirin triad"
"Warnings/Precautions" for more detail. (bronchial asthma, aspirin intolerance, rhinitis) may be
at increased risk. Contraindicated in patients who have
Canadian labeling: Additional contraindications (not in experienced an anaphylactic reaction with NSAID or
US labeling): Pregnancy (third trimester); women who aspirin therapy. The manufacturer’s labeling states to
are breastfeeding; severe, uncontrolled heart failure; not administer to patients with aspirin-sensitive asthma
active gastrointestinal ulcer (gastric, duodenal, pep- due to severe and potentially fatal bronchospasm that
tic); active gastrointestinal bleeding; inflammatory has been reported in such patients having received
bowel disease; cerebrovascular bleeding; severe liver aspirin and the potential for cross reactivity with other
impairment or active hepatic disease; severe renal
NSAIDs. The manufacturer also states to use with
impairment (CrCl <30 mL/minute) or deteriorating
caution in patients with other forms of asthma. How-
renal disease; known hyperkalemia; use in patients
ever, in patients with known aspirin-exacerbated respi-
<18 years of age
ratory disease (AERD), the use of celecoxib initiated at
Warnings/Precautions [US Boxed Warning]:
a low dose with gradual titration in patients with stable,
NSAIDs cause an increased risk of serious (and
mild to moderate persistent asthma has been used
potentially fatal) adverse cardiovascular thrombotic
events, including MI and stroke. Risk may occur without incident (Morales 2013).
early during treatment and may increase with dura- Use with caution in patients with decreased hepatic
tion of use. Relative risk appears to be similar in those (dosage adjustments are recommended for moderate
with and without known cardiovascular disease or risk hepatic impairment; not recommended for patients with
factors for cardiovascular disease; however, absolute severe hepatic impairment) or renal function. Trans-
incidence of cardiovascular events (which may occur aminase elevations have been reported with use;
early during treatment) was higher in patients with closely monitor patients with any abnormal LFT. Rare
known cardiovascular disease or risk factors. New (sometimes fatal), severe hepatic reactions (eg, fulmi-
onset hypertension or exacerbation of hypertension nant hepatitis, hepatic necrosis, hepatic failure) have
may occur (NSAIDs may also impair response to ACE occurred with NSAID use, rarely; discontinue if signs or
inhibitors, thiazide diuretics, or loop diuretics); may
symptoms of liver disease develop, if systemic mani-
contribute to cardiovascular events; monitor blood pres-
festations occur, or with persistent or worsening abnor-
sure; use with caution in patients with hypertension.
mal hepatic function tests. NSAID use may compromise
May cause sodium and fluid retention, use with caution
existing renal function; dose-dependent decreases in
in patients with edema. Avoid use in patients with heart
failure (ACCF/AHA [Yancy 2013]). Avoid use in patients prostaglandin synthesis may result from NSAID use,
with recent MI unless benefits outweigh risk of cardio- causing a reduction in renal blood flow which may
vascular thrombotic events. Long-term cardiovascular cause renal decompensation (usually reversible).
risk in children has not been evaluated. Use the lowest Patients with impaired renal function, dehydration,
effective dose for the shortest duration of time, consis- hypovolemia, heart failure, liver dysfunction, those tak-
tent with individual patient goals, to reduce risk of ing diuretics, ACE inhibitors, angiotensin II receptor
cardiovascular events; alternate therapies should be blockers, and the elderly are at greater risk for renal
considered for patients at high risk. toxicity. Rehydrate patient before starting therapy; mon-
itor renal function closely. Avoid use in patients with
[US Boxed Warning]: Celecoxib is contraindicated advanced renal disease; discontinue use with persistent
in the setting of coronary artery bypass graft sur- or worsening abnormal renal function tests. Long-term
gery (CABG). Risk of MI and stroke may be increased NSAID use may result in renal papillary necrosis.
with use following CABG surgery.
Use with caution in patients with known or suspected
[US Boxed Warning]: NSAIDs cause an increased
deficiency of cytochrome P450 isoenzyme 2C9; poor
risk of serious gastrointestinal inflammation, ulcer-
metabolizers may have higher plasma levels due to
ation, bleeding, and perforation (may be fatal); eld-
reduced metabolism; consider reduced initial doses.
erly patients and patients with history of peptic
Alternate therapies should be considered in patients
ulcer disease and/or GI bleeding are at greater risk
for serious GI events. These events may occur at with JIA who are poor metabolizers of CYP2C9.
any time during therapy and without warning. Avoid Anemia may occur with use; monitor hemoglobin or
use in patients with active GI bleeding. Use caution with hematocrit in patients on long-term treatment. Cele-
a history of GI ulcers, concurrent therapy known to coxib does not affect PT, PTT or platelet counts; does
increase the risk of GI bleeding (eg, aspirin, anticoagu- not inhibit platelet aggregation at approved doses.
lants and/or corticosteroids, selective serotonin reup- Potentially significant drug-drug interactions may exist,
take inhibitors), smoking, use of alcohol, or in the requiring dose or frequency adjustment, additional mon-
elderly or debilitated patients. Use the lowest effective itoring, and/or selection of alternative therapy.
dose for the shortest duration of time, consistent with
individual patient goals, to reduce risk of GI adverse Use with caution in pediatric patients with systemic-
events; alternate therapies should be considered for onset juvenile idiopathic arthritis (JIA); serious adverse
patients at high risk. When used concomitantly with reactions, including disseminated intravascular coagu-
aspirin, a substantial increase in the risk of lation, may occur.
283
CELECOXIB
Sulfonamide ("sulfa") allergy: The FDA-approved prod- Blockers; Angiotensin-Converting Enzyme Inhibitors;
uct labeling for many medications containing a sulfona- Aspirin; Corticosteroids (Systemic); CycloSPORINE
mide chemical group includes a broad contraindication (Systemic); CYP2C9 Inhibitors (Moderate); Dapsone
in patients with a prior allergic reaction to sulfonamides. (Topical); Dexketoprofen; Felbinac; Floctafenine;
There is a potential for cross-reactivity between mem- Herbs (Anticoagulant/Antiplatelet Properties); Ketoro-
bers of a specific class (eg, two antibiotic sulfona- lac (Nasal); Ketorolac (Systemic); Loop Diuretics;
mides). However, concerns for cross-reactivity have Lumacaftor; MiFEPRIStone; Morniflumate; Naftazone;
previously extended to all compounds containing the Nitric Oxide; Nonsteroidal Anti-Inflammatory Agents;
sulfonamide structure (SO2NH2). An expanded under- Pelubiprofen; Phenylbutazone; Probenecid; Selective
standing of allergic mechanisms indicates cross-reac- Serotonin Reuptake Inhibitors; Sodium Phosphates;
tivity between antibiotic sulfonamides and nonantibiotic Talniflumate; Tenoxicam; Thiazide and Thiazide-Like
sulfonamides may not occur or at the very least this Diuretics; Tolperisone; Tricyclic Antidepressants (Ter-
potential is extremely low (Brackett 2004; Johnson tiary Amine); Triflusal; Zaltoprofen
2005; Slatore 2004; Tornero 2004). In particular, mech- Decreased Effect
anisms of cross-reaction due to antibody production Celecoxib may decrease the levels/effects of: Aliski-
(anaphylaxis) are unlikely to occur with nonantibiotic ren; Angiotensin II Receptor Blockers; Angiotensin-
sulfonamides. T-cell-mediated (type IV) reactions (eg, Converting Enzyme Inhibitors; Beta-Blockers; Eplere-
maculopapular rash) are less well understood and it is none; HydrALAZINE; Loop Diuretics; Macimorelin;
not possible to completely exclude this potential based Mifamurtide; Potassium-Sparing Diuretics; Prosta-
on current insights. In cases where prior reactions were glandins (Ophthalmic); Selective Serotonin Reuptake
severe (Stevens-Johnson syndrome/TEN), some clini- Inhibitors; Sincalide; Thiazide and Thiazide-Like Diu-
cians choose to avoid exposure to these classes. retics
Warnings: Additional Pediatric Considerations
Consider alternate therapy in JIA patients who are The levels/effects of Celecoxib may be decreased by:
identified to be CYP2C9 poor metabolizers. In a small Bile Acid Sequestrants; CYP2C9 Inducers (Moderate);
pediatric study (n=4), the AUC of celecoxib was ~10 Dabrafenib; Enzalutamide; Lumacaftor; Rifapentine
times higher in a child who was homozygous for Food Interactions Peak concentrations are delayed
CYP2C9*3, compared to children who were homozy- and AUC is increased by 10% to 20% when taken with a
gous for the *1 allele (n=2) or who had the CYP2C9*1/ high-fat meal. Management: Administer without regard
*2 genotype; further studies are needed to determine if to meals.
carriers of the CYP2C9*3 allele are at increased risk for Pharmacodynamics/Kinetics
cardiovascular toxicity or dose related adverse effects Half-life Elimination Children and Adolescents
of celecoxib, especially with long-term, high-dose use of ~7-16 years (steady-state): 6 ± 2.7 hours (range:
the drug (Stempak 2005). Long-term (>6 months) car- 3-10 hours) (Stempak 2002); Adults: ~11 hours
diovascular toxicity in children and adolescents has not (fasted)
been studied. Time to Peak Children: Median: 3 hours (range: 1-5.8
Drug Interactions hours) (Stempak 2002); Adults: ~3 hours
Metabolism/Transport Effects Substrate of Pregnancy Risk Factor C (prior to 30 weeks gesta-
CYP2C9 (major), CYP3A4 (minor); Note: Assignment tion)/D (≥30 weeks gestation)
of Major/Minor substrate status based on clinically Pregnancy Considerations Birth defects have been
relevant drug interaction potential; Inhibits CYP2D6 observed following in utero NSAID exposure in some
(weak) studies, however data is conflicting (Bloor 2013). Non-
Avoid Concomitant Use teratogenic effects, including prenatal constriction of the
Avoid concomitant use of Celecoxib with any of the ductus arteriosus, persistent pulmonary hypertension of
following: Acemetacin; Aminolevulinic Acid (Sys- the newborn, oligohydramnios, necrotizing enterocolitis,
temic); Dexibuprofen; Dexketoprofen; Floctafenine; renal dysfunction or failure, and intracranial hemor-
Ketorolac (Nasal); Ketorolac (Systemic); Macimorelin; rhage have been observed in the fetus/neonate follow-
Mecamylamine; Mifamurtide; Morniflumate; Nonster- ing in utero NSAID exposure. In addition, non-closure of
oidal Anti-Inflammatory Agents; Nonsteroidal Anti- the ductus arteriosus postnatally may occur and be
Inflammatory Agents (COX-2 Selective); Omacetax- resistant to medical management (Bermas 2014; Bloor
ine; Pelubiprofen; Phenylbutazone; Talniflumate; 2013). Because NSAIDs may cause premature closure
Tenoxicam; Zaltoprofen of the ductus arteriosus, product labeling for celecoxib
Increased Effect/Toxicity specifically states use should be avoided starting at 30
Celecoxib may increase the levels/effects of: 5-Amino- weeks' gestation.
salicylic Acid Derivatives; Ajmaline; Aliskiren; Amino-
gl yco sid es; Am ino lev ulin ic Aci d (Sys temi c); Use of NSAIDs can be considered for the treatment of
Aminolevulinic Acid (Topical); Anticoagulants; ARIPi- mild rheumatoid arthritis flares in pregnant women,
prazole; Bisphosphonate Derivatives; CycloSPORINE however use should be minimized or avoided early
(Systemic); Deferasirox; Desmopressin; Dexibupro- and late in pregnancy (Bermas 2014; Saavedra Salinas
fen; Digoxin; Drospirenone; Eplerenone; Estrogen 2015). Some guidelines recommend avoiding use of
Derivatives; Haloperidol; Lithium; Local Anesthetics; selective Cox-2 inhibitors completely during pregnancy
Mecamylamine; Methotrexate; Nonsteroidal Anti- due to limited data (Flint 2016).
Inflammatory Agents (COX-2 Selective); Omacetax-
The chronic use of NSAIDs in women of reproductive
ine; Perhexiline; Porfimer; Potassium-Sparing Diu-
age may be associated with infertility that is reversible
retics; PRALAtrexate; Prilocaine; Quinolones;
upon discontinuation of the medication. Consider dis-
Sodium Nitrite; Tacrolimus (Systemic); Tenofovir Prod-
continuing use in women having difficulty conceiving or
ucts; Tolperisone; Triflusal; Vancomycin; Verteporfin;
those undergoing investigation of fertility. The use of
Vitamin K Antagonists
NSAIDs close to conception may be associated with an
The levels/effects of Celecoxib may be increased by: increased risk of miscarriage (Bermas 2014;
Acemetacin; Alcohol (Ethyl); Angiotensin II Receptor Bloor 2013).
284
CELLULOSE (OXIDIZED/REGENERATED)
Breastfeeding Considerations events in patients receiving either celecoxib or rofe-

Celecoxib is present in breast milk. coxib. They found an association between the use of
COX-2 inhibitors and cardiovascular events (including
The relative infant dose (RID) of celecoxib is 1.7% when MI and ischemic stroke). The annualized MI rate was
calculated using the highest breast milk concentration found to be significantly higher in patients receiving
located and compared to a weight-adjusted maternal celecoxib or rofecoxib than in the control (placebo)
dose of 200 mg/day. group from a recent meta-analysis of primary preven-
In general, breastfeeding is considered acceptable tion trials. Although cause and effect cannot be estab-
when the RID of a medication is <10% (Anderson lished (these trials were originally designed to assess
2016; Ito 2000). GI effects, not cardiovascular ones), the authors believe
the available data raise a cautionary flag concerning the
The RID of celecoxib was calculated using a milk risk of cardiovascular events with the use of COX-2
concentration of 330 ng/mL, providing an estimated inhibitors.
daily infant dose via breast milk of 0.05 mg/kg/day. This
milk concentration was obtained following maternal Cross-reactivity, including bronchospasm, is a concern
administration of celecoxib 200 mg as a single oral with aspirin and other NSAIDs, in aspirin-sensitive
dose to six postpartum women (Gardiner 2006). In patients. The manufacturer suggests that celecoxib
one study, the half-life of celecoxib in breast milk was should not be administered to patients with this type
calculated to be 4 to 6.5 hours (Knoppert 2003). Peak of aspirin sensitivity and should be used with caution in
concentrations occurred between 2 and 4 hours in patients with preexisting asthma.
breast milk (Gardner 2006; Hale 2004). The manufacturer studied the effect of celecoxib on the
Adverse events were not observed in two breastfeeding anticoagulant effect of warfarin and found no alteration
infants, 17 and 22 months of age. In general, NSAIDs of anticoagulant effect, as determined by prothrombin
may be used in postpartum women who wish to breast- time, in patients taking 2-5 mg daily. However, the
feed (Montgomery 2012); however, use should be manufacturer has issued a caution when using cele-
avoided in women breastfeeding infants with platelet coxib with warfarin since those patients are at increased
dysfunction or thrombocytopenia (Bloor 2013; Sammar- risk of bleeding complications.
itano 2014). Although other agents are preferred, cele-
coxib is considered acceptable for short-term use Cellulose (Oxidized/Regenerated)
(Montgomery 2012). According to the manufacturer, (SEL yoo lose, OKS i dyzed re JEN er aye ted)
the decision to breastfeed during therapy should con-
sider the risk of infant exposure, the benefits of breast- Related Information
feeding to the infant, and benefits of treatment to the Antiplatelet and Anticoagulation Considerations in Den-
mother. tistry on page 1454
Dosage Forms: US Brand Names: US Interceed; Surgicel SNoW 1"x2"
Capsule, Oral: [DSC]; Surgicel SNoW 2"x4" [DSC]; Surgicel SNoW
CeleBREX: 50 mg, 100 mg, 200 mg, 400 mg 4"x4" [DSC]
Generic: 50 mg, 100 mg, 200 mg, 400 mg Pharmacologic Category Hemostatic Agent
Dental Health Professional Considerations The Use Hemostasis: Adjunctive use in surgical procedures
product labeling for all prescription nonsteroidal anti- to control capillary, venous, or small arterial hemor-
inflammatory agents (NSAIDs) now include boxed rhage when ligation or other conventional methods of
warnings regarding an increased risk of cardiovascular control are impractical or ineffective.
(CV) events and gastrointestinal (GI) bleeding associ- Local Anesthetic/Vasoconstrictor Precautions
ated with their use and a contraindication for use in No information available to require special precautions
patients who have recently undergone coronary artery Effects on Dental Treatment No significant effects or
bypass graft (CABG) surgery. Medication guides are complications reported
also now required for these products. Manufacturers Effects on Bleeding No information available to
of over-the-counter products are to include warnings require special precautions
about potential skin reactions, which are already Adverse Reactions <1%, postmarketing, and/or case
included in prescription labeling. reports: Application site burning, application site edema
(encapsulation), blindness (when placed in anterior
The FDA encourages physicians to consider this infor-
cranial fossa), difficulty in micturition (after prostatec-
mation in risk-to-benefit evaluations while considering
tomy), foreign body reaction, headache, neurotoxicity,
the use of the COX-2 selective celecoxib (CeleBREX®)
paralysis, postoperative complication (adhesions; pro-
in patients. Similar COX-2 selective drugs, including
longed drainage after cholecystectomy), sneezing
rofecoxib (Vioxx®) and valdecoxib (Bextra®), were
(epistaxis and rhinological procedures), stinging sensa-
pulled from the market due to increased risks of
tion, ureteral obstruction (after kidney resection), vas-
adverse CV events associated with their use. In addi-
cular insufficiency (stenosis when applied as a wrap)
tion, the FDA advises an evaluation of alternative
Mechanism of Action Cellulose, oxidized regenerated
therapy. If physicians determine that continued use is
is saturated with blood at the bleeding site and swells
appropriate for individual patients, the lowest effective
into a brownish or black gelatinous mass which aids in
dose of celecoxib should be prescribed.
the formation of a clot. When used in small amounts, it
The association between selective COX-2 inhibitors is absorbed from the sites of implantation with little or no
and increased cardiovascular risk has been noted pre- tissue reaction. In addition to providing hemostasis,
viously and prompted by publication of a meta-analysis oxidized regenerated cellulose also has been shown
entitled "Risk of Cardiovascular Events Associated With in vitro to have bactericidal properties. Its hemostatic
Selective COX-2 Inhibitors" in the August 22, 2001, effect is not enhanced by the addition of thrombin.
edition of the Journal of the American Medical Associ- Pregnancy Considerations Has been evaluated for
ation (JAMA). The researchers re-evaluated four pre- use in gynecologic surgeries (Ahmad 2015; Sharma
viously published trials, assessing cardiovascular 2003; Sharma 2006).
285
CEMIPLIMAB-RWLC
response syndrome, uveitis, vasculitis, visual impair-

Cemiplimab-rwlc (SEM ip LI mab rwlc) ment, Vogt-Koyanagi-Harada syndrome
Mechanism of Action Cemiplimab-rwlc is a recombi-
Brand Names: US Libtayo nant human IgG4 monoclonal antibody that inhibits
Pharmacologic Category Antineoplastic Agent, Anti- programmed death-1 (PD-1) activity by binding to PD-
PD-1 Monoclonal Antibody; Antineoplastic Agent, 1 and blocking the interactions with the ligands PD-L1
Immune Checkpoint Inhibitor; Antineoplastic Agent, and PD-L2, releasing PD-1 pathway-mediated inhibition
Monoclonal Antibody of immune response, including anti-tumor response.
Use Cutaneous squamous cell carcinoma, meta- PD-1 ligand upregulation may occur in some tumors
static or locally advanced: Treatment of metastatic and signaling through this pathway can contribute to
cutaneous squamous cell carcinoma (CSCC) or locally inhibition of active T-cell immune surveillance of tumors.
advanced CSCC in patients who are not candidates for Blocking PD-1 activity has resulted in decreased tumor
curative surgery or curative radiation. growth.
No information available to require special precautions Half-life Elimination 19 days
Effects on Dental Treatment No significant effects or Pregnancy Considerations
complications reported Cemiplimab-rwlc is a recombinant human immunoglo-
Effects on Bleeding Therapy with immune checkpoint bulin (IgG4) monoclonal antibody; human IgG4 is
inhibitors may result in significant myelosuppression, known to cross the placenta. Based on the mechanism
including thrombocytopenia. In patients under active of action and information from animal reproduction
treatment a medical consult is suggested. studies, use of cemiplimab-rwlc during pregnancy may
Adverse Reactions cause fetal harm.
>10%:
Central nervous system: Fatigue (29%)
reproductive potential should use effective contracep-
Dermatologic: Skin rash (25%), dermatologic disor-
tion during therapy and for at least 4 months after the
ders (≤2%; with drug reinitiation: 22%), pruri-
last cemiplimab-rwlc dose.
tus (15%)
Gastrointestinal: Diarrhea (22%), nausea (19%), con-
stipation (12%) Cenegermin-bkbj (sen EH jer men bkbj)
Neuromuscular & skeletal: Musculoskeletal
pain (17%) Brand Names: US Oxervate
1% to 10%: Pharmacologic Category Recombinant Human
Cardiovascular: Hypertension (grades 3/4: ≥2%) Nerve Growth Factor
Dermatologic: Cellulitis (grades 3/4: ≥2%), skin infec- Use Neurotrophic keratitis: Treatment of neurotrophic
tion (grades 3/4: ≥2%), erythema multiforme (≤2%), keratitis
pemphigoid (≤2%) Local Anesthetic/Vasoconstrictor Precautions
Endocrine & metabolic: Hypothyroidism (6%), hypo- No information available to require special precautions
phosphatemia (grades 3/4: 4%), hyponatremia Effects on Dental Treatment No significant effects or
(grades 3/4: 3%), hyperthyroidism (2%), hypercalce- complications reported
mia (grades 3/4: 1%), hypoalbuminemia (grades Effects on Bleeding No information available to
3/4: 1%) require special precautions
Gastrointestinal: Decreased appetite (10%) Adverse Reactions
Genitourinary: Urinary tract infection (grades >10%: Ophthalmic: Eye pain (16%)
3/4: ≥2%) 1% to 10%:
Hematologic & oncologic: Lymphocytopenia (grades Central nervous system: Foreign body sensation
3/4: 7%), anemia (grades 3/4: 2%), increased INR Ophthalmic: Corneal deposits, lacrimation, ocular
(grades 3/4: 2%) hyperemia, ophthalmic inflammation
Hepatic: Increased serum aspartate aminotransferase Mechanism of Action Nerve growth factor is an
(grades 3/4: 3%), hepatitis (2%) endogenous protein involved in the differentiation and
Immunologic: Antibody development (1%) maintenance of neurons, which acts through specific
Infection: Sepsis (grades 3/4: ≥2%) high-affinity (ie, TrkA) and low-affinity (ie, p75NTR)
Respiratory: Pneumonia (grades 3/4: ≥2%), pneumo- nerve growth factor receptors in the anterior segment
nitis (≥2%) of the eye to support corneal innervation and integrity.
Frequency not defined: Dermatologic: Stevens-John- Pregnancy Considerations Adverse events were not
son syndrome, toxic epidermal necrolysis observed in animal reproduction studies.
<1%, postmarketing, and/or case reports: Adrenocort-
ical insufficiency, aplastic anemia, arthritis, blindness,
colitis, demyelinating disease, diabetes mellitus, duo- Cephalexin (sef a LEKS in)
denitis, encephalitis, gastritis, Guillain-Barre syn-
Related Information
drome, hematologic disease (hemophagocytic
lymphohistiocytosis), hemolytic anemia, hypophysitis, Antibiotic Prophylaxis on page 1502
immune thrombocytopenia, increased serum amylase, Bacterial Infections on page 1525
increased serum lipase, infusion related reaction, iritis, Related Sample Prescriptions
lymphadenitis (Kikuchi), meningitis, myasthenia, Bacterial Infections and Periodontal Diseases - Sample
myasthenia gravis, myelitis, myocarditis, myositis, Prescriptions on page 36
nephritis, neuropathy (autoimmune), ophthalmic Prevention of Endocarditis and to Reduce the Risk of
inflammation, organ transplant rejection, pancreatitis, Late Infections of Joint Prostheses - Sample Prescrip-
paresis (nerve), pericarditis, polymyalgia rheumatica, tions on page 41
renal failure syndrome, retinal detachment, rhabdo- Brand Names: US Daxbia [DSC]; Keflex
myolysis, sarcoidosis, systemic inflammatory Brand Names: Canada Keflex
286
CEPHALEXIN
Generic Availability (US) Yes Note: In general, patients with prosthetic joint implants
Pharmacologic Category Antibiotic, Cephalosporin do not require prophylactic antibiotics prior to dental
(First Generation) procedures. In planning an invasive oral procedure,
Dental Use Prophylaxis in total joint replacement dental consultation with the patient's orthopedic sur-
patients undergoing dental procedures; alternative oral geon may be advised to review the risks of infection.
antibiotic for prevention of infective endocarditis in Dosing
individuals allergic to penicillins or ampicillin Adult & Geriatric
Note: Individuals allergic to amoxicillin (penicillins) Usual dosage range: Oral: 250 to 1,000 mg every 6
may receive cephalexin provided they have not had hours or 500 mg every 12 hours (maximum: 4 g/day)
an immediate, local, or systemic IgE-mediated ana- Indication-specific dosing:
phylactic allergic reaction to penicillin. Cellulitis (nonpurulent)/erysipelas, mild (alterna-
Use tive agent): Oral: 500 mg 4 times daily for at least 5
Bone infections: Treatment of bone infections caused days (duration should be extended if not resolved/
by Staphylococcus aureus and/or Proteus mirabilis. slow response) (IDSA [Stevens 2014])
Genitourinary tract infections: Treatment of genito- Cystitis, uncomplicated (alternative agent): Oral:
urinary tract infections, including acute prostatitis, 500 mg every 12 hours for 5 to 7 days (Hoo-
caused by Escherichia coli, P. mirabilis, and Klebsiella ton 2018)
pneumoniae. Endocarditis, prophylaxis (dental or invasive res-
Otitis media: Treatment of otitis media caused by piratory tract procedures) (alternative agent)
Streptococcus pneumoniae, Haemophilus influenzae, (off-label use): Oral: 2 g 30 to 60 minutes prior to
S. aureus, Streptococcus pyogenes, and Moraxella procedure. Note: AHA guidelines recommend pro-
catarrhalis. phylaxis only in patients undergoing invasive pro-
Respiratory tract infections: Treatment of respiratory cedures and in whom underlying cardiac conditions
tract infections (including pharyngitis) caused by S. may predispose to a higher risk of adverse out-
pneumoniae and S. pyogenes. comes should infection occur (AHA [Wilson 2007]).
Skin and skin structure infections: Treatment of skin Impetigo or ecthyma: Oral: 250 to 500 mg 4 times
and skin structure infections caused by S. aureus and/ daily for 7 days. Note: Not an appropriate agent if
or S. pyogenes. MRSA is suspected or confirmed (Baddour 2018;
Local Anesthetic/Vasoconstrictor Precautions IDSA [Stevens 2014]).
No information available to require special precautions Prosthetic joint infection (off-label use): Oral:
Effects on Dental Treatment No significant effects or Treatment (following pathogen-specific IV therapy
complications reported (see Dental Health Professional in patients undergoing 1-stage exchange or
Considerations) debridement with retention of prosthesis). Note:
Effects on Bleeding No information available to Duration ranges from a minimum of 3 months to
require special precautions indefinitely, depending on patient-specific factors
Adverse Reactions Frequency not defined. (Berbari 2018):
Central nervous system: Agitation, confusion, dizzi- Staphylococci (methicillin-susceptible): 500 mg
ness, fatigue, hallucination, headache every 6 to 8 hours. For the first 3 to 6 months of
Dermatologic: Erythema multiforme (rare), genital pru- therapy, combine with rifampin (Berbari 2018;
ritus, skin rash, Stevens-Johnson syndrome (rare), IDSA [Osmon 2013]).
toxic epidermal necrolysis (rare), urticaria Streptococci, beta-hemolytic (alternative agent):
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, 500 mg every 6 to 8 hours (Berbari 2018; IDSA
gastritis, nausea (rare), pseudomembranous colitis, [Osmon 2013])
vomiting (rare) Cutibacterium spp (alternative agent): 500 mg
Genitourinary: Genital candidiasis, vaginal discharge, every 6 to 8 hours (IDSA [Osmon 2013]; Kanafani
vaginitis 2018)
Hematologic & oncologic: Eosinophilia, hemolytic ane- Streptococcal pharyngitis (group A) (alternative
mia, neutropenia, thrombocytopenia agent for mild [non-anaphylactic] penicillin
Hepatic: Cholestatic jaundice (rare), hepatitis (transient, allergy): Oral: 500 mg every 12 hours for 10 days
rare), increased serum ALT, increased serum AST (IDSA [Shulman 2012]; Pichichero 2018; manufac-
Hypersensitivity: Anaphylaxis, angioedema, hypersen- turer’s labeling)
sitivity reaction Renal Impairment: Adult
Neuromuscular & skeletal: Arthralgia, arthritis, CrCl ≥60 mL/minute: No dosage adjustment neces-
arthropathy sary.
Renal: Interstitial nephritis (rare) CrCl 30 to 59 mL/minute: There are no specific
Dental Usual Dosage dosage adjustments provided in the manufacturer’s
Prophylaxis against infective endocarditis (dental, oral, labeling; maximum recommended daily dose:
or respiratory tract procedures): Oral: 1,000 mg/day.
Children >1 year: 50 mg/kg 30 to 60 minutes prior to CrCl 15 to 29 mL/minute: 250 mg every 8 to 12 hours
procedure; maximum: 2 g CrCl 5 to 14 mL/minute (not yet on dialysis): 250
Children >15 years and Adults: 2 g 30 to 60 minutes every 24 hours
prior to procedure CrCl 1 to 4 mL/minute (not yet on dialysis): 250 mg
Note: American Heart Association (AHA) guidelines every 48 to 60 hours
now recommend prophylaxis only in patients under- End-stage renal disease (ESRD) on intermittent
going invasive procedures and in whom underlying hemodialysis: There are no dosage adjustments
cardiac conditions may predispose to a higher risk of provided in the manufacturer’s labeling; however,
adverse outcomes should infection occur. the following guidelines have been used by some
Prophylaxis in total joint replacement patients under- clinicians (Aronoff 2007): Oral: 250 to 500 mg every
going dental procedures which produce bacteremia: 12 to 24 hours; moderately dialyzable (20% to 50%);
Oral: Adults: 2 g 1 hour prior to procedure give dose after dialysis session.
287
CEPHALEXIN
Peritoneal dialysis: There are no dosage adjustments invasive procedures and in whom underlying cardiac
provided in the manufacturer’s labeling; however, the conditions may predispose to a higher risk of
following guidelines have been used by some clini- adverse outcomes should infection occur (AHA [Wil-
cians (Aronoff 2007): Oral: 250 to 500 mg every 12 son 2007]).
to 24 hours. Pneumonia, community-acquired: S. aureus
Hepatic Impairment: Adult There are no dosage (methicillin-susceptible), mild infection or step-
adjustments provided in the manufacturer’s labeling. down therapy: Infants >3 months, Children, and
Pediatric Adolescents: Oral: 75 to 100 mg/kg/day in 3 to 4
General dosing, susceptible infection: Infants, Chil- divided doses; maximum daily dose: 4,000 mg/day
dren, and Adolescents: (IDSA/PIDS [Bradley 2011])
Mild to moderate infection: Oral: 25 to 50 mg/kg/day Urinary tract infection:
divided every 6 or 12 hours; maximum daily dose: Empiric therapy in febrile patients: Infants ≥2 months
2,000 mg/day (Red Book [AAP 2015]) and Children <24 months: Oral: 50 to 100 mg/kg/
Severe infection: Oral: 75 to 100 mg/kg/day divided day divided every 6 hours for 7 to 14 days
every 6 to 8 hours; maximum daily dose: 4,000 mg/ (AAP 2011)
day (Bradley 2015; Red Book [AAP 2015]) Treatment:
Catheter (peritoneal dialysis); exit-site or tunnel Children and Adolescents <15 years: Oral: 25 to
infection: Limited data available: Infants, Children, 50 mg/kg/day divided every 6 to 12 hours for 7 to
and Adolescents: Oral: 10 to 20 mg/kg/day once 14 days, maximum dose: 500 mg/dose; for
daily or divided into 2 doses; maximum dose: severe infections, 50 to 100 mg/kg/day divided
1,000 mg/dose (Warady [ISPD] 2012) every 6 to 12 hours may be necessary; maximum
Pharyngitis/tonsillitis (group A streptococcal): daily dose: 4,000 mg/day
Manufacturer's labeling: Note: Experts recommend Adolescents ≥15 years: Oral: 250 mg every 6 hours
dosing on the higher end of the presented range or 500 mg every 12 hours for 7 to 14 days; higher
(IDSA [Shulman 2012]) doses may be necessary for severe infections;
Children and Adolescents <15 years: Oral: 25 to maximum daily dose: 4,000 mg/day.
50 mg/kg/day divided every 12 hours; maximum Osteoarticular infection (eg, septic arthritis, osteo-
dose: 500 mg/dose myelitis); step-down therapy: Infants, Children,
Adolescents ≥15 years: Oral: 500 mg every 12 and Adolescents: Oral: 100 mg/kg/day divided every
hours 6 to 8 hours; maximum daily dose: 4,000 mg/day;
Alternate dosing: IDSA recommendation: Infants, duration of therapy variable, dependent upon clinical
Children, and Adolescents: Oral: 20 mg/kg/dose response and typically extensive (weeks of therapy);
twice daily for 10 days, maximum dose: 500 mg/ compliance should be monitored (Bradley 2015; Red
dose (IDSA [Shulman 2012]) Book [AAP 2015]); a small (n=11) prospective, open-
Impetigo (staphylococcus or streptococcus): label pharmacokinetic study reported a median dose
Infants, Children, and Adolescents: Oral: 25 to of 40 mg/kg/dose every 8 hours (mean age: 7 years;
50 mg/kg/day divided every 6 or 8 hours; maximum range: 1 to 16 years; dose range: 19 to 51 mg/kg/
dose: 250 mg/dose; continue for at least 7 days, full dose every 8 hours) maintained serum concentra-
duration dependent upon clinical response (IDSA tions long enough to meet the pharmacokinetic/phar-
[Stevens 2014]) macodynamic target for efficacy (T>MIC ≥ 40%)
Otitis media, acute (AOM): Infants and Children: (Autmizguine 2013)
Oral: 75 to 100 mg/kg/day divided every 6 hours; Renal Impairment: Pediatric
maximum dose not established for AOM; usual max- Infants, Children, and Adolescents: There are no
imum adult dose for mild to moderate infections: recommendations in the manufacturer's labeling;
500 mg/dose and for severe infections: 1,000 mg/ the following adjustments have been recommended
dose. Note: Cephalexin is not routinely recom- (Aronoff 2007). Note: Renally adjusted dose rec-
mended as an empiric treatment option (AAP [Lie- ommendations are based on doses of 25 to
berthal 2013]). 50 mg/kg/day divided every 6 hours: Oral:
Skin and skin structure infections (eg, cellulitis, CrCl >50 mL/minute/1.73 m2: No adjustment nec-
erysipelas): essary
Manufacturer's labeling: CrCl 30 to 50 mL/minute/1.73 m2: 5 to 10 mg/kg/
Infants, Children, and Adolescents ≤15 years: Oral: dose every 8 hours (maximum dose:
25 to 50 mg/kg/day divided every 12 hours, max- 500 mg/dose)
imum dose: 500 mg/dose; for β-hemolytic strepto- CrCl 10 to 29 mL/minute/1.73 m2: 5 to 10 mg/kg/
coccal infections, a duration of 10 days is dose every 12 hours (maximum dose:
suggested 500 mg/dose)
Adolescents >15 years: 500 mg every 12 hours CrCl <10 mL/minute/1.73 m2: 5 to 10 mg/kg/dose
Alternate dosing: IDSA recommendations: Infants, every 24 hours (maximum dose: 500 mg/dose)
Children, and Adolescents: Oral: 25 to 50 mg/kg/ Intermittent hemodialysis: 5 to 10 mg/kg/dose
day divided every 6 hours; maximum dose: every 24 hours after dialysis (maximum dose:
500 mg/dose; continue for at least 5 days or longer 500 mg/dose)
depending upon clinical response (IDSA [Ste- Peritoneal dialysis: 5 to 10 mg/kg/dose every 24
vens 2014]) hours (maximum dose: 500 mg/dose)
Endocarditis; prophylaxis (dental, oral, or respira- Hepatic Impairment: Pediatric There are no dosing
tory tract procedures): Infants, Children, and Ado- adjustments provided in the manufacturer's labeling.
lescents: Oral: 50 mg/kg administered 30 to 60 Mechanism of Action Inhibits bacterial cell wall syn-
minutes prior to procedure; maximum dose: thesis by binding to one or more of the penicillin-binding
2,000 mg/dose (AHA [Wilson 2007]). Note: Ameri- proteins (PBPs) which in turn inhibits the final trans-
can Heart Association (AHA) guidelines now recom- peptidation step of peptidoglycan synthesis in bacterial
mend prophylaxis only in patients undergoing cell walls, thus inhibiting cell wall biosynthesis. Bacteria
288
CERITINIB
eventually lyse due to ongoing activity of cell wall Peak concentrations in pregnant patients are similar to
autolytic enzymes (autolysins and murein hydrolases) those in nonpregnant patients. Prolonged labor may
while cell wall assembly is arrested. decrease oral absorption (Griffith 1983; Paterson 1972).
Contraindications Hypersensitivity to cephalexin, Breastfeeding Considerations
other cephalosporins, or any component of the formu- Cephalexin is present in breast milk.
lation The relative infant dose (RID) of cephalexin is 0.13% to
Warnings/Precautions Allergic reactions (eg, rash, 0.52% when compared to an infant therapeutic dose
urticaria, angioedema, anaphylaxis, erythema multi- of 25 to 100 mg/kg/day.
forme, Stevens-Johnson syndrome, toxic epidermal In general, breastfeeding is considered acceptable
necrolysis [TEN]) have been reported. If an allergic when the relative infant dose is <10% (Anderson
reaction occurs, discontinue immediately and institute 2016; Ito 2000).
appropriate treatment. Use with caution in patients with The RID of cephalexin was calculated using a milk
a history of seizure disorder; high levels, particularly in concentration of 0.85 mcg/mL, providing an estimated
the presence of renal impairment, may increase risk of daily infant dose via breast milk of 0.13 mg/kg/day.
seizures. Modify dosage in patients with severe renal This milk concentration was obtained following a sin-
impairment. Use with caution in patients with a history gle maternal dose of cephalexin 1 g orally on the third
of penicillin allergy, especially IgE-mediated reactions postpartum day. The mean peak milk concentration
(eg, anaphylaxis, urticaria). Positive direct Coombs occurred 4 to 5 hours after the dose (Kafetzis 1981).
tests and acute intravascular hemolysis has been Slightly higher concentrations of cephalexin were
reported. If anemia develops during or after therapy, detected in the breast milk of a lactating woman also
discontinue use and work up for drug-induced hemolytic administered probenecid and cephalexin for ≥16 days
anemia. Prolonged use may result in fungal or bacterial (Ilett 2006).
superinfection, including C. difficile-associated diarrhea Diarrhea has been reported in breastfeeding infants
(CDAD) and pseudomembranous colitis; CDAD has (Ilett 2006; Ito 1993). In general, antibiotics that are
been observed >2 months postantibiotic treatment. present in breast milk may cause non-dose-related
May be associated with increased INR, especially in modification of bowel flora. Monitor infants for GI
nutritionally-deficient patients, prolonged treatment, disturbances (WHO 2002).
hepatic or renal disease. Potentially significant interac- When an antibiotic is needed, cephalexin may be used
tions may exist, requiring dose or frequency adjust- to treat mastitis in breastfeeding women allergic to
ment, additional monitoring, and/or selection of preferred agents (Amir 2014; Berens 2015). According
alternative therapy. to the manufacturer, the decision to breastfeed during
Drug Interactions therapy should consider the risk of infant exposure,
Metabolism/Transport Effects None known. the benefits of breastfeeding to the infant, and benefits
Avoid Concomitant Use of treatment to the mother
Avoid concomitant use of Cephalexin with any of the Dosage Forms: US
following: BCG (Intravesical); Cholera Vaccine Capsule, Oral:
Keflex: 250 mg, 500 mg, 750 mg
Generic: 250 mg, 500 mg, 750 mg
Cephalexin may increase the levels/effects of: Met-
Suspension Reconstituted, Oral:
FORMIN; Vitamin K Antagonists
Generic: 125 mg/5 mL (100 mL, 200 mL); 250 mg/5
The levels/effects of Cephalexin may be increased by: mL (100 mL, 200 mL)
Probenecid Tablet, Oral:
Decreased Effect Generic: 250 mg, 500 mg
Cephalexin may decrease the levels/effects of: BCG Dental Health Professional Considerations Ceph-
(Intravesical); BCG Vaccine (Immunization); Cholera alexin is effective against anaerobic bacteria, but the
Vaccine; Lactobacillus and Estriol; Sodium Picosul- sensitivity of alpha-hemolytic Streptococcus vary;
fate; Typhoid Vaccine approximately 10% of strains are resistant. Nearly
70% are intermediately sensitive. Patients allergic to
The levels/effects of Cephalexin may be decreased penicillins can use a cephalosporin; the incidence of
by: Multivitamins/Minerals (with ADEK, Folate, Iron); cross-reactivity between penicillins and cephalosporins
Multivitamins/Minerals (with AE, No Iron); Sucroferric is 1% to 5% when the allergic reaction to penicillin is
Oxyhydroxide; Zinc Salts delayed. If the patient has a history of anaphylaxis to
Food Interactions Peak antibiotic serum concentration penicillin, cephalosporins are contraindicated in these
is lowered and delayed, but total drug absorbed is not patients.
affected. Cephalexin serum levels may be decreased if
taken with food. Management: Administer without
regard to food. Ceritinib (se RI ti nib)
Brand Names: US Zykadia
Half-life Elimination Neonates: 5 hours; Children
3-12 months: 2.5 hours; Adults: 0.5 to 1.2 hours Brand Names: Canada Zykadia
(prolonged with renal impairment) Pharmacologic Category Antineoplastic Agent, Ana-
Time to Peak Serum: ~1 hour plastic Lymphoma Kinase Inhibitor; Antineoplastic
Agent, Tyrosine Kinase Inhibitor
Cephalexin crosses the placenta and produces thera-
Use Non-small cell lung cancer, metastatic: Treat-
ment of anaplastic lymphoma kinase (ALK)-positive
peutic concentrations in the fetal circulation and amni-
(as detected by an approved test) metastatic non-small
otic fluid (Creatsas 1980).
cell lung cancer (NSCLC).
An increased risk of major birth defects or other adverse Local Anesthetic/Vasoconstrictor Precautions
fetal or maternal outcomes has generally not been Ceritinib is one of the drugs confirmed to prolong the
observed following use of cephalosporin antibiotics, QT interval and is accepted as having a risk of causing
including cephalexin, during pregnancy torsade de pointes. The risk of drug-induced torsade de
289
CERITINIB
pointes is extremely low when a single QT interval also inhibits insulin-like growth factor 1 receptor (IGF-
prolonging drug is prescribed. In terms of epinephrine, 1R), insulin receptor (InsR), and ROS1. Ceritinib has
it is not known what effect vasoconstrictors in the local demonstrated activity in crizotinib-resistant tumors in
anesthetic regimen will have in patients with a known NSCLC xenograft models.
history of congenital prolonged QT interval or in patients Pharmacodynamics/Kinetics
taking any medication that prolongs the QT interval. Half-life Elimination 41 hours (following a single
Until more information is obtained, it is suggested that 750 mg fasted dose)
the clinician consult with the physician prior to the use of Time to Peak ~4 to 6 hours
a vasoconstrictor in suspected patients, and that the Pregnancy Considerations Based on findings in
vasoconstrictor (epinephrine, mepivacaine and levonor- animal reproduction studies and its mechanism of
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used action, ceritinib may cause fetal harm if administered
with caution. to a pregnant woman. Women of reproductive potential
Effects on Dental Treatment No significant effects or should use effective contraception during treatment and
complications reported for 6 months following therapy discontinuation. Based
Effects on Bleeding No information available to on the potential for genotoxicity, males with female
require special precautions partners of reproductive potential should use condoms
Adverse Reactions during treatment and for 3 months following completion
>10%: of therapy.
Cardiovascular: Prolonged Q-T interval on ECG (4% Dental Health Professional Considerations See
to 12%) Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Fatigue (45% to 52%), non-
cardiac chest pain (21%), headache (19%), neuro-
pathy (17%), dizziness (12%) Certolizumab Pegol (cer to LIZ u mab PEG ol)
Dermatologic: Skin rash (16% to 21%), pruritus (11%)
Endocrine & metabolic: Increased gamma-glutamyl Related Information
transferase (84%), hyperglycemia (49% to 53%), Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
decreased serum phosphate (36% to 38%), weight on page 1484
loss (24%) Brand Names: US Cimzia; Cimzia Prefilled; Cimzia
Gastrointestinal: Diarrhea (56% to 86%), nausea (45% Starter Kit
to 80%), vomiting (35% to 67%), abdominal pain Brand Names: Canada Cimzia
(40% to 54%), increased serum amylase (37%), Pharmacologic Category Antirheumatic, Disease
decreased appetite (34%), constipation (20% to Modifying; Gastrointestinal Agent, Miscellaneous;
29%), increased serum lipase (13% to 28%), dys- Tumor Necrosis Factor (TNF) Blocking Agent
pepsia (≤16%), dysphagia (≤16%), gastroesopha- Use
geal reflux disease (≤16%) Ankylosing spondylitis: Treatment of adults with
Hematologic & oncologic: Anemia (67% to 84%; active ankylosing spondylitis (AS)
grades 3/4: 4% to 5%), neutropenia (27%; grades Crohn disease: Treatment of moderately to severely
3/4: 2%), thrombocytopenia (16%; grades 3/4: 1%) active Crohn disease in patients who have inadequate
Hepatic: Increased serum ALT (80% to 91%; >5x ULN: response to conventional therapy
28%), increased serum AST (75% to 86%; >5x ULN: Plaque psoriasis: Treatment of moderate to severe
16%), increased serum alkaline phosphatase (81%), plaque psoriasis in adults who are candidates for
increased serum bilirubin (15%) systemic therapy or phototherapy
Neuromuscular & skeletal; Back pain (19%), limb pain Psoriatic arthritis: Treatment of adult patients with
(13%), musculoskeletal pain (11%) active psoriatic arthritis
Renal: Increased serum creatinine (58% to 77%) Rheumatoid arthritis: Treatment of adults with mod-
Respiratory: Cough (25%) erately to severely active rheumatoid arthritis (RA) (as
Miscellaneous: Fever (19%) monotherapy or in combination with nonbiological
1% to 10%: disease-modifying antirheumatic drugs [DMARDS])
Cardiovascular: Pericarditis (4%), bradycardia (1% to
4%) pericardial effusion (≥2%), sinus bradycar-
dia (1%)
Central nervous system: Seizure (≥2%) Effects on Dental Treatment Key adverse event(s)
Endocrine & metabolic: Dehydration (≥2%) related to dental treatment: Aphthous ulcers reported in
Hepatic: Hepatotoxicity (2%) <1% of patients.
Ophthalmic: Visual disturbance (4% to 9%) Effects on Bleeding No information available to
Renal: Renal failure (2%) require special precautions
Respiratory: Pleural effusion (4%), pneumonia (4%), Adverse Reactions
interstitial pulmonary disease (2% to 4%), pulmonary >10%:
infection (≥2%), severe dyspnea (≥2%) Gastrointestinal: Nausea (≤11% [Schreiber 2005])
<1%, postmarketing and/or case reports: Pancreatitis Immunologic: Antibody development (7% to 23%)
Mechanism of Action Ceritinib is a potent inhibitor of Infection: Infection (38%; serious: 3%)
anaplastic lymphoma kinase (ALK), a tyrosine kinase Respiratory: Upper respiratory tract infection (6%
involved in the pathogenesis of non-small cell lung to 20%)
cancer. ALK gene abnormalities due to mutations or 1% to 10%:
translocations may result in expression of oncogenic Cardiovascular: Hypertension (≤5%), angina pectoris
fusion proteins (eg, ALK fusion protein) which alter (<5%), atrial fibrillation (<5%), cardiac arrhythmia
signaling and expression and result in increased cellu- (<5%), cardiac failure (<5%; new or worsening),
lar proliferation and survival in tumors which express cerebrovascular accident (<5%), hypertensive heart
these fusion proteins. ALK inhibition reduces prolifer- disease (<5%), ischemic heart disease (<5%), myo-
ation of cells expressing the genetic alteration. Ceritinib cardial infarction (<5%), pericardial effusion (<5%),
290
CETIRIZINE (SYSTEMIC)
pericarditis (<5%), transient ischemic attacks (<5%), live or live-attenuated vaccines to exposed infants is not
vasculitis (<5%) known.
Central nervous system: Headache (5%), anxiety
If a biologic agent such as certolizumab is needed to
(<5%), bipolar mood disorder (<5%), suicidal tenden-
treat inflammatory bowel disease during pregnancy, it is
cies (<5%), fatigue (≤3%)
recommended to hold therapy after 30 weeks gestation
Dermatologic: Skin rash (≤9%), alopecia (<5%), der-
(Habal 2012). However, due to the low level of placental
matitis (<5%), erythema nodosum (<5%), urtica-
transfer compared to other biologic agents, certolizu-
ria (<5%)
mab may be considered for use throughout pregnancy
Endocrine & metabolic: Menstrual disease (<5%)
for rheumatic diseases when necessary (Götestam
Genitourinary: Urinary tract infection (≤8%), nephrotic
Skorpen 2016; Mariette 2018).
syndrome (<5%)
Hematologic & oncologic: Anemia (<5%), hemorrhage Health care providers are encouraged to enroll women
(<5%), hypercoagulability state (<5%), leukopenia exposed to certolizumab during pregnancy in the Moth-
(<5%), lymphadenopathy (<5%), pancytopenia erToBaby Pregnancy Studies by contacting the Organ-
(<5%), thrombophlebitis (<5%), positive ANA ization of Teratology Information Specialists (OTIS)
titer (≤4%) (877-311-8972) or http://mothertobaby.org/pregnancy-
Hepatic: Hepatitis (<5%), increased serum transami- studies/.
nases (<5%)
Neuromuscular & skeletal: Arthralgia (6% to 7%), back Cetirizine (Systemic) (se TI ra zeen)
pain (≤4%)
Ophthalmic: Optic neuritis (<5%), retinal hemorrhage Brand Names: US All Day Allergy Childrens [OTC]; All
(<5%), uveitis (<5%) Day Allergy [OTC]; Allergy Relief [OTC]; Allergy Relief/
Renal: Renal failure (<5%) Indoor/Outdoor [OTC]; Cetirizine HCl Allergy Child
Respiratory: Cough (≤6%), nasopharyngitis (5%), [OTC]; Cetirizine HCl Childrens Alrgy [OTC]; Cetirizine
tuberculosis (<5%; peritoneal, pulmonary, and dis- HCl Childrens [OTC]; Cetirizine HCl Hives Relief [OTC];
seminated), bronchitis (≤3%), pharyngitis (≤3%) GoodSense All Day Allergy [OTC]; ZyrTEC Allergy
Miscellaneous: Fever (3%) Childrens [OTC]; ZyrTEC Allergy [OTC]; ZyrTEC Child-
<1%, postmarketing, and/or case reports: Abdominal rens Allergy [OTC]
pain, aplastic anemia, autoimmune hepatitis (Shelton Brand Names: Canada Aller-Relief [OTC]; Apo-Cetir-
2015), cytopenia, demyelinating disease (exacerba- izine [OTC]; Extra Strength Allergy Relief [OTC]; PMS-
tion), diarrhea, fistula, hepatosplenic T-cell lymphoma, Cetirizine; Reactine; Reactine [OTC]
herpes virus infection, hypersensitivity reaction (eg, Pharmacologic Category Histamine H1 Antagonist;
allergic dermatitis, angioedema, dizziness [postural], Histamine H1 Antagonist, Second Generation; Pipera-
dyspnea, hepatotoxicity (idiosyncratic) (Chalasani zine Derivative
2014), hot flush, hypotension, injection site reactions, Use
malaise, serum sickness, syncope), intestinal obstruc- Upper respiratory allergies: Temporarily relieves
tion, leukemia, limb pain, lupus erythematosus, lupus- symptoms of upper respiratory allergies.
like syndrome, lymphoma, malignant melanoma, Urticaria: Relieves itching due to urticaria.
malignant neoplasm, Merkel cell carcinoma, neoplasm Local Anesthetic/Vasoconstrictor Precautions
(benign, malignant, and unspecified; including cysts No information available to require special precautions
and polyps), opportunistic infection (rare), peripheral Effects on Dental Treatment Key adverse event(s)
edema, peripheral neuropathy, pneumonia, psoriasis related to dental treatment: Xerostomia and decreased
(including new onset, palmoplantar, pustular, or exac- salivation (normal salivary flow resumes upon discon-
erbation), pyelonephritis, reactivation of HBV, sarcoi- tinuation).
dosis, seizure, sensory disturbance, Effects on Bleeding No information available to
thrombocytopenia, viral infection, weakness require special precautions
Mechanism of Action Certolizumab is a pegylated Adverse Reactions
humanized antibody Fab’ fragment of tumor necrosis >10%: Central nervous system: Drowsiness (adults
factor alpha (TNF-alpha) monoclonal antibody. Certoli- 14%; children 2% to 4%), headache (children 11% to
zumab binds to and selectively neutralizes human TNF- 14%, placebo 12%)
alpha activity. (Elevated levels of TNF-alpha have a role 2% to 10%:
in the inflammatory process associated with Crohn Central nervous system: Insomnia (children 9%;
disease and in joint destruction associated with rheu- adults <2%), fatigue (adults 6%), malaise (4%),
matoid arthritis.) Since it is not a complete antibody dizziness (adults 2%)
(lacks Fc region), it does not induce complement acti- Gastrointestinal: Abdominal pain (children 4% to 6%),
vation, antibody-dependent cell-mediated cytotoxicity, xerostomia (adults 5%), diarrhea (children 2% to
or apoptosis. Pegylation of certolizumab allows for 3%), nausea (children 2% to 3%; placebo 2%),
delayed elimination and therefore an extended half-life. vomiting (children 2% to 3%)
Pharmacodynamics/Kinetics Respiratory: Pharyngitis (children 3% to 6%; placebo
Half-life Elimination ~14 days 3%), epistaxis (children 2% to 4%; placebo 3%),
Time to Peak Plasma: 54 to 171 hours bronchospasm (children 2% to 3%; placebo 2%)
Pregnancy Considerations <2% (as reported in adults and/or children): Abnormality
Certolizumab crosses the placenta (Förger 2016; Mari- in thinking, accommodation disturbance, acne vulga-
ette 2018). Serum concentrations in 12 infants of 10 ris, ageusia, alopecia, altered sense of smell, amne-
mothers were ≥75% lower than the maternal serum at sia, anaphylaxis, angioedema, anorexia, anxiety,
delivery (last maternal dose of 400 mg given 5 to 42 aphthous stomatitis, arthralgia, arthritis, ataxia, back
days prior to birth). Although placental transfer was low, pain, blepharoptosis, blindness, bronchitis, bullous
infants may have a slower rate of elimination than rash, cardiac failure, chest pain, cholestasis, confu-
adults (Mahadevan 2013). The safety of administering sion, conjunctivitis, constipation, cutaneous nodules,
291
CETIRIZINE (SYSTEMIC)
cystitis, deafness, decreased libido, dehydration, leucovorin] as first-line treatment, in combination with
depersonalization, depression, dermatitis, dermato- irinotecan [in patients refractory to irinotecan-based
logical disease, diabetes mellitus, diaphoresis, dys- chemotherapy], or as a single agent in patients who
geusia, dysmenorrhea, dyspepsia, dyspnea, dysuria, have failed irinotecan- and oxaliplatin-based chemo-
eczema, edema, emotional lability, enlargement of therapy or who are intolerant to irinotecan).
abdomen, eructation, erythematous rash, euphoria, Limitation of use: Cetuximab is not indicated for the
eye pain, facial edema, fever, flatulence, flushing, treatment of RAS-mutant colorectal cancer or when
furunculosis, fussiness, gastritis, glaucoma, glomeru- results of the RAS mutation tests are unknown.
lonephritis, hematuria, hemolytic anemia, hemophthal- Head and neck cancer, squamous cell: Treatment of
mos, hemorrhoids, hepatic insufficiency, hepatitis, hot squamous cell cancer of the head and neck (as a
flash, hyperesthesia, hyperkeratosis, hyperkinesia, single agent for recurrent or metastatic disease after
hypermenorrhea, hypertension, hypertonia, hypertri- platinum-based chemotherapy failure; in combination
chosis, hyperventilation, hypoesthesia, hypotension, with radiation therapy as initial treatment of locally or
increased appetite, increased bronchial secretions, regionally advanced disease; in combination with plat-
increased liver enzymes (transient), increased serum inum and fluorouracil-based chemotherapy as first-line
bilirubin, increased thirst, intermenstrual bleeding, irri- treatment of locoregional or metastatic disease).
tability, lack of concentration, leg cramps, leukorrhea, Local Anesthetic/Vasoconstrictor Precautions
lower extremity edema, lymphadenopathy, maculo- No information available to require special precautions
papular rash, mastalgia (female), melena, migraine, Effects on Dental Treatment No significant effects or
myalgia, myasthenia, myelitis, myocardial infarction, complications reported
nasal polyposis, nervousness, nightmares, orofacial Effects on Bleeding No information available to
dyskinesia, osteoarthritis, otalgia, ototoxicity, pain, require special precautions
pallor, palpitations, paralysis, paresthesia, periorbital Adverse Reactions
edema, pneumonia, polyuria, pruritus, purpura, rectal >10%:
hemorrhage, respiratory tract disease, rhinitis, rigors, Cardiovascular: Cardiac disorder (6% to 11%)
seborrhea, sialorrhea, sinusitis, skin photosensitivity, Central nervous system: Fatigue (91%), malaise
skin rash, sleep disorder, stomatitis, syncope, tachy- (≤73%), pain (59%), peripheral sensory neuropathy
cardia, thrombocytopenia, tinnitus, tongue discolora- (45%; grades 3/4: 1%), headache (19% to 38%),
tion, tongue edema, tremor, twitching, upper insomnia (27%), confusion (18%), chills (≤16%),
respiratory tract infection, urinary frequency, urinary rigors (≤16%), anxiety (14%), depression (14%)
incontinence, urinary retention, urinary tract infection, Dermatologic: Desquamation (95%), acneiform erup-
urticaria, vaginitis, vertigo, visual field defect, voice tion (15% to 88%), radiodermatitis (86%), xeroderma
disorder, weakness, weight gain, xeroderma, xeroph- (14% to 57%), pruritus (14% to 47%), skin rash (28%
thalmia to 44%), changes in nails (31%), acne vulgaris (14%
Postmarketing and/or case reports: Aggressive behav- to 22%), paronychia (20%), palmar-plantar erythro-
ior, convulsions, hallucination, hypotension (severe), dysesthesia (19%), skin fissure (19%), alope-
suicidal ideation cia (12%)
Mechanism of Action Competes with histamine for Endocrine & metabolic: Weight loss (15% to 84%),
H1-receptor sites on effector cells in the gastrointestinal hypomagnesemia (6% to 55%), dehydration (13% to
tract, blood vessels, and respiratory tract 25%), hypocalcemia (12%), hypokalemia (12%)
Pharmacodynamics/Kinetics Gastrointestinal: Diarrhea (19% to 72%), nausea (49%
Onset of Action Suppression of skin wheal and flare: to 64%), abdominal pain (59%), constipation (53%),
0.7 hours (Simons, 1999) vomiting (29% to 40%), stomatitis (31% to 32%;
Duration of Action Suppression of skin wheal and grades 3/4: 1% to 3%), anorexia (25% to 30%),
flare: ≥24 hours (Simons, 1999) dyspepsia (14% to 16%), xerostomia (12%)
Half-life Elimination Children: 6.2 hours; Adults: 8 Hematologic & oncologic: Neutropenia (49%; grades
hours 3/4: 31%), leukopenia (grades 3/4: 17%)
Time to Peak Serum: 1 hour Hepatic: Increased serum alanine aminotransferase
Pregnancy Considerations Guidelines for the use of (43%), increased serum aspartate aminotransferase
antihistamines in the treatment of allergic rhinitis or (38%), increased serum alkaline phosphatase (33%)
urticaria in pregnancy are generally the same as in Infection: Infection (13% to 44%), infection without
nonpregnant females. Cetirizine may be used when a neutropenia (38%)
second generation antihistamine is needed. The lowest Local: Application site reaction (18%)
effective dose should be used (Powell 2015; Scadding Neuromuscular & skeletal: Asthenia (≤73%), ostealgia
2017; Wallace 2008; Zuberbier 2018). (15%), arthralgia (14%)
Ophthalmic: Conjunctivitis (10% to 18%)
Respiratory: Dyspnea (49%), cough (30%), pharyngi-
Cetuximab (se TUK see mab) tis (26%)
Miscellaneous: Fever (22% to 29%), infusion related
Brand Names: US Erbitux reaction (8% to 18%)
Brand Names: Canada Erbitux 1% to 10%:
Pharmacologic Category Antineoplastic Agent, Epi- Cardiovascular: Ischemic heart disease (2%)
dermal Growth Factor Receptor (EGFR) Inhibitor; Anti- Gastrointestinal: Dysgeusia (10%)
neoplastic Agent, Monoclonal Antibody Immunologic: Antibody development (<5%)
Use Infection: Sepsis (1% to 4%)
Colorectal cancer, metastatic: Treatment of KRAS Renal: Renal failure syndrome (1%: colorectal cancer
wild-type (without mutation), epidermal growth factor patients; frequency not defined in other populations)
receptor (EGFR)-expressing metastatic colorectal Frequency not defined:
cancer as determined by an approved test (in combi- Dermatologic: Hypertrichosis
nation with FOLFIRI [irinotecan, fluorouracil, and Endocrine & metabolic: Electrolyte disorder
292
CEVIMELINE
<1%, postmarketing, and/or case reports: Abscess, Warnings/Precautions If an amount greater than
aseptic meningitis, blepharitis, bullous pemphigoid, used for rinsing is swallowed, seek professional assis-
cardiac arrhythmia, cellulitis, cheilitis, corneal ulcer, tance or contact a poison control center immediately.
interstitial pulmonary disease, keratitis, mucositis, Stop use and consult a healthcare professional if symp-
myocardial infarction, skin infection, Stevens-Johnson toms or condition worsens or persists; if gingivitis,
syndrome, toxic epidermal necrolysis bleeding, or redness persists for more than 2 weeks;
Mechanism of Action Cetuximab is a recombinant if gums are painful and swollen; if pus from the gum line,
human/mouse chimeric monoclonal antibody which loose teeth, or increased spacing between the teeth
binds specifically to the epidermal growth factor recep- occurs. Avoid contact with eyes.
tor (EGFR, HER1, c-ErbB-1) and competitively inhibits Drug Interactions
the binding of epidermal growth factor (EGF) and other Metabolism/Transport Effects None known.
ligands. Binding to the EGFR blocks phosphorylation Avoid Concomitant Use There are no known inter-
and activation of receptor-associated kinases, resulting actions where it is recommended to avoid concomitant
in inhibition of cell growth, induction of apoptosis, and use.
decreased matrix metalloproteinase and vascular endo- Increased Effect/Toxicity There are no known sig-
thelial growth factor production. EGFR signal trans- nificant interactions involving an increase in effect.
duction results in RAS wild-type activation; cells with Decreased Effect There are no known significant
RAS mutations appear to be unaffected by EGFR interactions involving a decrease in effect.
inhibition. Pregnancy Considerations Cetylpyridinium chloride
Pharmacodynamics/Kinetics mouthwash (alcohol free) has been associated with a
Half-life Elimination ~112 hours (range: 63 to 230 reduction in preterm births in pregnant women with
hours) periodontal disease (Jeffcoat, 2011).
Pregnancy Considerations Dosage Forms: US
Based on animal data and the mechanism of action, Liquid, Mouth/Throat:
cetuximab may be expected to cause fetal harm if Cepacol Antibacterial [OTC]: 0.05% (710 mL)
administered during pregnancy. Clean Zing [OTC]: 0.06% (480 mL)
Lozenge, Mouth/Throat:
Verify pregnancy status in females of reproductive Larynex [OTC]: (500 ea)
potential prior to treatment initiation. The manufacturer Dental Health Professional Considerations
recommends that females of reproductive potential use Numerous mouthwashes contain cetylpyridinium,
effective contraception during therapy and for 2 months review product labeling for additional information.
following the last dose of cetuximab.
Cevimeline (se vi ME leen)

Cetylpyridinium (SEE til peer i DI nee um)
Related Information
Brand Names: US Antiseptic Oral Rinse [OTC] [DSC]; Dentin Hypersensitivity, Acid Erosion, High Caries
Breath Rx [OTC] [DSC]; Cepacol Antibacterial [OTC]; Index, Management of Alveolar Osteitis, and Xerosto-
Clean Zing [OTC]; Larynex [OTC] mia on page 1548
Generic Availability (US) Yes Perioral Premalignant Lesions and Management of
Pharmacologic Category Antiseptic, Oral Mouth- Patients Undergoing Cancer Therapy on page 1567
wash Brand Names: US Evoxac
Dental Use Antiseptic to aid in the prevention and Generic Availability (US) Yes
reduction of plaque and gingivitis, and to freshen breath Pharmacologic Category Cholinergic Agonist
Use Antiseptic to aid in the prevention and reduction of Dental Use Treatment of symptoms of dry mouth in
plaque and gingivitis, and to freshen breath patients with Sjögren's syndrome
Local Anesthetic/Vasoconstrictor Precautions Use Xerostomia (associated with Sjögren's syn-
No information available to require special precautions drome): Treatment of symptoms of dry mouth in
Effects on Dental Treatment Key adverse event(s) patients with Sjögren's syndrome.
related to dental treatment: Tooth and tongue staining Local Anesthetic/Vasoconstrictor Precautions
and oral irritation. No information available to require special precautions
require special precautions related to dental treatment: Excessive salivation, sali-
Adverse Reactions Frequency not defined. Gastro- vary gland pain
intestinal: Dental discoloration, mouth irritation, tongue Effects on Bleeding No information available to
discoloration require special precautions
Dental Usual Dosage Prevention and reduction of Adverse Reactions Frequency not always defined.
plaque and gingivitis, and to freshen breath: Children >10%:
≥6 years and Adults: Oral (OTC labeling): Rinse or Dermatologic: Diaphoresis (19%)
gargle as directed; may be used before or after brush- Gastrointestinal: Nausea (14%)
ing (2 times/day) Respiratory: Sinusitis (12%), rhinitis (11%), upper res-
Dosing piratory tract infection (11%)
Adult & Geriatric Antiseptic (OTC labeling): Oral: 1% to 10%:
Swish 20 mL thoroughly between teeth for 30 seconds Cardiovascular: Chest pain, edema, palpitations,
then spit; use twice daily; may be used before or after peripheral edema
brushing; do not swallow. Central nervous system: Fatigue (3%), insomnia (2%),
Pediatric Antiseptic (OTC labeling): Children ≥6 depression, hypertonia, hypoesthesia, hyporeflexia,
years: Refer to adult dosing. migraine, vertigo
Contraindications Hypersensitivity to cetylpyridinium Dermatologic: Dermatological disease, erythematous
or any component of the formulation rash, pruritus
293
CEVIMELINE
Endocrine & metabolic: Hot flash (2%), increased Warnings/Precautions May alter cardiac conduction
amylase and/or heart rate; use caution in patients with significant
Gastrointestinal: Abdominal pain (8%), vomiting (5%), cardiovascular disease, including angina, or myocardial
sialorrhea (2%), anorexia, aphthous stomatitis, con- infarction. Cevimeline has the potential to increase
stipation, eructation, flatulence, gastroesophageal bronchial smooth muscle tone, airway resistance, and
reflux disease, hiccups, salivary gland pain, sialade- bronchial secretions; use with caution in patients with
nitis, toothache, xerostomia controlled asthma, COPD, or chronic bronchitis. May
Genitourinary: Urinary tract infection (6%), cystitis, cause blurred vision, decreased visual acuity (particu-
vaginitis larly at night and in patients with central lens changes)
Hematologic & oncologic: Anemia and impaired depth perception. Patients should be
Hypersensitivity: Hypersensitivity reaction cautioned about driving at night or performing hazard-
Infection: Abscess, candidiasis, fungal infection, ous activities in reduced lighting. Use with caution in
infection patients with a history of cholelithiasis; may induce
Neuromuscular & skeletal: Back pain (5%), arthralgia contractions of the gallbladder or biliary smooth muscle,
(4%), skeletal pain (3%), weakness (1%), leg precipitating complications such as cholangitis, chole-
cramps, myalgia, tremor cystitis, or biliary obstruction.
Ophthalmic: Eye disease, eye infection, eye pain, Use with caution in patients with a history of cholelithia-
visual disturbance, xerophthalmia sis; may induce contractions of the gallbladder or biliary
Otic: Otalgia, otitis media smooth muscle, precipitating complications such as
Respiratory: Cough (6%), bronchitis (4%), epistaxis, cholangitis, cholecystitis, or biliary obstruction. Use with
flu-like symptoms, pneumonia caution in patients with a history of nephrolithiasis; may
Miscellaneous: Accidental injury (5%), fever induce smooth muscle spasms, precipitating renal colic
<1%, postmarketing, and/or case reports: acute exac- or ureteral reflux in patients with nephrolithiasis.
erbations of multiple sclerosis, aggressive behavior, Patients with a known or suspected deficiency of
alopecia, angina pectoris, anterior chamber eye hem- CYP2D6 may be at higher risk of adverse effects.
orrhage, aphasia, apnea, arthropathy, avascular Drug Interactions
necrosis of femoral head, bronchospasm, bullous Metabolism/Transport Effects Substrate of
rash, bundle branch block, cardiac arrhythmia, cardiac CYP2D6 (minor), CYP3A4 (minor); Note: Assignment
disease, cholecystitis, cholelithiasis, cholinergic syn- of Major/Minor substrate status based on clinically
drome, deafness, dehydration, delirium, dementia, relevant drug interaction potential
depersonalization, diabetes mellitus, dyskinesia, Avoid Concomitant Use There are no known inter-
ECG abnormality, emotional lability, eosinophilia, actions where it is recommended to avoid concomitant
esophageal stenosis, esophagitis, extrasystoles, facial use.
edema, gastric ulcer, gastrointestinal hemorrhage, Increased Effect/Toxicity
gingival hyperplasia, glaucoma, granulocytopenia, The levels/effects of Cevimeline may be increased by:
hallucination, hematoma, hematuria, hepatic insuffi- Acetylcholinesterase Inhibitors; Beta-Blockers
ciency, hyperglycemia, hyperkalemia, hypertension, Decreased Effect
hypoglycemia, hypotension, hypothyroidism, immune Cevimeline may decrease the levels/effects of: Cime-
thrombocytopenia, impotence, increased liver tropium; Sincalide
enzymes, intestinal obstruction, inversion T wave on Pharmacodynamics/Kinetics
ECG, irritable bowel syndrome, leukopenia, lympho- Half-life Elimination 5 ± 1 hours
cytosis, manic reaction, menstrual disease, myocar- Time to Peak 1.5 to 2 hours
dial infarction, nephrolithiasis, neuropathy, paralysis, Pregnancy Considerations Adverse effects were
paranoia, paresthesia, peptic ulcer, pericarditis, observed in animal reproduction studies.
peripheral ischemia, skin photosensitivity reaction, Breastfeeding Considerations It is not known if
pleural effusion, pulmonary embolism, pulmonary fib- cevimeline is excreted in breast milk. Due to the poten-
rosis, rectal disease, renal insufficiency, seizure, sep- tial for serious adverse reactions in the nursing infant,
sis, supraventricular tachycardia, syncope, systemic the manufacturer recommends a decision be made
lupus erythematosus, tachycardia, tenosynovitis, whether to discontinue nursing or to discontinue the
thrombocytopenia, thrombophlebitis, ulcerative colitis, drug, taking into account the importance of treatment
urinary retention, urination disorder, vasculitis to the mother.
Dental Usual Dosage Dry mouth (in Sjögren's syn- Dosage Forms: US
drome): Adults: Oral: 30 mg 3 times/day Capsule, Oral:
Dosing Evoxac: 30 mg
Adult & Geriatric Xerostomia (associated with Sjög- Generic: 30 mg
ren's syndrome): Oral: 30 mg 3 times/day Dental Health Professional Considerations
Renal Impairment: Adult There are no dosage Patient may experience sweating and/or facial flushing
adjustment provided in the manufacturer’s labeling. when beginning treatment.
adjustment provided in the manufacturer’s labeling. Chlorambucil (klor AM byoo sil)
Mechanism of Action Binds to muscarinic (choliner-
gic) receptors, causing an increase in secretion of Brand Names: US Leukeran
exocrine glands (such as salivary and sweat glands) Brand Names: Canada Leukeran
and increase tone of smooth muscle in gastrointestinal Pharmacologic Category Antineoplastic Agent, Alky-
and urinary tracts lating Agent; Antineoplastic Agent, Alkylating Agent
Contraindications Hypersensitivity to cevimeline or (Nitrogen Mustard)
any component of the formulation; uncontrolled asthma; Use
when miosis is undesirable (eg, narrow-angle glau- Chronic lymphocytic leukemia: Management of
coma, acute iritis) chronic lymphocytic leukemia (CLL)
294
CHLORDIAZEPOXIDE
Lymphomas: Management of Hodgkin lymphoma (HL) Haemophilus influenzae, Rickettsia, Salmonella spp.
and non-Hodgkin lymphomas (NHL) (acute infections), and other organisms when other
Local Anesthetic/Vasoconstrictor Precautions less toxic agents are ineffective or contraindicated.
No information available to require special precautions Guideline recommendations: Chloramphenicol may
Effects on Dental Treatment Key adverse event(s) be considered for use as an alternative agent to
related to dental treatment: Stomatitis. doxycycline in the treatment of tickborne rickettsial
Effects on Bleeding Thrombocytopenia has been diseases (eg, Rocky Mountain spotted fever [RMSF]);
reported to occur 1-2 weeks after a short course of however, epidemiologic studies suggest that chloram-
therapy and persist for up to 4 weeks. phenicol-treated patients with RMSF are at a higher
Adverse Reactions Frequency not defined. risk of death compared to tetracycline-treated patients.
Central nervous system: Drug fever, peripheral neuro- In addition, chloramphenicol is not effective in the
pathy treatment of human ehrlichiosis or anaplasmosis,
Dermatologic: Allergic skin reaction, skin rash, urticaria therefore, use with caution in the empiric treatment
Endocrine & metabolic: Amenorrhea of tickborne rickettsial diseases (CDC [Biggs 2016]).
Gastrointestinal: Diarrhea (infrequent), nausea (infre- Local Anesthetic/Vasoconstrictor Precautions
quent), oral mucosa ulcer (infrequent), vomiting (infre- No information available to require special precautions
quent) Effects on Dental Treatment Key adverse event(s)
Genitourinary: Azoospermia, cystitis (sterile), infertility related to dental treatment: Glossitis and stomatitis.
Hematologic & oncologic: Anemia, bone marrow
Effects on Bleeding Thrombocytopenia has been
depression, bone marrow failure (irreversible), leuke-
reported with short or long courses of therapy due to
mia (secondary), leukopenia, lymphocytopenia, malig-
bone marrow suppression.
nant neoplasm (secondary), neutropenia (onset: 3
weeks; recovery: 10 days after last dose), pancytope- Adverse Reactions Frequency not defined.
nia, thrombocytopenia Central nervous system: Confusion, delirium, depres-
Hepatic: Hepatotoxicity, jaundice sion, headache
Hypersensitivity: Angioedema, hypersensitivity reaction Dermatologic: Skin rash, urticaria
Respiratory: Interstitial pneumonitis, pulmonary fibrosis Gastrointestinal: Diarrhea, enterocolitis, glossitis, nau-
Miscellaneous: Fever sea, stomatitis, vomiting
1%, postmarketing, and/or case reports: Agitation, Hematologic & oncologic: Aplastic anemia, bone mar-
ataxia, confusion, erythema multiforme, flaccid para- row depression, granulocytopenia, hypoplastic ane-
lysis, seizure (focal/generalized), hallucination, mia, pancytopenia, thrombocytopenia
muscle twitching, myoclonus, SIADH (syndrome of Hypersensitivity: Anaphylaxis, angioedema, hypersen-
inappropriate antidiuretic hormone secretion), Ste- sitivity reaction
vens-Johnson syndrome, toxic epidermal necrolysis, Ophthalmic: Optic neuritis
tremor Miscellaneous: Drug toxicity (Gray syndrome), fever
Mechanism of Action Alkylating agent; interferes with Mechanism of Action Reversibly binds to 50S ribo-
DNA replication and RNA transcription by alkylation and somal subunits of susceptible organisms preventing
cross-linking the strands of DNA amino acids from being transferred to growing peptide
Pharmacodynamics/Kinetics chains thus inhibiting protein synthesis
Half-life Elimination ~1.5 hours; Phenylacetic acid Pharmacodynamics/Kinetics
mustard: ~1.8 hours Half-life Elimination
Time to Peak Within 1 hour; Phenylacetic acid mus- Neonates: 1 to 2 days: 24 hours; 10 to 16 days: 10
tard: Within 1.9 ± 0.7 hours hours
Pregnancy Risk Factor D Chloramphenicol: Infants: Significantly prolonged
Pregnancy Considerations Animal reproduction (Powell 1982); Children 4 to 6 hours; Adults: ~4
studies have demonstrated teratogenicity. Chlorambucil hours (Ambrose 1984)
crosses the human placenta. Following exposure during Hepatic disease: Prolonged (Ambrose 1984)
the first trimester, case reports have noted adverse Pregnancy Risk Factor C
renal effects (unilateral agenesis). Women of childbear- Pregnancy Considerations Animal reproduction
ing potential should avoid becoming pregnant while studies have not been conducted. Chloramphenicol
receiving treatment. [U.S. Boxed Warning]: Affects crosses the placenta producing cord concentrations
human fertility; probably mutagenic and terato- approaching maternal serum concentrations. An
genic as well; chromosomal damage has been docu- increased risk of teratogenic effects has not been
mented. Reversible and irreversible sterility (when associated with the use of chloramphenicol in preg-
administered to prepubertal and pubertal males), azoo-
nancy (Czeizel 2000; Heinonen 1977). "Gray Syn-
spermia (in adult males) and amenorrhea (in females)
drome" has occurred in premature infants and
have been observed. Fibrosis, vasculitis and depletion
newborns receiving chloramphenicol. Chloramphenicol
of primordial follicles have been noted on autopsy of the
may be used as an alternative agent for the treatment of
ovaries.
Rocky Mountain spotted fever in pregnant women
although caution should be used when administration
Chloramphenicol (Systemic) occurs during the third trimester (CDC [Biggs 2016]).
(klor am FEN i kole)
Brand Names: Canada Chloromycetin; Chloromycetin ChlordiazePOXIDE (klor dye az e POKS ide)
Succinate; Diochloram; Pentamycetin
Pharmacologic Category Antibiotic, Miscellaneous Related Information
Use Dentin Hypersensitivity, Acid Erosion, High Caries
Serious infections: Treatment of serious infections, Index, Management of Alveolar Osteitis, and Xerosto-
including cystic fibrosis exacerbations, bacterial men- mia on page 1548
ingitis, and bacteremia, caused by Chlamydiaceae, Pharmacologic Category Benzodiazepine
295
CHLORDIAZEPOXIDE
Use Dental Use

Acute alcohol withdrawal: Management of acute alco- Antibacterial dental rinse; chlorhexidine is active
hol withdrawal against gram-positive and gram-negative organisms,
Anxiety: Management of anxiety disorders or short- facultative anaerobes, aerobes, and yeast
term relief of anxiety symptoms Chip, for periodontal pocket insertion: Indicated as an
Preoperative anxiety: Management of preoperative adjunct to scaling and root planing procedures for
apprehension and anxiety reduction of pocket depth in patients with adult perio-
Local Anesthetic/Vasoconstrictor Precautions dontitis; may be used as part of a periodontal main-
No information available to require special precautions tenance program
Effects on Dental Treatment Key adverse event(s) Use
related to dental treatment: Xerostomia (normal salivary Gingivitis: Oral rinse: Antimicrobial dental rinse for
flow resumes upon discontinuation). gingivitis treatment
Effects on Bleeding No information available to Periodontitis: Periodontal chip: Adjunctive therapy to
require special precautions scaling and root planning procedures to reduce pocket
Adverse Reactions Frequency not defined depth in patients with periodontitis
Cardiovascular: Edema, syncope Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Abnormal electroencephalo- No information available to require special precautions
gram, ataxia, confusion, drowsiness, drug-induced Effects on Dental Treatment Key adverse event(s)
extrapyramidal reaction related to dental treatment: Increased tartar on teeth,
Dermatologic: Skin rash altered taste perception, staining of oral surfaces
Endocrine & metabolic: Change in libido, menstrual (mucosa, teeth, dorsum of tongue), and oral/tongue
disease irritation. Staining may be visible as soon as 1 week
Gastrointestinal: Constipation, nausea after therapy begins and is more pronounced when
Hematologic & oncologic: Agranulocytosis, bone mar- there is a heavy accumulation of unremoved plaque
row depression and when teeth fillings have rough surfaces. Stain does
Hepatic: Hepatic insufficiency, jaundice not have a clinically adverse effect but because removal
Miscellaneous: Paradoxical reaction may not be possible, patient with anterior restorations
Mechanism of Action Binds to stereospecific benzo- should be advised of the potential permanency of the
stain.
diazepine receptors on the postsynaptic GABA neuron
at several sites within the CNS, including the limbic Effects on Bleeding No information available to
system, reticular formation. Enhancement of the inhib- require special precautions
itory effect of GABA on neuronal excitability results by Adverse Reactions
increased neuronal membrane permeability to chloride >10%:
ions. This shift in chloride ions results in hyperpolariza- Gastrointestinal: Toothache (51%)
tion (a less excitable state) and stabilization. Benzodia- Respiratory: Upper respiratory tract infection (28%),
zepine receptors and effects appear to be linked to the sinusitis (14%)
GABA-A receptors. Benzodiazepines do not bind to 1% to 10%:
GABA-B receptors (Vinkers 2012). Gastrointestinal: Gingival hyperplasia (4%), aphthous
Pharmacodynamics/Kinetics stomatitis (2%)
Half-life Elimination Parent: 24 to 48 hours; demox- Neuromuscular & skeletal: Arthritis (3%), tendoni-
epam 14 to 95 hours (Schwartz 1971) tis (2%)
Respiratory: Bronchitis (6%), pharyngitis (4%)
Time to Peak Serum: 0.5 to 2 hours (Baskin 1982)
Pregnancy Considerations Adverse events have Dermatologic: Cellulitis
been observed in some animal reproduction studies. Gastrointestinal: Dental discoloration (with oral rinse),
Chlordiazepoxide crosses the human placenta and fetal dental discomfort, increased tartar formation, mouth
serum concentrations are similar to those in the mother. discoloration
Teratogenic effects have been observed with some Infection: Abscess
benzodiazepines (including chlordiazepoxide); how- <1%, postmarketing, and/or case reports: Coated
ever, additional studies are needed. The incidence of tongue, desquamation, dysgeusia, erythema, geo-
premature birth and low birth weights may be increased graphic tongue, gingivitis, glossitis, hyperkeratosis,
following maternal use of benzodiazepines; hypoglyce- hypersensitivity reaction, hypoesthesia, mouth irrita-
mia and respiratory problems in the neonate may occur tion, oral lesion, oral mucosa ulcer, paresthesia, paro-
following exposure late in pregnancy. Neonatal with- tid gland enlargement, sialadenitis, stomatitis, tongue
drawal symptoms may occur within days to weeks after changes (short frenum), tongue edema, tongue irrita-
birth and "floppy infant syndrome" (which also includes tion, trauma, xerostomia
withdrawal symptoms) has been reported with some Dental Usual Dosage Adults:
benzodiazepines (Bergman 1992; Iqbal 2002; Wikner Oral rinse (Peridex, PerioGard):
2007). Floss and brush teeth, completely rinse toothpaste
Controlled Substance C-IV from mouth and swish 15 mL (one capful) undiluted
oral rinse around in mouth for 30 seconds, then
Chlorhexidine Gluconate (Oral) expectorate. Caution patient not to swallow the med-
(klor HEKS i deen GLOO koe nate) icine and instruct not to eat for 2-3 hours after treat-
ment (cap on bottle measures 15 mL).
Brand Names: US Paroex; Peridex; Periogard Treatment of gingivitis: Oral prophylaxis: Swish for 30
Brand Names: Canada GUM Paroex; ORO-Clense; seconds with 15 mL chlorhexidine, then expectorate;
Perichlor; Peridex Oral Rinse; Periogard repeat twice daily (morning and evening). Patient
Generic Availability (US) Yes should have a re-evaluation followed by a dental
Pharmacologic Category Antibiotic, Oral Rinse prophylaxis every 6 months.
296
CHLORHEXIDINE GLUCONATE (ORAL)
Periodontal chip: One chip is inserted into a periodontal result of the binding of this cationic molecule to neg-
pocket with a probing pocket depth ≥5 mm. Up to 8 atively charged bacterial cell walls and extramicrobial
chips may be inserted in a single visit. Treatment is complexes. At low concentrations, this causes an alter-
recommended every 3 months in pockets with a ation of bacterial cell osmotic equilibrium and leakage of
remaining depth ≥5 mm. If dislodgment occurs 7 days potassium and phosphorous resulting in a bacteriostatic
or more after placement, the subject is considered to effect. At high concentrations of chlorhexidine, the
have had the full course of treatment. If dislodgment cytoplasmic contents of the bacterial cell precipitate
occurs within 48 hours, a new chip should be inserted. and result in cell death.
The chip biodegrades completely and does not need Contraindications Hypersensitivity to chlorhexidine or
to be removed. Patients should avoid dental floss at any component of the formulation
the site of periochip® insertion for 10 days after place- Warnings/Precautions Serious allergic reactions,
ment because flossing might dislodge the chip. including anaphylaxis, have been reported with use.
Insertion of periodontal chip: Pocket should be iso-
lated and surrounding area dried prior to chip inser- Oral rinse: Staining of oral surfaces (teeth, tooth resto-
tion. The chip should be grasped using forceps with rations, dorsum of tongue) may occur; patients exhib-
the rounded edges away from the forceps. The chip ited a measurable increase of staining in the facial
should be inserted into the periodontal pocket to its anterior after six months of therapy that is more pro-
maximum depth. It may be maneuvered into position nounced when there is a heavy accumulation of unre-
using the tips of the forceps or a flat instrument. moved plaque. Stain does not adversely affect health of
Dosing the gingivae or other oral tissues, and most stain can be
Adult & Geriatric removed from most tooth surfaces by dental prophy-
Gingivitis: Oral rinse: Swish for 30 seconds with 15 laxis. Because removal may not be possible, patients
mL (one capful) of undiluted oral rinse after tooth- with anterior facial restorations with rough surfaces or
brushing, then expectorate; repeat twice daily (morn- margins should be advised of the potential permanency
ing and evening). Therapy should be initiated of the stain. An increase in supragingival calculus has
immediately following a dental prophylaxis. Patient been observed with use; it is not known if the incidence
should be reevaluated and given a dental prophy- of subgingival calculus is increased. Dental prophylaxis
laxis at intervals no longer than every 6 months. to remove calculus deposits should be performed at
Periodontitis: Periodontal chip: One chip is inserted least every 6 months. May alter taste perception during
into a periodontal pocket with a probing pocket depth use; has rarely been associated with permanent taste
≥5 mm. Up to 8 chips may be inserted in a single alteration.
visit. Treatment is recommended every 3 months in
pockets with a remaining depth ≥5 mm. If dislodg- Effect on periodontitis has not been determined; has not
ment occurs 7 days or more after placement, the been tested in patients with acute necrotizing ulcerative
subject is considered to have had the full course of gingivitis.
treatment. If dislodgment occurs within 48 hours, a Periodontal chip: Infectious events (eg, abscesses,
new chip should be inserted. cellulitis) have been observed rarely with adjunctive
Oropharyngeal decontamination (to reduce the chip placement post scaling and root planing; use with
risk of hospital-acquired or ventilator-associated caution in patients with periodontal disease and con-
pneumonia) (off-label use): Oral rinse: comitant diseases potentially decreasing immune sta-
Cardiac surgical patients: 15 mL swished and
tus (eg, diabetes, cancer). Use in acute periodontal
gargled or applied to intubated patients by swab-
abscess pocket is not recommended.
bing the oral cavity (buccal, pharyngeal, gingival,
tongue, and tooth surfaces) for 30 seconds twice
daily. Initiate preoperatively and continue postoper-
atively for 10 days or until extubation. Avoid food or neonates large amounts of propylene glycol delivered
drink for 30 minutes after rinsing (DeRiso 1996; orally, intravenously (eg, >3,000 mg/day), or topically
Houston 2002). have been associated with potentially fatal toxicities
Mechanically-ventilated patients: No specific dosing which can include metabolic acidosis, seizures, renal
recommended due to the heterogeneous nature of failure, and CNS depression; toxicities have also been
the studies and paucity of conclusive data. reported in children and adults including hyperosmolal-
Renal Impairment: Adult There are no dosage ity, lactic acidosis, seizures, and respiratory depression;
adjustments provided in the manufacturer's labeling. use caution (AAP 1997; Shehab 2009).
Hepatic Impairment: Adult There are no dosage Drug Interactions
adjustments provided in the manufacturer's labeling. Metabolism/Transport Effects None known.
Pediatric Gingivitis: Limited data available: Children Avoid Concomitant Use There are no known inter-
≥8 years and Adolescents: Oral: Oral rinse (0.12%): actions where it is recommended to avoid concomitant
Swish 15 mL (one capful) for 30 seconds after tooth- use.
brushing, then expectorate; repeat twice daily (morn- Increased Effect/Toxicity There are no known sig-
ing and evening) (de la Rosa 1998) nificant interactions involving an increase in effect.
Renal Impairment: Pediatric There are no dosage Decreased Effect There are no known significant
adjustments provided in the manufacturer's labeling. interactions involving a decrease in effect.
Hepatic Impairment: Pediatric There are no dos- Pharmacodynamics/Kinetics
age adjustments provided in the manufacturer's label- Duration of Action Serum concentrations: Detect-
ing. able levels are not present in the plasma 12 hours
Mechanism of Action Chlorhexidine has activity after administration
against gram-positive and gram-negative organisms, Pregnancy Risk Factor B/C (manufacturer specific)
facultative anaerobes, aerobes, and yeast; it is both Pregnancy Considerations Adverse events have not
bacteriostatic and bactericidal, depending on its con- been observed in animal reproduction studies following
centration. The bactericidal effect of chlorhexidine is a use of the oral rinse; use of periodontal chip has not
297
CHLORHEXIDINE GLUCONATE (ORAL)
been studied. Chlorhexidine oral rinse is poorly Note: Prior to use with electrocautery proce-
absorbed from the GI tract. dures, consult specific product labeling to deter-
Breastfeeding Considerations It is not known if mine if the ChloraPrep product may be used
chlorhexidine is excreted in breast milk. The manufac- near an ignition source.
turer recommends that caution be exercised when Moist surgical sites (eg, inguinal area): Com-
administering chlorhexidine oral rinse to nursing pletely wet treatment area; use gentle back and
women. However, oral rinse is not intended for inges- forth strokes for ~2 minutes. Allow solution to air
tion; patient should expectorate after rinsing. dry for ~1 minute. If using an ignition source (eg,
Dosage Forms: US electrocautery), allow solution to completely dry
Solution, Mouth/Throat: for a minimum of 3 minutes for hairless skin and
Paroex: 0.12% (473 mL) up to 1 hour in hair; do not blot or wipe away.
Peridex: 0.12% (118 mL, 473 mL, 1893 mL) Note: Prior to use with electrocautery proce-
Periogard: 0.12% (473 mL) dures, consult specific product labeling to deter-
Generic: 0.12% (15 mL, 118 mL, 473 mL) mine if the ChloraPrep product may be used
near an ignition source.
Wound care and general skin cleansing: Rinse area
Chlorhexidine Gluconate (Topical) with water, then apply minimum amount necessary
(klor HEKS i deen GLOO koe nate)
to cover skin or wound area and wash gently. Rinse
Brand Names: US Antiseptic Skin Cleanser [OTC] again thoroughly.
[DSC]; Betasept Surgical Scrub [OTC]; ChloraPrep Renal Impairment: Adult There are no dosage
One Step [OTC] [DSC]; Dyna-Hex 2 [OTC]; Dyna-Hex adjustments provided in the manufacturer's labeling.
4 [OTC]; Hibiclens [OTC]; Tegaderm CHG Dressing Hepatic Impairment: Adult There are no dosage
[OTC] adjustments provided in the manufacturer's labeling.
Generic Availability (US) May be product dependent Pediatric
Pharmacologic Category Antibiotic, Topical Skin cleanser for preoperative skin preparation,
Dental Use External surgical antiseptic scrub; not to be skin wound and general skin cleanser for
used as an oral rinse, see Chlorhexidine Gluconate patients: Topical:
(Oral) Infants <2 months: Note: It is recommended to use
Use Antiseptic: Skin cleanser for preoperative skin with care in this population due to potential risk of
preparation, skin wound and general skin cleanser for dermal irritation or chemical burns. Expert sugges-
patients; surgical scrub and antiseptic hand rinse for tions are variable depending upon site and clinical
healthcare personnel scenario. Not all products may be appropriate for
Local Anesthetic/Vasoconstrictor Precautions use in this population; refer to product specific
No information available to require special precautions labeling. Some experience in neonatal patients
Effects on Dental Treatment No significant effects or applicable to this patient population (Garland
complications reported 2009; Tamma 2010).
Effects on Bleeding No information available to Preoperative skin preparation: Solution: Apply lib-
require special precautions erally to surgical site and swab for at least 2
Adverse Reactions minutes. Dry with sterile towel. Repeat procedure
Dermatologic: Allergic sensitization, erythema, hyper- (swab for additional 2 minutes and dry with sterile
sensitivity reaction, rough skin, xeroderma towel).
<1%, postmarketing, and/or case reports: Anaphylaxis Wound care and general skin cleansing: Rinse area
(Health Canada May 2016), dyspnea, facial edema, with water, then apply the minimum amount of
nasal congestion chlorhexidine necessary to cover skin or wound
Dosing area and wash gently. Rinse again thoroughly.
Adult & Geriatric Note: General dosing guidelines Infants ≥2 months, Children, and Adolescents: Top-
provided; refer to specific product labeling for dosing ical solution:
instructions. Preoperative skin preparation: Solution: Apply lib-
Antiseptic: Topical: erally to surgical site and swab for at least 2
Surgical scrub: Scrub hands and forearms with ~5 minutes. Dry with sterile towel. Repeat procedure
mL for 3 minutes paying close attention to nails, (swab for additional 2 minutes and dry with sterile
cuticles, and interdigital spaces, and rinse thor- towel).
oughly, wash for an additional 3 minutes with 5 Wound care and general skin cleansing: Rinse area
mL, rinse, and dry thoroughly. with water, then apply the minimum amount of
Health care personnel hand antiseptic: Liquid or chlorhexidine necessary to cover skin or wound
solution: Wash with ~5 mL for 15 seconds; rinse area and wash gently. Rinse again thoroughly.
thoroughly with water and dry Renal Impairment: Pediatric There are no dosage
Preoperative skin preparation: adjustments provided in the manufacturer's labeling.
Solution: Apply liberally to surgical site and swab Hepatic Impairment: Pediatric There are no dos-
for at least 2 minutes. Dry with sterile towel. age adjustments provided in the manufacturer's label-
Repeat procedure (swab for additional 2 minutes ing.
and dry with sterile towel). Mechanism of Action Chlorhexidine has activity
Applicator (ChloraPrep One-Step): against gram-positive and gram-negative organisms,
Dry surgical sites (eg, abdomen, arm): Completely facultative anaerobes, aerobes, and yeast; it is both
wet treatment area; use gentle back and forth bacteriostatic and bactericidal, depending on its con-
strokes for ~30 seconds. Allow solution to air dry centration. The bactericidal effect of chlorhexidine is a
for ~30 seconds. If using an ignition source (eg, result of the binding of this cationic molecule to neg-
electrocautery), allow solution to completely dry atively charged bacterial cell walls and extramicrobial
for a minimum of 3 minutes for hairless skin and complexes. At low concentrations, this causes an alter-
up to 1 hour in hair; do not blot or wipe away. ation of bacterial cell osmotic equilibrium and leakage of
298
CHLOROPROCAINE
potassium and phosphorous resulting in a bacteriostatic Pregnancy Considerations No reports of adverse

effect. At high concentrations of chlorhexidine, the effects in newborns have been reported, even though
cytoplasmic contents of the bacterial cell precipitate chlorhexidine is commonly used during labor and in the
and result in cell death. neonate. Moreover, only very small amounts of disin-
Contraindications Hypersensitivity to chlorhexidine or fectant reach the maternal circulation and the fetus.
any component of the formulation Breastfeeding Considerations It is not known if
Warnings/Precautions Serious allergic reactions, chlorhexidine is excreted in breast milk.
including anaphylaxis, have been reported with use. Dosage Forms: US
For topical use only. Keep out of eyes, ears, and the Liquid, External:
mouth; if contact occurs, rinse with cold water immedi- Betasept Surgical Scrub [OTC]: 4% (118 mL, 237 mL,
ately; permanent eye injury may result if agent enters 473 mL, 946 mL)
and remains in the eye. Deafness has been reported Hibiclens [OTC]: 4% (15 mL, 118 mL, 236 mL, 473 mL,
following instillation in the middle ear through perforated 946 mL, 3790 mL)
ear drums. Avoid applying to wounds that involve more Generic: 2% (118 mL); 4% (118 mL, 237 mL, 473 mL,
than the superficial skin layers. Avoid repeated use as 946 mL, 3800 mL)
general skin cleansing of large surfaces (unless neces- Miscellaneous, External:
sary for condition). Not for preoperative preparation of Tegaderm CHG Dressing [OTC]: (Dressing) (1 ea)
face or head; avoid contact with meninges (do not use Pad, External:
on lumbar puncture sites). Avoid applying to genital Generic: 2% (2 ea, 6 ea)
areas; generalized allergic reactions, irritation, and Solution, External:
sensitivity have been reported. Solutions may be flam- Dyna-Hex 2 [OTC]: 2% (473 mL)
mable (products may contain alcohol); avoid exposure Dyna-Hex 4 [OTC]: 4% (118 mL)
to open flame and/or ignition source (eg, electrocau-
tery) until completely dry; avoid application to hairy
areas which may significantly delay drying time. Use Chloroprocaine (klor oh PROE kane)
with caution in children <2 months of age due to
Related Information
potential for increased absorption, and risk of irritation
or chemical burns. May cause staining of fabrics (brown
stain) due to a chemical reaction between chlorhexidine Brand Names: US Clorotekal; Nesacaine; Nesacaine-
gluconate bound to fabric and chlorine (if sufficient MPF
chlorine is present from certain laundry detergents used Pharmacologic Category Local Anesthetic
during laundering process). When used as a topical Use
antiseptic, improper use may lead to product contami- Local anesthesia:
nation. Although infrequent, product contamination has Chloroprocaine (with preservatives):
been associated with reports of localized and systemic Production of local anesthesia by infiltration and
infections. To reduce the risk of infection, ensure anti- peripheral nerve block.
septic products are used according to the labeled Chloroprocaine (without preservatives):
instructions; avoid diluting products after opening; and Production of local anesthesia by infiltration and
apply single-use containers only one time to one patient peripheral nerve block, as well as epidural and
and discard any unused solution (FDA Drug Safety caudal administration; production of local anesthe-
Communication, 2013). sia by subarachnoid block (spinal anesthesia) in
Warnings: Additional Pediatric Considerations adults (Clorotekal only).
Although topical chlorhexidine is widely used in many Note: Due to chloroprocaine’s fast onset and short
NICUs as a skin cleanser prior to procedures (eg, duration of action, it is most often used to establish
central venous line placement/care) (Tamma 2010), adequate epidural anesthesia (eg, in a parturient
data is lacking to support use in premature infants. prior to delivery) or possibly, for peripheral nerve
Manufacturer's labeling recommends using with caution block in a patient undergoing short (<60 minutes)
in premature neonates and infants <2 months of age as ambulatory surgery that is not anticipated to produce
chlorhexidine-containing products may cause irritation significant postoperative pain (Alley 2014;
or chemical burns. A survey of US NICU chlorhexidine Miller 2010).
use reports dermal burns occurring more frequently in Limitations of use: Nesacaine, Nesacaine-MPF: The
neonates with birth weight <1,500 g (Tamma 2010). If manufacturer recommends against using either for-
used for neonatal dermal site cleansing, some suggest mulation (ie, with or without preservatives) for subar-
using sterile water or normal saline to remove excess achnoid administration (ie, spinal anesthesia);
disinfectant after procedures may help avoid chemical however, the use of chloroprocaine without preserva-
burns (Eichenwald 2017; Nuntnarumit 2013). Several tives (Nesacaine-MPF) has been safely used off-label
studies have noted detectable serum concentrations in for spinal anesthesia (Goldblum 2013; Miller 2010;
neonates after chlorhexidine exposure; no correlation Yoos 2005). Do not use chloroprocaine with preserva-
between serum concentration and GA, birth weight, or tives (Nesacaine) for epidural or spinal anesthesia.
PNA was identified; the clinical significance is undeter- Local Anesthetic/Vasoconstrictor Precautions
mined (Chapman 2013; Garland 2009). No information available to require special precautions
Drug Interactions Effects on Dental Treatment No significant effects or
Metabolism/Transport Effects None known. complications reported
Avoid Concomitant Use There are no known inter- Effects on Bleeding No information available to
actions where it is recommended to avoid concomitant require special precautions
use. Adverse Reactions
Increased Effect/Toxicity There are no known sig- >10%: Central nervous system: Procedural pain (16%)
nificant interactions involving an increase in effect. 1% to 10%:
Decreased Effect There are no known significant Cardiovascular: Hypotension (5%)
interactions involving a decrease in effect. Central nervous system: Headache (<2%)
299
CHLOROPROCAINE
Endocrine & metabolic: Hyperglycemia (<2%) drugs during labor and delivery may diminish muscle
Gastrointestinal: Nausea (<2%) strength and tone for the first day or two of life. Admin-
Local: Injection site pain (4%) istration as a paracervical block is not recommended
Frequency not defined. with toxemia of pregnancy, fetal distress, or prematurity.
Cardiovascular: Syncope, ventricular arrhythmia Administration of a paracervical block early in preg-
Central nervous system: Central nervous system nancy has resulted in maternal seizures and cardiovas-
depression, central nervous system stimulation, cular collapse. Fetal bradycardia and acidosis also
increased body temperature have been reported. Fetal depression has occurred
Dermatologic: Diaphoresis, erythema following unintended fetal intracranial injection while
Gastrointestinal: Loss of anal sphincter control administering a paracervical and/or pudendal block.
Hypersensitivity: Anaphylactoid reaction, angioedema
Respiratory: Laryngeal edema, respiratory arrest,
sneezing Chloroquine (KLOR oh kwin)
<1%, postmarketing, and/or case reports: Akathisia,
Related Information
anaphylaxis, anxiety, arachnoiditis, auditory impair-
ment, back pain, blurred vision, bradycardia, burning Clinical Risk Related to Drugs Prolonging QT Interval
sensation, cardiac arrest, cardiac arrhythmia, cardiac on page 1462
insufficiency, cauda equine syndrome, chondrolysis of Brand Names: Canada Aralen
articular cartilage, diplopia, dizziness, drowsiness, Pharmacologic Category Aminoquinoline (Antimalar-
dysesthesia, dyspnea, erythema multiforme, fecal ial); Antimalarial Agent
incontinence, feeling hot, groin pain, hypersensitivity Use
reaction, hypertension, hypoesthesia, limb pain, local- Malaria: Treatment of uncomplicated malaria due to
ized numbness (perineal; causing sexual dysfunction), susceptible strains of Plasmodium vivax, Plasmodium
loss of consciousness, malaise, motor dysfunction, malariae, Plasmodium ovale, and Plasmodium falci-
myoclonus, oral hypoesthesia, oral paresthesia, par- parum; prophylaxis of malaria (in geographic areas
esthesia, peripheral neuropathy, photophobia, presyn- where chloroquine resistance is not present).
cope, prolonged emergency from anesthesia, pruritus, Limitations of use: Chloroquine does not prevent
respiratory arrest, respiratory depression, restless- relapses in patients with vivax or ovale malaria (not
ness, seizure, sexual disorder, speech disturbance, effective against exoerythrocytic forms). Do not use
spinal cord injury, tachycardia, tinnitus, tremor, urinary for the treatment of complicated malaria (high-grade
incontinence, urinary retention, urticaria, visual dis- parasitemia and/or complications [eg, cerebral
turbance, vomiting malaria, acute renal failure]) or for malaria prophy-
Mechanism of Action Chloroprocaine is an ester-type laxis in areas where chloroquine resistance occurs
local anesthetic, which stabilizes the neuronal mem- (resistance to chloroquine is widespread in P. falci-
branes and prevents initiation and transmission of parum and reported in P. vivax).
nerve impulses thereby affecting local anesthetic Extraintestinal amebiasis: Treatment of extraintesti-
actions. Chloroprocaine reversibly prevents generation nal amebiasis.
and conduction of electrical impulses in neurons by Local Anesthetic/Vasoconstrictor Precautions
decreasing the transient increase in permeability to Chloroquine is one of the drugs confirmed to prolong
sodium. The differential sensitivity generally depends the QT interval and is accepted as having a risk of
on the size of the fiber; small fibers are more sensitive causing torsade de pointes. The risk of drug-induced
than larger fibers and require a longer period for recov- torsade de pointes is extremely low when a single QT
ery. Sensory pain fibers are usually blocked first, fol-
lowed by fibers that transmit sensations of temperature,
touch, and deep pressure. High concentrations block
sympathetic somatic sensory and somatic motor fibers.
The spread of anesthesia depends upon the distribution
of the solution. This is primarily dependent on the
volume of drug injected. interval. Until more information is obtained, it is sug-
Pharmacodynamics/Kinetics gested that the clinician consult with the physician prior
Onset of Action 6 to 12 minutes to the use of a vasoconstrictor in suspected patients,
Duration of Action Up to 60 minutes (patient, type of and that the vasoconstrictor (epinephrine, mepivacaine
block, concentration, and method of anesthesia and levonordefrin [Carbocaine® 2% with Neo-Cobe-
dependent) frin®]) be used with caution.
Half-life Elimination In vitro, plasma: Neonates: 43 ± Effects on Dental Treatment Key adverse event(s)
2 seconds; Adults: 21 ± 2 seconds (males), 25 ± 1 related to dental treatment: Stomatitis.
second (females) Effects on Bleeding Thrombocytopenia has been
Pregnancy Risk Factor C reported.
Pregnancy Considerations Animal reproduction Adverse Reactions Frequency not defined.
studies have not been conducted. Local anesthetics Cardiovascular: Atrioventricular block, bundle branch
rapidly cross the placenta and may cause varying block, cardiac arrhythmia, cardiomyopathy, ECG
degrees of maternal, fetal, and neonatal toxicity. Close changes (including prolonged QRS and QTc intervals,
maternal and fetal monitoring (heart rate and electronic T-wave inversion, or depression), hypotension, tor-
fetal monitoring advised) are required during obstetrical sades de pointes, ventricular fibrillation, ventricular
use. Maternal hypotension has resulted from regional tachycardia
anesthesia. Positioning the patient on her left side and Central nervous system: Agitation, anxiety, confusion,
elevating the legs may help. Epidural, paracervical, or decreased deep tendon reflex, delirium, depression,
pudendal anesthesia may alter the forces of parturition extrapyramidal reaction (dystonia, dyskinesia, protru-
through changes in uterine contractility or maternal sion of the tongue, torticollis), hallucination, headache,
expulsive efforts. The use of some local anesthetic insomnia, motor dysfunction (sensorimotor disorder),
300
CHLOROTHIAZIDE
personality changes, polyneuropathy, psychosis, seiz- (CDC 2013; CDC 2018; Lalloo 2016). Due to preg-
ure, suicidal tendencies nancy-induced physiologic changes, some pharmaco-
Dermatologic: Alopecia, bleaching of hair, blue gray kinetic properties of chloroquine may be altered
skin pigmentation, erythema multiforme, exacerbation (Chukwuani 2004; Fakeye 2002; Karunajeewa 2010;
of psoriasis, exfoliative dermatitis, lichen planus, pleo- Lee 2008; Massele 1997; Salman 2017; Wilby 2011).
morphic rash, pruritus, skin photosensitivity, Stevens- Dental Health Professional Considerations See
Johnson syndrome, toxic epidermal necrolysis, urti- Local Anesthetic/Vasoconstrictor Precautions
caria
Endocrine & metabolic: Hypoglycemia
Gastrointestinal: Abdominal cramps, anorexia, diar- Chlorothiazide (klor oh THYE a zide)
rhea, nausea, vomiting Related Information
Hematologic & oncologic: Agranulocytosis (reversible),
aplastic anemia, hemolytic anemia (in G6PD-deficient
patients), neutropenia, pancytopenia, thrombocyto-
Brand Names: US Diuril; Sodium Diuril
penia Pharmacologic Category Antihypertensive; Diuretic,
Hepatic: Hepatitis, increased liver enzymes Thiazide
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, Use
angioedema Edema: Adjunctive treatment of edema
Immunologic: DRESS syndrome Hypertension: Management of hypertension
Neuromuscular & skeletal: Myopathy, neuromuscular Guideline recommendations: The 2017 Guideline for
disease, proximal myopathy the Prevention, Detection, Evaluation, and Manage-
Ophthalmic: Accommodation disturbances, blurred ment of High Blood Pressure in Adults recommends
vision, corneal opacity (reversible), macular degener- if monotherapy is warranted, in the absence of
ation (may be irreversible), maculopathy (may be comorbidities (eg, cerebrovascular disease, chronic
irreversible), nocturnal amblyopia, retinopathy (includ- kidney disease, diabetes, heart failure, ischemic
ing irreversible changes in some patients' long-term or heart disease, etc), that thiazide-like diuretics or
high-dose therapy), transient scotomata, visual field dihydropyridine calcium channel blockers may be
defects preferred options due to improved cardiovascular
Otic: Deafness (nerve), hearing loss (risk increased in endpoints (eg, prevention of heart failure and stroke).
patients with preexisting auditory damage), tinnitus ACE inhibitors and ARBs are also acceptable for
Mechanism of Action Binds to and inhibits DNA and monotherapy. Combination therapy may be required
RNA polymerase; interferes with metabolism and to achieve blood pressure goals and is initially pre-
hemoglobin utilization by parasites; inhibits prostaglan- ferred in patients at high risk (stage 2 hypertension or
din effects; chloroquine concentrates within parasite atherosclerotic cardiovascular disease [ASCVD] risk
acid vesicles and raises internal pH resulting in inhib- ≥10%) (ACC/AHA [Whelton 2017]).
ition of parasite growth; may involve aggregates of Local Anesthetic/Vasoconstrictor Precautions
ferriprotoporphyrin IX acting as chloroquine receptors No information available to require special precautions
causing membrane damage; may also interfere with Effects on Dental Treatment Key adverse event(s)
nucleoprotein synthesis related to dental treatment: Patients may experience
Pharmacodynamics/Kinetics orthostatic hypotension as they stand up after treat-
Half-life Elimination 3 to 5 days ment; especially if lying in dental chair for extended
Time to Peak Serum: Oral: Within 1-2 hours periods of time. Use caution with sudden changes in
Pregnancy Considerations position during and after dental treatment.
Chloroquine and its metabolites cross the placenta and Effects on Bleeding No information available to
can be detected in the cord blood and urine of the require special precautions
newborn infant (Akintonwa 1988; Essien 1982; Law Adverse Reactions Frequency not defined.
2008). Cardiovascular: Hypotension, necrotizing angiitis,
orthostatic hypotension
In one study, chloroquine and its metabolites were Central nervous system: Dizziness, headache, pares-
measurable in the cord blood 89 days (mean) after thesia, restlessness, vertigo
the last maternal dose (Law 2008). Chloroquine has Dermatologic: Alopecia, erythema multiforme, exfolia-
not been found to increase the risk of adverse fetal tive dermatitis, skin photosensitivity, skin rash, Ste-
events when used in recommended doses for malaria vens-Johnson syndrome, toxic epidermal necrolysis,
prophylaxis. However, malaria infection increases the urticaria
risk of prematurity, spontaneous abortion, and stillbirth
Endocrine & metabolic: Glycosuria, hypercalcemia,
(CDC 2018).
hyperglycemia, hyperuricemia, hypochloremic alkalo-
Malaria infection in pregnant women may be more sis, hypokalemia, hypomagnesemia, hyponatremia,
severe than in nonpregnant women and has a high risk increased serum cholesterol, increased serum trigly-
of maternal and perinatal morbidity and mortality. cerides
Therefore, pregnant women and women who are likely Gastrointestinal: Abdominal cramps, anorexia, consti-
to become pregnant are advised to avoid travel to pation, diarrhea, gastric irritation, nausea, pancreatitis,
malaria-risk areas. If travel cannot be avoided, chlor- sialadenitis, vomiting
oquine may be used as prophylaxis. Chloroquine is Genitourinary: Hematuria (IV), impotence
recommended for the treatment of pregnant women Hematologic & oncologic: Agranulocytosis, aplastic
with uncomplicated malaria in chloroquine-sensitive anemia, hemolytic anemia, leukopenia, purpura,
regions; when caused by chloroquine-sensitive P. vivax thrombocytopenia
or P. ovale, infected pregnant women should be main- Hepatic: Jaundice
tained on chloroquine prophylaxis for the duration of Hypersensitivity: Anaphylaxis
their pregnancy (refer to current guidelines). Chloro- Neuromuscular & skeletal: Muscle spasm, systemic
quine may be used in all trimesters of pregnancy lupus erythematosus, weakness
301
CHLOROTHIAZIDE
Ophthalmic: Blurred vision, xanthopsia Endocrine & metabolic: Weight gain

Renal: Interstitial nephritis, renal failure, renal insuffi- Gastrointestinal: Abdominal pain, diarrhea, increased
ciency appetite, nausea, xerostomia
Respiratory: Pneumonitis, pulmonary edema, respira- Genitourinary: Urinary retention
tory distress Neuromuscular & skeletal: Arthralgia, weakness
Miscellaneous: Fever Ophthalmic: Diplopia
Mechanism of Action Inhibits sodium and chloride Renal: Polyuria
reabsorption in the distal tubules causing increased Respiratory: Pharyngitis
excretion of sodium, chloride, and water resulting in Mechanism of Action Competes with histamine for
diuresis. Loss of potassium, hydrogen ions, magne-
H1-receptor sites on effector cells in the gastrointestinal
sium, phosphate, and bicarbonate also occurs.
tract, blood vessels, and respiratory tract
Onset of Action Diuresis: Oral: Within 2 hours; IV: 15
minutes; Peak effect: Oral: ~4 hours; IV: 30 minutes
Half-life Elimination Serum: Children and Adoles-
cents 6 to 16 years: 13.1 ± 6.6 hours (range: 6.3 to
Duration of Action Diuretic action: Oral: ~6 to 12
hours; IV: 2 hours 23.1 hours) (Simons 1982); Adults: 14-24 hours
Half-life Elimination 45 to 120 minutes (Paton 1985)
Pregnancy Risk Factor C Time to Peak Children and Adolescents 6 to 16 years:
Pregnancy Considerations Adverse events were not Oral: 2.5 ± 1.5 hours (range: 1 to 6 hours) (Simons
observed in animal reproduction studies; however, 1982); Adults: 2-3 hours (Sharma 2003)
studies were not complete. Chlorothiazide crosses the Pregnancy Considerations Maternal chlorphenir-
placenta and is found in cord blood. Maternal use may amine use has generally not resulted in an increased
cause may cause fetal or neonatal jaundice, thrombo- risk of birth defects (Aselton 1985; Gilboa 2009; Heino-
cytopenia, or other adverse events observed in adults. nen 1977; Jick 1981). Antihistamines may be used for
Use of thiazide diuretics to treat edema during normal the treatment of rhinitis, urticaria, and pruritus with rash
pregnancies is not appropriate; use may be considered in pregnant women (although second generation anti-
when edema is due to pathologic causes (as in the histamines may be preferred) (Angier 2010; Murase
nonpregnant patient); monitor. Untreated chronic mater- 2014; Wallace 2008; Zuberbier 2014). Antihistamines
nal hypertension is associated with adverse events in are not recommended for treatment of pruritus associ-
the fetus, infant, and mother (ACOG, 2013). Women ated with intrahepatic cholestasis in pregnancy
who required thiazide diuretics for the treatment of (Ambros-Rudolph 2011; Kremer 2011).
hypertension prior to pregnancy may continue their
use (ACOG, 2013).
Chlorpheniramine and
Chlorpheniramine (klor fen IR a meen)
Pseudoephedrine
(klor fen IR a meen & soo doe e FED rin)
Related Information Related Information
Bacterial Infections on page 1525
Chlorpheniramine on page 302
Brand Names: US Aller-Chlor [OTC]; Allergy Relief
Pseudoephedrine on page 1135
[OTC]; Allergy-Time [OTC]; Chlor-Trimeton Allergy
[OTC]; Chlor-Trimeton [OTC]; Ed Chlorped Jr [OTC]; Brand Names: US LoHist-D [OTC]; Maxichlor PSE
Ed ChlorPed [OTC] [DSC]; Ed-Chlortan [OTC] [DSC]; [OTC]; Neutrahist Pediatric [OTC] [DSC]; SudoGest
Pharbechlor [OTC] Sinus & Allergy [OTC]
Brand Names: Canada Chlor-Tripolon®; Novo-Phe- Brand Names: Canada Triaminic Cold & Allergy
niram Pharmacologic Category Alkylamine Derivative;
Pharmacologic Category Alkylamine Derivative; His- Alpha/Beta Agonist; Decongestant; Histamine H 1
tamine H1 Antagonist; Histamine H1 Antagonist, First Antagonist; Histamine H1 Antagonist, First Generation
Generation Use Upper respiratory tract conditions: Temporary
Use Allergic symptoms, allergic rhinitis, urticaria, relief of symptoms (nasal congestion; sinus conges-
pruritus: Perennial and seasonal allergic rhinitis and tion/pressure, runny nose; sneezing; itching of the eyes,
other allergic symptoms including urticaria, pruritus nose, or throat) associated with the common cold,
Local Anesthetic/Vasoconstrictor Precautions allergic rhinitis, and other upper respiratory tract con-
No information available to require special precautions ditions.
related to dental treatment: Xerostomia (normal salivary Use with caution since pseudoephedrine is a sympa-
flow resumes upon discontinuation). Chronic use of thomimetic amine which could interact with epinephrine
antihistamines will inhibit salivary flow, particularly in to cause a pressor response
elderly patients; this may contribute to periodontal dis-
ease, tooth decay, and oral discomfort.
related to dental treatment:
Chlorpheniramine: Prolonged use will cause significant
xerostomia (normal salivary flow resumes upon dis-
Adverse Reactions
>10%: continuation).
Central nervous system: Drowsiness (slight to mod- Pseudoephedrine: Xerostomia (prolonged use wor-
erate) sens; normal salivary flow resumes upon discontinu-
Respiratory: Thickening of bronchial secretions ation).
Central nervous system: Dizziness, excitability, require special precautions
fatigue, headache, nervousness Adverse Reactions See individual agents.
302
CHLORPROMAZINE
Mechanism of Action
Chlorpheniramine competes with histamine for H1- ChlorproMAZINE (klor PROE ma zeen)
receptor sites on effector cells in the gastrointestinal
tract, blood vessels, and respiratory tract.
Related Information
Pseudoephedrine is a sympathomimetic amine and Clinical Risk Related to Drugs Prolonging QT Interval
on page 1462
isomer of ephedrine; acts as a decongestant in respi-
ratory tract mucous membranes with less vasocon- Brand Names: Canada Chlorpromazine Hydrochlor-
strictor action than ephedrine in normotensive ide Inj
individuals. Pharmacologic Category Antimanic Agent; First
Pregnancy Risk Factor C Generation (Typical) Antipsychotic; Phenothiazine
Pregnancy Considerations Reproduction studies Derivative
have not been conducted with this combination product. Use
See individual agents. Behavioral problems: Treatment of severe behavioral
problems in children 1 to 12 years of age marked by
Chlorpheniramine, Pseudoephedrine, combativeness and/or explosive hyperexcitable
behavior (out of proportion to immediate provoca-
and Codeine tions).
(klor fen IR a meen, soo doe e FED rin, & KOE deen)
Bipolar disorder: Treatment of manic episodes asso-
Related Information ciated with bipolar disorder.
Chlorpheniramine on page 302 Hiccups: Treatment of intractable hiccups.
Codeine on page 357 Hyperactivity: Short-term treatment of hyperactive
Pseudoephedrine on page 1135 children who show excessive motor activity with
Brand Names: US Phenylhistine DH [OTC] [DSC]; accompanying conduct disorders consisting of some
Tricode AR [DSC] or all of the following symptoms: impulsivity, difficulty
Pharmacologic Category Alkylamine Derivative; sustaining attention, aggressiveness, mood lability,
Alpha/Beta Agonist; Analgesic, Opioid; Antitussive; and poor frustration tolerance.
Decongestant; Histamine H1 Antagonist; Histamine H1 Nausea/Vomiting: Management of nausea and vom-
Antagonist, First Generation iting.
Use Cough and upper respiratory allergy symptoms: Porphyria, acute intermittent: Treatment of acute
Temporary relief of symptoms (runny nose, sneezing, intermittent porphyria.
itching of nose or throat, itchy/watery eyes, cough due Schizophrenia/Psychotic disorders: Treatment of
to minor throat and bronchial irritation, nasal conges- schizophrenia and psychotic disorders.
tion, reduces swelling of nasal passages) associated Surgery: Management of restlessness and apprehen-
with the common cold, allergic rhinitis, or other upper sion prior to surgery.
respiratory allergies. Tetanus: Adjunctive therapy in the treatment of tetanus.
Local Anesthetic/Vasoconstrictor Precautions Local Anesthetic/Vasoconstrictor Precautions
Use with caution since pseudoephedrine is a sympa- Chlorpromazine is one of the drugs confirmed to pro-
thomimetic amine which could interact with epinephrine long the QT interval and is accepted as having a risk of
to cause a pressor response causing torsade de pointes. The risk of drug-induced
Effects on Dental Treatment Key adverse event(s) torsade de pointes is extremely low when a single QT
related to dental treatment: interval prolonging drug is prescribed. In terms of epi-
Chlorpheniramine: Significant xerostomia with pro- nephrine, it is not known what effect vasoconstrictors in
longed use (normal salivary flow resumes upon dis- the local anesthetic regimen will have in patients with a
continuation). known history of congenital prolonged QT interval or in
Pseudoephedrine: Xerostomia (normal salivary flow patients taking any medication that prolongs the QT
resumes upon discontinuation). interval. Until more information is obtained, it is sug-
gested that the clinician consult with the physician prior
and that the vasoconstrictor (epinephrine, mepivacaine
Adverse Reactions Also see individual agents. and levonordefrin [Carbocaine® 2% with Neo-Cobe-
<1%, postmarketing, and/or case reports: Hypogonad- frin®]) be used with caution.
ism (Brennan 2013; Debono 2011)
Mechanism of Action Effects on Dental Treatment Key adverse event(s)
Codeine: Binds to opioid receptors in the CNS, causing
Xerostomia (normal salivary flow resumes upon dis-
inhibition of ascending pain pathways, altering the
continuation).
perception of and response to pain; causes cough
Significant hypotension may occur, especially when the
suppression by direct central action in the medulla;
drug is administered parenterally. Patients may expe-
produces generalized CNS depression. rience orthostatic hypotension as they stand up after
Chlorpheniramine: A propylamine derivative antihist- treatment; especially if lying in dental chair for
amine drug (H1 receptor antagonist) that also pos- extended periods of time. Use caution with sudden
sesses anticholinergic and sedative activity. It changes in position during and after dental treatment.
prevents released histamine from dilating capillaries Orthostatic hypotension is due to alpha-receptor
and causing edema of the respiratory mucosa. blockade; elderly are at greater risk.
Pseudoephedrine: Directly stimulates alpha-adrenergic Tardive dyskinesia: Prevalence rate may be 40% in
receptors of respiratory mucosa causing vasoconstric- elderly; development of the syndrome and the irrever-
tion; directly stimulates beta-adrenergic receptors sible nature are proportional to duration and total
causing bronchial relaxation. cumulative dose over time. Extrapyramidal reactions
Controlled Substance C-V
303
CHLORPROMAZINE
are more common in elderly with up to 50% develop-

ing these reactions after 60 years of age. Drug- ChlorproPAMIDE (klor PROE pa mide)
induced Parkinson's syndrome occurs often; akathisia
is the most common extrapyramidal reaction in elderly. Related Information
Increased confusion, memory loss, psychotic behavior, Endocrine Disorders and Pregnancy on page 1471
and agitation frequently occur as a consequence of Brand Names: Canada Apo-Chlorpropamide
anticholinergic effects. Antipsychotic-associated seda- Pharmacologic Category Antidiabetic Agent, Sulfo-
tion in nonpsychotic patients is extremely unpleasant nylurea
due to feelings of depersonalization, derealization, Use Diabetes mellitus, type 2: As an adjunct to diet
and dysphoria. and exercise to improve glycemic control in adults with
Effects on Bleeding No information available to type 2 diabetes mellitus
Cardiovascular: ECG abnormality (nonspecific QT
related to dental treatment: Patients with diabetes
changes), orthostatic hypotension, tachycardia
should be questioned by the dental professional at each
Central nervous system: Akathisia, dizziness, drowsi-
dental visit to assess their risk for stress-induced hypo-
ness, dystonia, neuroleptic malignant syndrome, par-
glycemia. The dental professional should inquire about
kinsonian-like syndrome, seizure, tardive dyskinesia the patient's routine (ie, work, sleep schedule, eating
Dermatologic: Dermatitis, skin photosensitivity, skin pig- patterns), history of hypoglycemia, time of last medica-
mentation (slate gray) tion dose, last meal, and most recent blood sugar
Endocrine & metabolic: Amenorrhea, gynecomastia, assessment. Keep a supply of glucose tablets and other
hyperglycemia, hypoglycemia carbohydrates in the office to prepare for a hypoglyce-
Gastrointestinal: Constipation, nausea, xerostomia mic event. Seek medical attention when necessary
Genitourinary: Breast engorgement, ejaculatory disor- (American Diabetes Association, 2018).
der, false positive pregnancy test, impotence, lacta- Effects on Bleeding No information available to
tion, urinary retention require special precautions
Hematologic & oncologic: Agranulocytosis, aplastic Adverse Reactions Frequency not always defined.
anemia, eosinophilia, hemolytic anemia, immune Central nervous system: Disulfiram-like reaction, dizzi-
thrombocytopenia, leukopenia ness, headache
Hepatic: Jaundice Dermatologic: Pruritus (<3%), maculopapular rash
Ophthalmic: Blurred vision, corneal changes, epithelial (≤1%), urticaria (≤1%), erythema multiforme, exfolia-
keratopathy, retinitis pigmentosa tive dermatitis, skin photosensitivity
Mechanism of Action Chlorpromazine is an aliphatic Endocrine & metabolic: Hepatic porphyria, hypoglyce-
phenothiazine antipsychotic which blocks postsynaptic mia, porphyria cutanea tarda, SIADH (syndrome of
mesolimbic dopaminergic receptors in the brain; exhib- inappropriate antidiuretic hormone secretion),
its a strong alpha-adrenergic blocking effect and weight gain
depresses the release of hypothalamic and hypophy- Gastrointestinal: Nausea (<5%), anorexia (<2%), diar-
seal hormones; believed to depress the reticular acti- rhea (<2%), hunger (<2%), vomiting (<2%)
vating system, thus affecting basal metabolism, body Hematologic & oncologic: Agranulocytosis, aplastic
temperature, wakefulness, vasomotor tone, and emesis anemia, eosinophilia, hemolytic anemia, leukopenia,
Pharmacodynamics/Kinetics pancytopenia, thrombocytopenia
Onset of Action IM: 15 minutes; Oral: 30 to 60 Hepatic: Cholestatic jaundice, hepatic failure, hepatitis
minutes; Antipsychotic effects: Gradual, may take up <1%, postmarketing, and/or case reports: Proctocolitis
to several weeks; Maximum antipsychotic effect: 6 Mechanism of Action Stimulates insulin release from
weeks to 6 months the pancreatic beta cells; reduces glucose output from
Duration of Action Oral: 4 to 6 hours the liver; insulin sensitivity is increased at peripheral
target sites
Half-life Elimination Biphasic: Initial: Children: 1.1 Pharmacodynamics/Kinetics
hours; Adults: ~2 hours; Terminal: Children: 7.7 hours; Onset of Action 1 hour; Peak effect: 3-6 hours
Adults: ~30 hours
Duration of Action 24 hours
Pregnancy Considerations Half-life Elimination ~36 hours, prolonged in elderly
Jaundice or hyper- or hyporeflexia have been reported or with renal impairment; End-stage renal disease:
in newborn infants following maternal use of phenothia- 50-200 hours
zines. Antipsychotic use during the third trimester of Time to Peak Serum: 2-4 hours
pregnancy has a risk for abnormal muscle movements Pregnancy Risk Factor C
(extrapyramidal symptoms [EPS]) and withdrawal
Pregnancy Considerations Chlorpropamide crosses
symptoms in newborns following delivery. Symptoms the placenta and measurable serum concentrations can
in the newborn may include agitation, feeding disorder, be found in infants exposed in utero. Severe hypogly-
hypertonia, hypotonia, respiratory distress, somno- cemia lasting 4 to 10 days has been noted in infants
lence, and tremor; these effects may be self-limiting or born to mothers taking a sulfonylurea (including chlor-
require hospitalization. propamide) at the time of delivery; additional adverse
Chlorpromazine may be considered for the adjunctive events have also been reported and may be influenced
treatment of nausea and vomiting in pregnant women. by maternal glycemic control (Jackson 1962; Kemball
Use is reserved for women with dehydration when 1970; Uhrig 1983; Zucker 1968).
symptoms persist following preferred pharmacologic In women with diabetes, maternal hyperglycemia can
therapies (ACOG 189 2018). be associated with congenital malformations as well as
Dental Health Professional Considerations See adverse effects in the fetus, neonate, and the mother
Local Anesthetic/Vasoconstrictor Precautions (ACOG 2005; ADA 2018c; Metzger 2007). To prevent
304
CHOLECALCIFEROL
adverse outcomes, prior to conception and throughout Pharmacodynamics/Kinetics

pregnancy maternal blood glucose and HbA1c should Onset of Action ~2.6 hours; Peak effect: 2 to 6 hours
be kept as close to target goals as possible but without (Carter 2004)
causing significant hypoglycemia (ADA 2018c; Blumer Duration of Action Single dose: 24 to 48 hours;
2013). Agents other than chlorpropamide are currently Long-term dosing: 48 to 72 hours (Carter 2004)
recommended to treat diabetes in pregnant women Half-life Elimination Single dose: 40 hours; Long-
(ADA 2018c). The manufacturer recommends if chlor- term dosing: 45 to 60 hours (Carter 2004); may be
propamide is used during pregnancy, it should be prolonged with renal impairment
discontinued at least 1 month before the expected Pregnancy Risk Factor B
delivery date. Pregnancy Considerations Adverse events have not
been observed in animal reproduction studies. Chlor-
thalidone crosses the placenta and can be detected in
Chlorthalidone (klor THAL i done)
cord blood. Maternal use may cause fetal or neonatal
Related Information jaundice, thrombocytopenia, or other adverse events
observed in adults. Use of thiazide diuretics to treat
edema during normal pregnancies is not appropriate;
Brand Names: Canada Apo-Chlorthalidone use may be considered when edema is due to patho-
Pharmacologic Category Antihypertensive; Diuretic, logic causes (as in the nonpregnant patient); monitor.
Thiazide-Related Untreated chronic maternal hypertension is associated
Use with adverse events in the fetus, infant, and mother.
Edema: Adjunctive treatment of edema associated with Women who require thiazide diuretics for the treatment
heart failure, renal impairment, hepatic cirrhosis, or of hypertension prior to pregnancy may continue their
corticosteroid and estrogen therapy. use (ACOG 2013).
Hypertension: Management of hypertension.
Guideline recommendations: The 2017 Guideline for
the Prevention, Detection, Evaluation, and Manage- Chlorzoxazone (klor ZOKS a zone)
ment of High Blood Pressure in Adults recommends Related Information
if monotherapy is warranted, in the absence of Temporomandibular Dysfunction (TMD), Chronic Pain,
comorbidities (eg, cerebrovascular disease, chronic and Fibromyalgia on page 1559
kidney disease, diabetes, heart failure, ischemic Brand Names: US Lorzone; Parafon Forte DSC [DSC]
heart disease, etc), that thiazide-like diuretics or Pharmacologic Category Skeletal Muscle Relaxant
dihydropyridine calcium channel blockers may be
Use Musculoskeletal conditions: Adjunct to rest,
preferred options due to improved cardiovascular physical therapy, and other measures for the relief of
endpoints (eg, prevention of heart failure and stroke). discomfort associated with acute, painful musculoske-
ACE inhibitors and ARBs are also acceptable for letal conditions
monotherapy. Combination therapy may be required Local Anesthetic/Vasoconstrictor Precautions
to achieve blood pressure goals and is initially pre- No information available to require special precautions
ferred in patients at high risk (stage 2 hypertension or Effects on Dental Treatment No significant effects or
atherosclerotic cardiovascular disease [ASCVD] risk complications reported
≥10%) (ACC/AHA [Whelton 2017]). Effects on Bleeding No information available to
No information available to require special precautions Adverse Reactions Frequency not defined.
Effects on Dental Treatment No significant effects or Central nervous system: Dizziness, drowsiness,
complications reported malaise, paradoxical central nervous system stimu-
Effects on Bleeding No information available to lation
require special precautions Genitourinary: Urine discoloration
Adverse Reactions Frequency not defined: <1%, postmarketing, and/or case reports: Allergic skin
Cardiovascular: Necrotizing angiitis, orthostatic hypo- rash, anaphylaxis (very rare), angioedema (very rare),
tension, vasculitis ecchymoses, gastrointestinal hemorrhage, hepatotox-
Central nervous system: Dizziness, headache, pares- icity, petechia
thesia, restlessness, vertigo Mechanism of Action Centrally acting agent; acts on
Dermatologic: Skin photosensitivity, skin rash, toxic the spinal cord and subcortical areas of the brain to
epidermal necrolysis, urticaria inhibit polysynaptic reflex arcs involved in causing and
Endocrine & metabolic: Glycosuria, hyperglycemia, maintaining skeletal muscle spasms
hyperuricemia, hypochloremic alkalosis, hypokale- Pharmacodynamics/Kinetics
mia, hyponatremia Onset of Action Within 1 hour (Desiraju 1983)
Gastrointestinal: Abdominal cramps, anorexia, consti- Duration of Action Up to 6 hours (Desiraju 1983)
pation, diarrhea, gastric irritation, nausea, pancreati- Half-life Elimination ~1 hour (Desiraju 1983)
tis, vomiting Time to Peak ~1 to 2 hours
Genitourinary: Impotence Pregnancy Considerations Animal reproduction
Hematologic & oncologic: Agranulocytosis, aplastic studies have not been conducted.
anemia, hypersensitivity angiitis, leukopenia, non-
thrombocytopenic purpura, thrombocytopenia
Hepatic: Intrahepatic cholestatic jaundice
Cholecalciferol (kole e kal SI fer ole)
Neuromuscular & skeletal: Asthenia, muscle spasm Brand Names: US Aqueous Vitamin D [OTC]; Bio-D-
Ophthalmic: Xanthopsia Mulsion Forte [OTC] [DSC]; Bio-D-Mulsion [OTC]
Mechanism of Action Sulfonamide-derived diuretic [DSC]; BProtected Pedia D-Vite [OTC]; D-3-5 [OTC];
that inhibits sodium and chloride reabsorption in the D-Vi-Sol [OTC]; D-Vita [OTC] [DSC]; D3 Vitamin [OTC];
cortical-diluting segment of the ascending loop of Henle D3-50 [OTC]; Decara [OTC]; Delta D3 [OTC]; Dialyvite
305
CHOLECALCIFEROL
Vitamin D 5000 [OTC]; Dialyvite Vitamin D3 Max [OTC]; Cardiovascular: Edema, syncope
Pronutrients Vitamin D3 [OTC]; Vitamin D3 Super Central nervous system: Anxiety, dizziness, drowsi-
Strength [OTC]; Vitamin D3 Ultra Potency [OTC] ness, fatigue, headache, neuralgia, paresthesia,
Brand Names: Canada D-Vi-Sol vertigo
Pharmacologic Category Vitamin D Analog Dermatologic: Perianal skin irritation, skin irritation, skin
Use Dietary supplement: As a vitamin D dietary sup- rash, urticaria
plement Endocrine & metabolic: Hyperchloremic metabolic
Local Anesthetic/Vasoconstrictor Precautions acidosis (children), increased libido, weight gain,
No information available to require special precautions weight loss
Effects on Dental Treatment Key adverse event(s) Gastrointestinal: Abdominal pain, anorexia, biliary colic,
related to dental treatment: Metallic taste and xerosto- constipation, dental bleeding, dental caries, dental
mia (normal salivary flow resumes upon discontinua- discoloration, diarrhea, diverticulitis, duodenal ulcer
tion). with hemorrhage, dysgeusia, dysphagia, eructation,
Effects on Bleeding No information available to flatulence, gallbladder calcification, gastric ulcer, gas-
require special precautions trointestinal hemorrhage, hemorrhoidal bleeding, hic-
Adverse Reactions No adverse reactions listed in the cups, intestinal obstruction (rare), melena, nausea,
manufacturer's labeling. pancreatitis, rectal pain, steatorrhea, tongue irritation,
Mechanism of Action Cholecalciferol (vitamin D3) is a tooth enamel damage (dental erosion), vomiting
provitamin. The active metabolite, 1,25-dihydroxyvita- Genitourinary: Diuresis, dysuria, hematuria
min D (calcitriol), stimulates calcium and phosphate Hematologic & oncologic: Adenopathy, anemia, bruise,
absorption from the small intestine, promotes secretion hemorrhage, hypoprothrombinemia, prolonged pro-
of calcium from bone to blood; promotes renal tubule thrombin time, rectal hemorrhage
phosphate resorption (IOM 2011) Hepatic: Abnormal hepatic function tests
Pharmacodynamics/Kinetics Neuromuscular & skeletal: Arthralgia, arthritis, back
Half-life Elimination Circulating: 25(OH)D: 2 to 3 pain, myalgia, osteoporosis
weeks; 1,25-dihydroxyvitamin D: ~4 hours Ophthalmic: Nocturnal amblyopia (rare), uveitis
Pregnancy Considerations The cholecalciferol Otic: Tinnitus
metabolite, 25(OH)D, crosses the placenta; maternal Respiratory: Asthma, dyspnea, wheezing
serum concentrations correlate with fetal concentra- Mechanism of Action Forms a nonabsorbable com-
tions at birth (Misra 2008; Wagner 2008). plex with bile acids in the intestine, releasing chloride
ions in the process; inhibits enterohepatic reuptake of
Adequate maternal vitamin D is required for fetal growth intestinal bile salts and thereby increases the fecal loss
and development (Misra 2008). Vitamin D deficiency in of bile salt-bound low density lipoprotein cholesterol
a pregnant woman may lead to a vitamin D deficiency in Pharmacodynamics/Kinetics
the neonate (Misra 2008; Wagner 2008). Serum 25(OH) Onset of Action Peak effect: 21 days
D concentrations should be measured in pregnant
women considered to be at increased risk of deficiency
(ACOG 2011). The amount of vitamin D contained in
prenatal vitamins may not be adequate to treat a Lipid concentrations increase during pregnancy as
deficiency during pregnancy; although larger doses required for normal fetal development. When
may be needed, current guidelines recommend a total increases are greater than expected, supervised diet-
of 1,000 to 2,000 units/day until more safety data is ary intervention should be initiated. Bile acid seques-
available (ACOG 2011). In women not at risk for defi- trants are recommended when treatment is needed
ciency, doses larger than the RDA should be avoided (Avis 2009; Jacobson 2015).
during pregnancy (ACOG 2011; IOM 2011). Cholestyramine is not absorbed systemically, but may
interfere with maternal vitamin absorption; therefore,
regular prenatal supplementation may not be
Cholestyramine Resin adequate.
(koe LES teer a meen REZ in)
Related Information Ciclesonide (Nasal) (sye KLES oh nide)

Brand Names: US Prevalite; Questran; Questran Light Brand Names: US Omnaris; Zetonna
Brand Names: Canada Novo-Cholamine; Novo-Chol- Brand Names: Canada Drymira; Omnaris; Omnaris
amine Light; Olestyr; PMS-Cholestyramine; Questran; HFA
Questran Light Sugar Free; ZYM-Cholestyramine-Light; Pharmacologic Category Corticosteroid, Nasal
ZYM-Cholestyramine-Regular Use Seasonal and perennial allergic rhinitis: Man-
Pharmacologic Category Antilipemic Agent, Bile Acid agement of seasonal and perennial allergic rhinitis.
Sequestrant Local Anesthetic/Vasoconstrictor Precautions
Use No information available to require special precautions
Dyslipidemia: Adjunct in the management of primary Effects on Dental Treatment No significant effects or
hypercholesterolemia; regression of arteriolosclerosis complications reported
Pruritus associated with cholestasis: Treatment of Effects on Bleeding No information available to
pruritus associated with partial biliary obstruction require special precautions
Local Anesthetic/Vasoconstrictor Precautions Adverse Reactions
No information available to require special precautions >10%:
Effects on Dental Treatment No significant effects or Respiratory: Epistaxis (≤11%)
complications reported 1% to 10%:
Effects on Bleeding No information available to Central nervous system: Headache (3% to 7%)
require special precautions Gastrointestinal: Nausea (≥2%)
Adverse Reactions Frequency not defined. Genitourinary: Urinary tract infection (≥2%)
306
CICLOPIROX
Infection: Influenza (≥2%) 1% to 10%:

Neuromuscular & skeletal: Back pain (≥2%), Cardiovascular: Facial edema (≥3%)
strain (≥2%) Central nervous system: Dizziness (≥3%), fatigue
Otic: Otalgia (2%) (≥3%), voice disorder (1%)
Respiratory: Nasopharyngitis (2% to 7%), nasal dis- Dermatologic: Urticaria (≥3%)
comfort (3% to 6%), pharyngolaryngeal pain (≥3%), Gastrointestinal: Gastroenteritis (≥3%), oral candidia-
bronchitis (≥2%), cough (≥2%; may be dose-respon- sis (≥3%)
sive), nasal septum disorder (≥2%; may be dose-
Infection: Influenza (≥3%)
responsive), oropharyngeal pain (≥2%), sinusitis
Neuromuscular & skeletal: Arthralgia (≥3%), back pain
(≥2%), streptococcal pharyngitis (≥2%), viral upper
respiratory tract infection (≥2%), upper respiratory (≥3%), limb pain (≥3%), musculoskeletal chest
infection (≤2%) pain (≥3%)
<1%, postmarketing, and/or case reports: Angioedema Ophthalmic: Conjunctivitis (≥3%)
(with angioedema of the lips, angioedema of the Otic: Otalgia (2%)
oropharynx, and angioedema of the tongue), dizzi- Respiratory: Upper respiratory tract infection (≤9%),
ness, dysgeusia, dyspepsia, leukocytosis, nasal can- nasal congestion (≤6%), pharyngolaryngeal pain
didiasis, nasal congestion, nasal mucosa ulcer, (≤5%), hoarseness (≥3%), pneumonia (≥3%), sinus-
pharyngeal candidiasis, rhinorrhea, throat irritation, itis (≥3%), paradoxical bronchospasm (2%)
xerostomia <1%, postmarketing, and/or case reports: Angioedema
Pharmacodynamics/Kinetics (with swelling of lip/pharynx/tongue), cataract, chest
Onset of Action 24-48 hours; further improvement discomfort, increased gamma-glutamyl transferase,
observed over 1-2 weeks in seasonal allergic rhinitis increased intraocular pressure, increased serum
or 5 weeks in perennial allergic rhinitis ALT, nausea, palpitations, pharyngeal candidiasis,
Pregnancy Risk Factor C skin rash, weight gain, xerostomia
Mechanism of Action Ciclesonide is a nonhalogen-
observed in some animal reproduction studies. Hypoa-
ated, glucocorticoid prodrug that is hydrolyzed to the
drenalism may occur in newborns following maternal
use of corticosteroids in pregnancy; monitor. Intranasal pharmacologically active metabolite des-ciclesonide fol-
corticosteroids may be used in the treatment of rhinitis lowing administration. Des-ciclesonide has a high affin-
during pregnancy; the lowest effective dose should be ity for the glucocorticoid receptor and exhibits anti-
used (NAEPP, 2005; Wallace, 2008). inflammatory activity. The mechanism of action for
corticosteroids is believed to be a combination of three
important properties − anti-inflammatory activity, immu-
Ciclesonide (Oral Inhalation) nosuppressive properties, and antiproliferative actions.
(sye KLES oh nide)
Related Information Onset of Action >4 weeks for maximum benefit
Respiratory Diseases on page 1467 Half-life Elimination Ciclesonide: 0.7 hours; des-
Brand Names: US Alvesco ciclesonide: 6 to 7 hours
Brand Names: Canada Alvesco Time to Peak ~1 hour (des-ciclesonide)
Pharmacologic Category Corticosteroid, Inhalant Pregnancy Risk Factor C
(Oral) Pregnancy Considerations
Use Hypoadrenalism may occur in infants born to mothers
Asthma: Maintenance treatment of asthma as prophy-
receiving corticosteroids during pregnancy.
lactic therapy in patients ≥12 years of age.
Limitations of use: Not indicated for relief of acute Uncontrolled asthma is associated with adverse events
bronchospasm. in pregnancy (increased risk of perinatal mortality, pre-
Guideline recommendations: A low-dose inhaled corti- eclampsia, preterm birth, low birth weight infants).
costeroid (in addition to an as-needed, short-acting Poorly controlled asthma or asthma exacerbations
beta2-agonist) is the initial preferred long-term control may have a greater fetal/maternal risk than what is
medication for children, adolescents, and adult associated with appropriately used asthma medications
(ACOG 2008; GINA 2018).
for treatment according to a stepwise treatment
approach (GINA 2018; NAEPP 2007). Inhaled corticosteroids are recommended for the treat-
Local Anesthetic/Vasoconstrictor Precautions ment of asthma during pregnancy (ACOG 2008; GINA
No information available to require special precautions 2018; Namazy 2016). Pregnant females adequately
Effects on Dental Treatment Key adverse event(s) controlled on ciclesonide for asthma may continue
related to dental treatment: Dysphonia has been therapy; if initiating treatment during pregnancy, use of
reported with use of this medication. Localized infec- an agent with more data in pregnant females may be
tions with Candida albicans or Aspergillus niger occur preferred (Namazy 2016).
frequently in the mouth and pharynx with repetitive use
of an oral inhaler; may require treatment with appro-
priate antifungal therapy or discontinuance of inhaler Ciclopirox (sye kloe PEER oks)
use.
Effects on Bleeding No information available to Brand Names: US Ciclodan; Ciclodan Cream [DSC];
require special precautions Ciclodan Solution; Ciclopirox Treatment; CNL8 Nail
Adverse Reactions [DSC]; Loprox; Penlac
>10%: Brand Names: Canada Apo-Ciclopirox; Loprox; Pen-
Central nervous system: Headache (≤11%) lac; PMS-Ciclopirox; Stieprox; Taro-Ciclopirox
Respiratory: Nasopharyngitis (≤11%) Pharmacologic Category Antifungal Agent, Topical
307
CICLOPIROX
Use Adverse Reactions

Dermatologic conditions (infectious and sebor- Frequency not defined. *Incidence not specifically
rheal): defined, but reported in the range of >10%. **Inci-
Cream, suspension: Topical treatment of tinea pedis, dence not specifically defined, but reported in the
tinea cruris, and tinea corporis due to Trichophyton range of 1% to 10%.
rubrum, Trichophyton mentagrophytes, Epidermo- Cardiovascular: Cardiac disease, cardiac failure, cardi-
phyton floccosum, and Microsporum canis; candidia- omyopathy, edema, orthostatic hypotension, shock,
sis (moniliasis) due to Candida albicans; tinea syncope, tachycardia
(pityriasis) versicolor due to Malassezia furfur. Central nervous system: Chills,* headache,* pain,* agi-
Gel: Topical treatment of interdigital tinea pedis and tation, amnesia, anxiety, confusion, convulsions, dizzi-
tinea corporis due to T. rubrum, T. mentagrophytes, ness, hallucination, insomnia, malaise, vertigo
or E. floccosum; seborrheic dermatitis of the scalp. Dermatologic: Alopecia,* skin rash,* skin discoloration,
Nail lacquer topical solution: Topical treatment of skin photosensitivity, urticaria
immunocompetent patients with mild to moderate Endocrine & metabolic: Decreased serum bicarbonate,*
onychomycosis of fingernails and toenails, without Fanconi’s syndrome,** adrenocortical insufficiency
lunula involvement, due to Trichophyton rubrum, as a Gastrointestinal: Anorexia,* diarrhea,* nausea,* oral
component of a comprehensive management candidiasis,* vomiting,* abdominal pain, aphthous sto-
program. matitis, colitis, constipation, dysphagia, fecal inconti-
Shampoo: Topical treatment of seborrheic dermatitis nence, gastritis, gastrointestinal hemorrhage,
of the scalp in adults. gingivitis, melena, proctitis, stomatitis, tongue discol-
Local Anesthetic/Vasoconstrictor Precautions oration
No information available to require special precautions Genitourinary: Nephrotoxicity,* proteinuria,* urinary
Effects on Dental Treatment No significant effects or incontinence
complications reported Hematologic & oncologic: Anemia,* neutropenia,* hypo-
Effects on Bleeding No information available to chromic anemia, immune thrombocytopenia, leukocy-
require special precautions tosis, leukopenia, lymphadenopathy, pancytopenia,
Adverse Reactions Frequency not always defined. pseudolymphoma, splenomegaly, thrombocytopenia
Cardiovascular: Facial edema, ventricular tachycardia Hepatic: Abnormal liver function tests, hepatic disease,
(shampoo) hepatic necrosis, hepatomegaly, hepatosplenomegaly,
Central nervous system: Headache jaundice
Dermatologic: Acne vulgaris, alopecia, contact derma- Hypersensitivity: Hypersensitivity reaction
titis, erythema, hair discoloration (rare; shampoo for- Infection: Infection,* sepsis
mulation in light-haired individuals), localized Local: Injection site reaction
erythema, nail disease (shape or color change with Neuromuscular & skeletal: Weakness,* tremor
lacquer), pruritus, skin rash, xeroderma Ophthalmic: Decreased intraocular pressure,* iritis,*
Local: Application site burning (gel: 7% to 34%; other uveitis,* amblyopia, blindness, cataract, conjunctivitis,
dose forms: ≤1%), local irritation, local pain corneal lesion, diplopia, visual disturbance
Ophthalmic: Eye pain Otic: Hearing loss
Mechanism of Action Inhibiting transport of essential Renal: Increased serum creatinine*
elements in the fungal cell disrupting the synthesis of Respiratory: Cough,* dyspnea,* pneumonia**
DNA, RNA, and protein Miscellaneous: Fever*
Pharmacodynamics/Kinetics <1%, postmarketing, and/or case reports: Hepatic fail-
Half-life Elimination Biologic: Cream, suspension: ure, metabolic acidosis, pancreatitis
1.7 hours; Elimination: Gel: 5.5 hours Mechanism of Action Cidofovir is converted to cido-
Pregnancy Risk Factor B fovir diphosphate (the active intracellular metabolite);
Pregnancy Considerations Adverse events were not cidofovir diphosphate suppresses CMV replication by
observed in animal reproduction studies. selective inhibition of viral DNA synthesis. Incorporation
of cidofovir diphosphate into growing viral DNA chain
Cidofovir (si DOF o veer) results in viral DNA synthesis rate reduction.
Related Information Half-life Elimination Plasma: ~2.6 hours; intracellu-
Systemic Viral Diseases on page 1496 lar elimination half-lives of metabolites are longer
Brand Names: US Vistide [DSC] (range: 24 to 87 hours) (Lea, 1996)
Pharmacologic Category Antiviral Agent Pregnancy Risk Factor C
Use Pregnancy Considerations
Cytomegalovirus retinitis: Treatment of cytomegalo- [US Boxed Warning]: Possibly carcinogenic and
virus (CMV) retinitis in patients with AIDS. teratogenic based on animal data. May cause
Limitations of use: Safety and efficacy have not been hypospermia. Women of childbearing potential
established for treatment of other CMV infections (eg, should use effective contraception during therapy
pneumonitis, gastroenteritis), congenital or neonatal and for 1 month following treatment. Males should
CMV disease, or CMV disease in non-HIV infected use a barrier contraceptive during therapy and for 3
individuals. months following treatment.
Local Anesthetic/Vasoconstrictor Precautions The indications for treating CMV retinitis during preg-
No information available to require special precautions nancy are the same as in nonpregnant HIV infected
Effects on Dental Treatment Key adverse event(s) woman; however systemic therapy should be avoided
related to dental treatment: Stomatitis and abnormal during the first trimester when possible. When therapy
taste. is needed to treat maternal infection, agents other
Effects on Bleeding No reports of bleeding or throm- than cidofovir are recommended (DHHS [Adult
bocytopenia with cidofovir alone. OI 2014]).
308
CILAZAPRIL
failure, cerebrovascular accident (rare), chest pain,

Cilazapril (sye LAY za pril) confusion, conjunctivitis, constipation, decreased
libido, depression, dermatitis, diarrhea, diaphoresis,
Brand Names: Canada Inhibace drowsiness, dysgeusia, dyspepsia, dyspnea, dysuria,
Pharmacologic Category Angiotensin-Converting epistaxis, erythema multiforme (rare), exacerbation of
Enzyme (ACE) Inhibitor; Antihypertensive psoriasis (rare), exfoliative dermatitis (rare), extrasys-
Use Note: Not approved in the US toles, fatigue, flatulence, flushing, gastrointestinal
Heart failure: Adjunctive treatment of heart failure hemorrhage, gout, hemolytic anemia, hyperbilirubine-
Guideline recommendations:The American College mia, hyperglycemia, hyperkalemia (more common in
of Cardiology/American Heart Association (ACC/ renal patients), hypoesthesia, immune thrombocyto-
AHA) 2013 Heart Failure Guidelines recommend penia (rare), impotence, increased liver enzymes
the use of ACE inhibitors, along with other guide- (rare), increased serum transaminases, insomnia,
line-directed medical therapies, to prevent progres- leg cramps, leukopenia, lichen planus (rare), lupus-
sion of HF and reduced ejection fraction in like syndrome (rare), malaise, migraine, myalgia, myo-
asymptomatic patients with or without a history of cardial infarction (rare), nausea, nervousness, neutro-
myocardial infarction (Stage B HF), or to treat those penia (rare), pancreatitis (rare), paresthesia,
with symptomatic heart failure and reduced ejection pemphigus, pharyngitis, photophobia, polyuria, protei-
fraction to reduce morbidity and mortality (Stage C nuria, pruritus, psoriasiform eruption (rare), purpura
HFrEF). (rare), rectal hemorrhage, renal failure (rare), respira-
Hypertension: Management of hypertension tory tract infection, rhinitis, rigors, sinusitis, skin rash
Guideline recommendations: The 2017 Guideline (rare; including erythematous rash and maculopapular
for the Prevention, Detection, Evaluation, and Man- rash), Stevens-Johnson syndrome (rare), syncope,
agement of High Blood Pressure in Adults recom- tachycardia, tinnitus, toxic epidermal necrolysis, tran-
mends if monotherapy is warranted, in the absence sient ischemic attacks (rare), tremor, uremia, urinary
of comorbidities (eg, cerebrovascular disease, frequency, urticaria (rare), vertigo, visual disturbance,
chronic kidney disease, diabetes, heart failure, ische- visual hallucination (Doane 2013), voice disorder,
mic heart disease, etc.), that thiazide-like diuretics or vomiting, xerostomia
dihydropyridine calcium channel blockers may be Mechanism of Action Cilazapril is a prodrug that is
preferred options due to improved cardiovascular rapidly converted to cilazaprilat (active metabolite), a
endpoints (eg, prevention of heart failure and stroke). competitive inhibitor of angiotensin-converting enzyme
ACE inhibitors and ARBs are also acceptable for (ACE); prevents conversion of angiotensin I to angio-
monotherapy. Combination therapy may be required tensin II, a potent vasoconstrictor; results in lower levels
to achieve blood pressure goals and is initially pre- of angiotensin II which causes an increase in plasma
ferred in patients at high risk (stage 2 hypertension or renin activity and a reduction in aldosterone secretion.
atherosclerotic cardiovascular disease [ASCVD] risk Pharmacodynamics/Kinetics
≥10%) (ACC/AHA [Whelton 2017]). Onset of Action ~1 to 2 hours; Peak effect: Antihy-
Local Anesthetic/Vasoconstrictor Precautions pertensive effect: 3 to 7 hours; Heart failure (reduction
No information available to require special precautions of systemic vascular resistance and pulmonary capil-
Effects on Dental Treatment Key adverse event(s) lary wedge pressure): 2 to 4 hours
related to dental treatment: Patients may experience Duration of Action Therapeutic effect: Up to 24
orthostatic hypotension as they stand up after treat- hours
ment; especially if lying in dental chair for extended Half-life Elimination Cilazaprilat: Terminal: Single
periods of time. Use caution with sudden changes in dose: 36 to 49 hours; Multidose: ~54 hours
Time to Peak Cilazaprilat: Within 2 hours
An angiotensin-converting enzyme (ACE) Inhibitor Pregnancy Considerations [Canadian Boxed
cough is a dry, hacking, nonproductive cough that can Warning]: Use of cilazapril is contraindicated dur-
potentially interfere with longer dental procedures if ing pregnancy. Drugs that act on the renin-angio-
patient has this side effect. tensin system can cause injury and death to the
Effects on Bleeding No information available to developing fetus. Discontinue as soon as possible
require special precautions once pregnancy is detected. Females planning
Adverse Reactions pregnancy should be switched to alternative ther-
Frequency not always defined. apy that has been proven safe during pregnancy.
1% to 10%: Teratogenic effects may occur following maternal use
Cardiovascular: Orthostatic hypotension (2%), palpi- during pregnancy. Drugs that act on the renin-angioten-
tations (≤1%), symptomatic hypotension (heart fail- sin system are associated with oligohydramnios. Oligo-
ure patients: ≤1%) hydramnios, due to decreased fetal renal function, may
Central nervous system: Dizziness (3% to 8%), head- lead to fetal lung hypoplasia and skeletal malforma-
ache (3% to 5%), fatigue (2% to 3%) tions. Their use in pregnancy is also associated with
Gastrointestinal: Nausea (1% to 3%) anuria, hypotension, renal failure, skull hypoplasia, and
Neuromuscular & skeletal: Weakness (≤2%) death in the fetus/neonate. Chronic maternal hyper-
Renal: Increased serum creatinine tension itself is also associated with adverse events in
Respiratory: Cough (hypertension patients: 2%; heart the mother and fetus/infant. However, ACE inhibitors
failure patients: ≤8%; sometimes severe) are not recommended during pregnancy to treat mater-
1%, postmarketing, and/or case reports: Abdominal nal hypertension or heart failure. Use of an ACE inhib-
pain, agranulocytosis (rare), alopecia, anaphylaxis itor should also be avoided in any woman of
(rare), anemia, angina pectoris, angioedema (includ- reproductive age. The exposed fetus should be moni-
ing facial edema), anorexia, anxiety, arthralgia, ataxia, tored for fetal growth, amniotic fluid volume, and organ
atrial fibrillation, atrioventricular block, bradycardia, formation. Infants exposed to an ACE inhibitor in utero
bronchitis, bronchospasm, bullous dermatitis (rare), should be monitored for hyperkalemia, hypotension,
cardiac arrhythmia, cardiac decompensation, cardiac and oliguria.
309
CILAZAPRIL
Product Availability Not available in the US Hypersensitivity: Tongue edema (<2%)

Neuromuscular & skeletal: Back pain (7%), myalgia
(3%), arthralgia (<2%), bursitis (<2%), neck stiffness
Cilostazol (sil OH sta zol)
(<2%), ostealgia (<2%)
Related Information Ophthalmic: Amblyopia (<2%), blindness (<2%), con-
Antiplatelet and Anticoagulation Considerations in Den- junctivitis (<2%), diplopia (<2%), retinal hemor-
tistry on page 1454 rhage (<2%)
Cardiovascular Diseases on page 1442 Otic: Otalgia (<2%), tinnitus (<2%)
Renal: Increased serum creatinine (<2%)
Brand Names: US Pletal [DSC]
Respiratory: Pharyngitis (10%), cough (3% to 4%),
Pharmacologic Category Antiplatelet Agent; Phos-
asthma (<2%), epistaxis (<2%), hemoptysis (<2%),
phodiesterase-3 Enzyme Inhibitor; Vasodilator
pneumonia (<2%), sinusitis (<2%)
Use Intermittent claudication: Reduction of symptoms
Miscellaneous: Fever (<2%)
of intermittent claudication, as indicated by an
Postmarketing and/or case reports: Abnormal hepatic
increased walking distance.
function tests, agranulocytosis, anaphylaxis, angina
pectoris, angioedema, aplastic anemia, cerebrovascu-
lar accident, cerebral hemorrhage, chest pain, coro-
nary thrombosis (stent), fixed drug eruption,
gastrointestinal hemorrhage, granulocytopenia, hem-
Effects on Bleeding Cilostazol causes reversible atoma (extradural), hematuria, hemorrhagic diathesis,
inhibition of platelet aggregation. To restore platelet
hepatic insufficiency, hot flash, hyperglycemia, hyper-
function, cilostazol should be discontinued for 96 hours
sensitivity, hypertension, increased blood pressure,
(4 days). A medical consult is recommended to deter-
increased blood urea nitrogen, interstitial pneumonitis,
mine the benefit:risk of continuing or discontinuing
intracranial hemorrhage, jaundice, left ventricular dys-
cilostazol for invasive dental procedures.
function (outflow tract obstruction; in patients with
Adverse Reactions
sigmoid-shaped interventricular septum), leukopenia,
>10%:
pain, pancytopenia, pulmonary hemorrhage, pruritus,
Central nervous system: Headache (27% to 34%)
prolonged Q-T interval on ECG, skin rash, Stevens-
Gastrointestinal: Diarrhea (12% to 19%), abnormal
Johnson syndrome, subcutaneous hemorrhage, sub-
stools (12% to 15%)
dural hematoma, thrombocytopenia, thrombosis, tor-
sades de pointes, vasodilatation, vomiting
Respiratory: Rhinitis (7% to 12%)
1% to 10%: Mechanism of Action Cilostazol and its metabolites
Cardiovascular: Palpitations (5% to 10%), peripheral are inhibitors of phosphodiesterase III. As a result,
edema (7% to 9%), tachycardia (4%), atrial fibrilla- cyclic AMP is increased leading to reversible inhibition
tion (<2%), atrial flutter (<2%), cardiac arrest (<2%), of platelet aggregation, vasodilation, and inhibition of
cardiac failure (<2%), cerebral infarction (<2%), vascular smooth muscle cell proliferation.
edema (<2%), facial edema (<2%), hypotension Pharmacodynamics/Kinetics
(<2%), myocardial infarction (<2%), nodal arrhythmia Onset of Action Effect on walking distance: 2 to 4
(<2%), orthostatic hypotension (<2%), supraventric- weeks; may require up to 12 weeks
ular tachycardia (<2%), syncope (<2%), varicose Half-life Elimination ~11 to 13 hours
veins (<2%), ventricular premature contractions Pregnancy Risk Factor C
(<2%), ventricular tachycardia (<2%) Pregnancy Considerations Adverse events have
Central nervous system: Dizziness (9% to 10%), ver- been observed in animal reproduction studies.
tigo (3%), anxiety (<2%), chills (<2%), insomnia
(<2%), malaise (<2%), neuralgia (<2%)
Dermatologic: Ecchymoses (<2%), furunculosis (eye:
Ciprofloxacin (Systemic) (sip roe FLOKS a sin)
<2%), skin hypertrophy (<2%), urticaria (<2%), xero- Related Information

derma (<2%) Periodontal Diseases on page 1534
Endocrine & metabolic: Albuminuria (<2%), diabetes
Brand Names: US Cipro; Cipro in D5W; Cipro XR
mellitus (<2%), gout (<2%), hyperlipidemia (<2%),
hyperuricemia (<2%), increased gamma-glutamyl
Brand Names: Canada Cipro; Cipro XL; Ciprofloxacin
Injection; Ciprofloxacin Injection USP; Ciprofloxacin
transferase (<2%)
Gastrointestinal: Nausea (7%), dyspepsia (6%), Intravenous Infusion
abdominal pain (4% to 5%), flatulence (3%), ano- Pharmacologic Category Antibiotic, Fluoroquinolone
rexia (<2%), cholelithiasis (<2%), colitis (<2%), duo- Use
denal ulcer (<2%), duodenitis (<2%), esophageal Children and Adolescents: Treatment of complicated
hemorrhage (<2%), esophagitis (<2%), gastric ulcer urinary tract infections and pyelonephritis due to E.
(<2%), gastritis (<2%), gastroenteritis (<2%), gingival coli. Note: Although effective, ciprofloxacin is not the
hemorrhage (<2%), hematemesis (<2%), melena drug of first choice in children.
(<2%), peptic ulcer (<2%), periodontal Infants, Children, Adolescents, and Adults: Prophylaxis
abscess (<2%) to reduce incidence or progression of disease follow-
Genitourinary: Cystitis (<2%), pelvic pain (<2%), uri- ing inhalation exposure to Bacillus anthracis; prophy-
nary frequency (<2%), vaginal hemorrhage (<2%), laxis and treatment of plague (Yersinia pestis).
vaginitis (<2%) Adults: Treatment of the following infections when
Hematologic & oncologic: Anemia (<2%), hemorrhage caused by susceptible bacteria: Urinary tract infec-
(<2%), hemorrhage (eye, <2%), iron deficiency ane- tions; acute uncomplicated cystitis in females, chronic
mia (<2%), polycythemia (<2%), purpura (<2%), bacterial prostatitis, bone and joint infections, compli-
rectal hemorrhage (<2%), retroperitoneal hemor- cated intra-abdominal infections (in combination with
rhage (<2%) metronidazole), infectious diarrhea, typhoid fever
310
CIPROFLOXACIN AND FLUOCINOLONE
(Salmonella typhi), hospital-acquired (nosocomial) nystagmus, orthostatic hypotension, palpitations, pan-

pneumonia. creatitis, pancytopenia (life-threatening), paranoia,
Limitations of use: Because fluoroquinolones have paresthesia, peripheral neuropathy, petechia, phobia,
been associated with disabling and potentially irrever- phototoxicity, pneumonitis, polyneuropathy, prolonged
sible serious adverse reactions (eg, tendinitis and prothrombin time (in patients treated with vitamin K
tendon rupture, peripheral neuropathy, CNS effects), antagonists), pseudotumor cerebri, pulmonary edema,
reserve ciprofloxacin for use in patients who have no rupture of tendon, seizure (including grand mal),
alternative treatment options for acute uncomplicated serum sickness-like reaction, skin photosensitivity,
cystitis. status epilepticus, Stevens-Johnson syndrome, suici-
Local Anesthetic/Vasoconstrictor Precautions dal ideation, suicidal tendencies, syncope, tachycar-
No information available to require special precautions dia, tendonitis, thrombocythemia, thrombocytopenia,
Effects on Dental Treatment No significant effects or thrombophlebitis, tinnitus, torsades de pointes, toxic
complications reported epidermal necrolysis, toxic psychosis, tremor, twitch-
Effects on Bleeding No information available to ing, unresponsive to stimuli, urethral bleeding, vagi-
require special precautions nitis, vasculitis, ventricular arrhythmia, ventricular
Adverse Reactions ectopy, visual disturbance, vulvovaginal candidiasis,
1% to 10%: weakness
Central nervous system: Neurological signs and Mechanism of Action Inhibits DNA-gyrase in suscep-
symptoms (children 2%; includes dizziness, insom- tible organisms; inhibits relaxation of supercoiled DNA
nia, nervousness, somnolence), headache (IV and promotes breakage of double-stranded DNA
administration), restlessness (IV administration) Pharmacodynamics/Kinetics
Dermatologic: Skin rash (children 2%, adults 1%) Half-life Elimination Children: 4 to 5 hours; Adults:
Gastrointestinal: Diarrhea (children 5%; adults 2%), Normal renal function: 4 to 6 hours
vomiting (children 5%; adults 1%), abdominal pain Time to Peak Oral:
(children 3%; adults <1%), dyspepsia (children 3%; Immediate release tablet: 0.5 to 2 hours
adults <1%), nausea (3%) Extended release tablet: Cipro XR: 1 to 2.5 hours
Hepatic: Increased serum AST (adults 1%), increased Pregnancy Risk Factor C
serum ALT Pregnancy Considerations
Local: Injection site reactions (IV administration) Ciprofloxacin crosses the placenta and produces meas-
Respiratory: Rhinitis (children 3%) urable concentrations in the amniotic fluid and cord
Miscellaneous: Fever (children 2%; adults <1%) serum (Ludlam 1997). Based on available data, an
<1%, postmarketing, and/or case reports: Abnormal increased risk of teratogenic effects has not been
gait, acute generalized exanthematous pustulosis, observed following ciprofloxacin use during pregnancy
acute gout attack, acute renal failure, ageusia, agita- (Bar-Oz 2009; Padberg 2014). Ciprofloxacin is recom-
tion, agranulocytosis, albuminuria, anaphylactic mended for prophylaxis and treatment of pregnant
shock, anaphylaxis, anemia, angina pectoris, angioe- women exposed to anthrax (Meaney-Delman 2014).
dema, anorexia, anosmia, anxiety, arthralgia, ataxia, Serum concentrations of ciprofloxacin may be lower
atrial flutter, bone marrow depression (life-threaten- during pregnancy than in nonpregnant patients (Gia-
ing), bronchospasm, candidiasis, candiduria, cardior- marellou 1989).
espiratory arrest, casts in urine, cerebral thrombosis,
chills, cholestatic jaundice, chromatopsia, Clostri-
dioides (formerly Clostridium) difficile-associated diar- Ciprofloxacin and Fluocinolone
rhea, confusion, constipation, crystalluria (particularly (sip roe FLOKS a sin & floo oh SIN oh lone)
in alkaline urine), decreased hematocrit, decreased Brand Names: US Otovel
hemoglobin, decreased prothrombin time, delirium,
Brand Names: Canada Otixal
depersonalization, depression (including self-injurious
Pharmacologic Category Antibiotic, Fluoroquinolone;
behavior), dizziness, drowsiness, dyspepsia (adults),
Antibiotic, Otic; Antibiotic/Corticosteroid, Otic; Cortico-
dysphagia, dysphasia, dyspnea, edema, eosinophilia,
steroid, Otic
erythema multiforme, erythema nodosum, exacerba-
tion of myasthenia gravis, exfoliative dermatitis, fixed Use Acute otitis media: Treatment of acute otitis media
drug eruption, flatulence, gastrointestinal hemorrhage, with tympanostomy tubes (AOMT) due to susceptible
hallucination, headache (oral), hematuria, hemolytic isolates of Staphylococcus aureus, Streptococcus
anemia, hepatic failure, hepatic necrosis, hepatotox- pneumoniae, Haemophilus influenza, Moraxella catar-
icity (idiosyncratic) (Chalasani 2014), hyperesthesia, rhalis, and Pseudomonas aeruginosa in pediatric
hyperglycemia, hyperpigmentation, hypersensitivity patients 6 months and older.
reaction, hypertension, hypertonia, hypoglycemia, Local Anesthetic/Vasoconstrictor Precautions
hypotension, increased blood urea nitrogen, increased No information available to require special precautions
creatine phosphokinase, increased INR (in patients Effects on Dental Treatment No significant effects or
treated with vitamin K antagonists), increased intra- complications reported
cranial pressure, increased lactate dehydrogenase, Effects on Bleeding No information available to
increased serum alkaline phosphatase, increased require special precautions
serum bilirubin, increased serum cholesterol, Adverse Reactions
increased serum creatinine, increased serum glucose, 1% to 10%:
increased serum lipase, increased serum triglycer- Dermatologic: Connective tissue disorder (excessive
ides, increased uric acid, insomnia, interstitial neph- granulation tissue; 1%)
ritis, intestinal perforation, irritability, jaundice, Local: Application site discharge (otorrhea: 5%)
laryngeal edema, lethargy, lymphadenopathy, Frequency not defined: Infection: Bacterial superin-
malaise, manic behavior, mastalgia, methemoglobine- fection
mia, migraine, myalgia, myocardial infarction, myoclo- <1%, postmarketing, and/or case reports: Auricular
nus, nephritis, nephrolithiasis, nightmares, edema, candidiasis, dizziness, dysgeusia, equilibrium
311
CIPROFLOXACIN AND FLUOCINOLONE
disturbance, eustachian tube congestion, exfoliation of Respiratory: Cough, sinusitis, upper respiratory tract
skin, flushing, headache, hypersensitivity reaction, infection
hypoacusis, otalgia, otic infection, paresthesia, pruri- <1%, postmarketing, and/or case reports: Apnea, bron-
tus of ear, tinnitus, tympanic membrane disease, chospasm, gynecomastia, hyperprolactinemia, meth-
tympanostomy tube blockage (device occlusion) emoglobinemia, psychiatric disturbance, skin
Mechanism of Action photosensitivity
Ciprofloxacin: Inhibits DNA-gyrase in susceptible Mechanism of Action Enhances the release of ace-
organisms; inhibits relaxation of supercoiled DNA tylcholine at the myenteric plexus. In vitro studies have
and promotes breakage of double-stranded DNA. shown cisapride to have serotonin-4 receptor agonistic
Fluocinolone: Topical corticosteroids have anti-inflam- properties which may increase gastrointestinal motility
matory, antipruritic, and vasoconstrictive properties. and cardiac rate; increases lower esophageal sphincter
May depress the formation, release, and activity of pressure and lower esophageal peristalsis; accelerates
endogenous chemical mediators of inflammation gastric emptying of both liquids and solids.
(kinins, histamine, liposomal enzymes, prostaglan- Pharmacodynamics/Kinetics
dins) through the induction of phospholipase A2 inhib- Onset of Action 0.5-1 hour
itory proteins (lipocortins) and sequential inhibition of Half-life Elimination 6-12 hours
the release of arachidonic acid. Pregnancy Risk Factor C
Pregnancy Considerations Due to limited systemic Pregnancy Considerations Adverse events were
absorption, exposure of ciprofloxacin or fluocinolone to observed in animal reproduction studies.
the fetus is not expected following maternal otic admin- Prescribing and Access Restrictions In U.S., avail-
istration. able via limited-access protocol only. Call 877-795-4247
for more information.
Cisapride (SIS a pride) Dental Health Professional Considerations See
Brand Names: US Propulsid®
Pharmacologic Category Gastrointestinal Agent, CISplatin (SIS pla tin)
Prokinetic
Use Treatment of nocturnal symptoms of gastroesopha- Brand Names: Canada Cisplatin Injection; Cisplatin
geal reflux disease (GERD); has demonstrated effec- Injection BP; Cisplatin Injection, Mylan STD
tiveness for gastroparesis, refractory constipation, and Pharmacologic Category Antineoplastic Agent, Alky-
nonulcer dyspepsia lating Agent; Antineoplastic Agent, Platinum Analog
Local Anesthetic/Vasoconstrictor Precautions Use
Cisapride is one of the drugs confirmed to prolong the Bladder cancer, advanced: Treatment of advanced
QT interval and is accepted as having a risk of causing bladder cancer
torsade de pointes. The risk of drug-induced torsade de Ovarian cancer, advanced: Treatment of advanced
pointes is extremely low when a single QT interval ovarian cancer
prolonging drug is prescribed. In terms of epinephrine, Testicular cancer, advanced: Treatment of advanced
it is not known what effect vasoconstrictors in the local testicular cancer
anesthetic regimen will have in patients with a known Local Anesthetic/Vasoconstrictor Precautions
history of congenital prolonged QT interval or in patients No information available to require special precautions
taking any medication that prolongs the QT interval. Effects on Dental Treatment No significant effects or
Until more information is obtained, it is suggested that complications reported
the clinician consult with the physician prior to the use of Effects on Bleeding Cisplatin causes relatively less
a vasoconstrictor in suspected patients, and that the bone marrow suppression than many other antineo-
vasoconstrictor (epinephrine, mepivacaine and levonor- plastic agents. Thrombocytopenia may occur 18-23
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used days following treatment.
with caution. Adverse Reactions
Effects on Dental Treatment Key adverse event(s) >10%:
related to dental treatment: Xerostomia (normal salivary Central nervous system: Neurotoxicity (peripheral
flow resumes upon discontinuation). neuropathy is dose and duration dependent)
Effects on Bleeding No information available to Gastrointestinal: Nausea and vomiting (76% to 100%)
require special precautions Genitourinary: Nephrotoxicity (28% to 36%; acute
Adverse Reactions renal failure and chronic renal insufficiency)
Frequency not defined. Hematologic & oncologic: Anemia (≤40%), leukopenia
>5%: (25% to 30%; nadir: Day 18 to 23; recovery: By day
Central nervous system: Headache 39; dose related), thrombocytopenia (25% to 30%;
Dermatologic: Skin rash nadir: Day 18 to 23; recovery: By day 39; dose
Gastrointestinal: Abdominal cramps, diarrhea, dys- related)
pepsia, flatulence, nausea, xerostomia Hepatic: Increased liver enzymes
Respiratory: Rhinitis Otic: Ototoxicity (children 40% to 60%; adults 10% to
<5%: 31%; as tinnitus, high frequency hearing loss)
Cardiovascular: Tachycardia 1% to 10%: Local: Local irritation
Central nervous system: Anxiety, drowsiness, extrap- <1%, postmarketing, and/or case reports: Alopecia
yramidal reaction, fatigue, insomnia, seizure (mild), ageusia, anaphylaxis, autonomic neuropathy,
Hematologic & oncologic: Aplastic anemia, granulocy- bradycardia (Schlumbrecht 2015), bronchoconstric-
topenia, leukopenia, pancytopenia, thrombocyto- tion, cardiac arrhythmia, cardiac failure, cerebral arter-
penia itis, cerebrovascular accident, dehydration, diarrhea,
Hepatic: Increased liver enzymes dysgeusia (Rehwaldt 2009), extravasation, heart
Infection: Viral infection (increased incidence) block, hemolytic anemia (acute), hemolytic-uremic
312
CITALOPRAM
syndrome, hiccups, hypercholesterolemia, hyperurice- Citalopram is one of the drugs confirmed to prolong the
mia, hypocalcemia, hypokalemia, hypomagnesemia, QT interval and is accepted as having a risk of causing
hyponatremia, hypophosphatemia, hypotension, torsade de pointes. The risk of drug-induced torsade de
increased serum amylase, ischemic heart disease, pointes is extremely low when a single QT interval
leukoencephalopathy, Lhermitte's sign, mesenteric prolonging drug is prescribed. In terms of epinephrine,
ischemia (acute; Morgan 2011), myocardial infarction, it is not known what effect vasoconstrictors in the local
neutropenic enterocolitis (Furonaka 2005), optic neu- anesthetic regimen will have in patients with a known
ritis, pancreatitis (Trivedi 2005), papilledema, periph- history of congenital prolonged QT interval or in patients
eral ischemia (acute), phlebitis (Tokuda 2015), taking any medication that prolongs the QT interval.
reversible posterior leukoencephalopathy syndrome, Until more information is obtained, it is suggested that
seizure, SIADH, skin rash, tachycardia, tetany, throm- the clinician consult with the physician prior to the use of
bosis (aortic; Fernandes 2011), thrombotic thrombo- a vasoconstrictor in suspected patients, and that the
cytopenic purpura, vasospasm (acute arterial; Morgan vasoconstrictor (epinephrine, mepivacaine and levonor-
2011), vision color changes, vision loss defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used
Mechanism of Action Cisplatin inhibits DNA synthesis with caution.
by the formation of DNA cross-links; denatures the Effects on Dental Treatment Key adverse event(s)
double helix; covalently binds to DNA bases and dis- related to dental treatment: Xerostomia (normal salivary
rupts DNA function; may also bind to proteins; the cis- flow resumes upon discontinuation). Premarketing trials
isomer is 14 times more cytotoxic than the trans-isomer; reported abnormal taste. See Effects on Bleeding and
both forms cross-link DNA but cis-platinum is less easily Dental Health Professional Considerations.
recognized by cell enzymes and, therefore, not Effects on Bleeding Selective serotonin reuptake
repaired. Cisplatin can also bind two adjacent guanines inhibitors, such as citalopram, may impair platelet
on the same strand of DNA producing intrastrand cross- aggregation due to platelet serotonin depletion, possi-
linking and breakage. bly increasing the risk of a bleeding complication. The
Pharmacodynamics/Kinetics risk of a bleeding complication can be increased by
Half-life Elimination coadministration of other antiplatelet agents, such as
Children: Free drug: 1.3 hours; Total platinum: 44 NSAIDs and aspirin.
hours Adverse Reactions
Adults: Cisplatin: 20 to 30 minutes; Platinum: ≥5 days >10%:
Pregnancy Considerations Central nervous system: Drowsiness (18%; dose
Cisplatin has been reported to cross the human pla- related), insomnia (15%; dose related)
centa. Cisplatin may cause fetal harm if administered to Dermatologic: Diaphoresis (11%; dose related)
a pregnant female. Gastrointestinal: Nausea (21%), xerostomia (20%)
1% to 10%:
Females of reproductive potential should use effective
Cardiovascular: Prolonged Q-T interval on ECG (2%),
contraception during treatment and for 14 months after
hypotension (≥1%), orthostatic hypotension (≥1%),
the last cisplatin dose. Verify pregnancy status prior to
tachycardia (≥1%), bradycardia (1%)
treatment initiation in females of reproductive potential.
Central nervous system: Fatigue (5%; dose related),
Male patients with female partners of reproductive
anxiety (4%), agitation (3%), yawning (2%; dose
potential should use effective contraception during
related), amnesia (≥1%), apathy (≥1%), confusion
treatment and for 11 months after the last cispla-
(≥1%), depression (≥1%), lack of concentration
tin dose.
(≥1%), migraine (≥1%), paresthesia (≥1%)
Cisplatin has been associated with cumulative dose- Dermatologic: Skin rash (≥1%), pruritus (≥1%)
dependent ovarian failure, premature menopause, Endocrine & metabolic: Decreased libido (1% to 4%),
impairment of spermatogenesis (oligospermia, azoo- amenorrhea (≥1%), weight gain (≥1%), weight
spermia; possibly irreversible). and reduced female loss (≥1%)
and male fertility. Gastrointestinal: Diarrhea (8%), dyspepsia (5%), ano-
rexia (4%), vomiting (4%), abdominal pain (3%),
dysgeusia (≥1%), flatulence (≥1%), increased appe-
Citalopram (sye TAL oh pram)
tite (≥1%), sialorrhea (≥1%)
Related Information Genitourinary: Ejaculatory disorder (6%), dysmenor-
Clinical Risk Related to Drugs Prolonging QT Interval rhea (3%), impotence (3%; dose related)
on page 1462 Neuromuscular & skeletal: Tremor (8%), arthralgia
(2%), myalgia (2%)
Escitalopram on page 517
Ophthalmic: Accommodation disturbance (≥1%)
Vasoconstrictor Interactions With Antidepressants on Renal: Polyuria (≥1%)
page 1606 Respiratory: Rhinitis (5%), upper respiratory tract
Brand Names: US CeleXA infection (5%), sinusitis (3%), cough (≥1%)
Brand Names: Canada Celexa Miscellaneous: Fever (2%)
Generic Availability (US) Yes <1%, postmarketing, and/or case reports: Abnormal
Pharmacologic Category Antidepressant, Selective gait, abnormal lacrimation, abnormal serum prolactin
Serotonin Reuptake Inhibitor levels, acne vulgaris, acute renal failure, aggressive
Use Major depressive disorder (unipolar): Treatment behavior, akathisia, alopecia, altered serum glucose,
of unipolar major depressive disorder anaphylaxis, anemia, angina pectoris, angioedema,
Local Anesthetic/Vasoconstrictor Precautions angle-closure glaucoma, arthritis, asthma, ataxia,
Although caution should be used in patients taking atrial fibrillation, blepharoptosis, blood coagulation dis-
tricyclic antidepressants, no interactions have been order, breast hypertrophy, bronchitis, bronchospasm,
reported with vasoconstrictors and citalopram, a non- bruxism, bundle branch block, bursitis, cardiac arrest,
tricyclic antidepressant which acts to increase seroto- cardiac failure, cataract, catatonia, cellulitis, cerebro-
nin; no precautions appear to be needed vascular accident, cholecystitis, cholelithiasis,
313
CITALOPRAM
choreoathetosis, colitis, conjunctivitis, dehydration, tolerability at intervals ≥1 week to 40 mg once daily.

delirium, delusions, depersonalization, dermatitis, dip- Although doses up to 60 mg/day have been studied,
lopia, diverticulitis, drug dependence, dry eye syn- due to safety considerations the recommended max-
drome, duodenal ulcer, dyskinesia, dysphagia, imum dose is 40 mg/day for adults ≤60 years of age
dyspnea, dystonia, dysuria, ecchymoses, eczema, and 20 mg/day for adults >60 years (McElroy 2003).
emotional lability, epistaxis, eructation, erythema mul- Generalized anxiety disorder (off-label use): Oral:
tiforme, esophagitis, euphoria, extrapyramidal reac- Initial: 10 mg once daily; may gradually increase
tion, extrasystoles, eye pain, facial edema, flu-like dose based on response and tolerability in 10 mg
symptoms, flushing, galactorrhea, gastric ulcer, gas- increments at intervals ≥1 week to a maximum dose
tritis, gastroenteritis, gastroesophageal reflux disease, of 40 mg/day for adults ≤60 years and 20 mg/day for
gastrointestinal hemorrhage, gingival hemorrhage, adults >60 years of age (Blank 2006; Varia 2002).
gingivitis, glossitis, goiter, granulocytopenia, gyneco- Major depressive disorder (unipolar): Oral: Initial:
mastia, hallucination, hematuria, hemolytic anemia, 20 mg once daily. In adults ≤60 years of age, may
hemorrhoids, hepatic necrosis, hepatitis, hiccups, hot gradually increase dose based on response and
flash, hyperbilirubinemia, hyperesthesia, hyperkine- tolerability at intervals ≥1 week to a maximum dose
sia, hypersensitivity reaction, hypertension, hyperto- of 40 mg/day; for adults >60 years of age, do not
nia, hypertrichosis, hypochromic anemia, exceed the maximum dose of 20 mg/day. Daily
hypoesthesia, hypoglycemia, hypohidrosis, hypokale- doses that exceeded these limits have been studied
mia, hypokinesia, hyponatremia, hypoprothrombine- but are not recommended due to safety considera-
mia, hypothyroidism, increased libido, increased liver tions.
enzymes, increased serum alkaline phosphatase, Obsessive-compulsive disorder (off-label use):
increased thirst, involuntary muscle movements, Oral: Initial: 20 mg once daily. In adults ≤60 years
ischemic heart disease, jaundice, keratitis, laryngitis, of age, may gradually increase dose based on
leg cramps, leukocytosis, leukopenia, lymphadenop- response and tolerability in 10 to 20 mg increments
athy, lymphocytopenia, lymphocytosis, mastalgia, at intervals ≥1 week to a maximum dose of
melanosis, myasthenia, mydriasis, myocardial infarc- 40 mg/day; for adults >60 years of age, do not
tion, myoclonus, nephrolithiasis, neuralgia, neuroleptic exceed the maximum dose of 20 mg/day. Daily
malignant syndrome (Stevens 2008), nightmares, nys- doses that exceeded these limits have been studied
tagmus, obesity, oliguria, osteoporosis, pancreatitis, but are not recommended due to safety considera-
panic attack, paranoia, peripheral edema, phlebitis, tions (APA [Koran 2007]; Montgomery 2001). Note:
photophobia, pneumonia, pneumonitis, priapism, pru- An adequate trial for assessment of effect in obses-
ritus ani, psoriasis, psychosis, pulmonary embolism, sive-compulsive disorder is considered to be ≥6
purpura, pyelonephritis, Raynaud's phenomenon weeks at maximum tolerated dose (Issari 2016).
(Khouri 2016; Peiró 2007), renal pain, rhabdomyoly- Panic disorder (off-label use): Oral: Initial: 10 mg
sis, rigors, seasonal allergic rhinitis, seizure, serotonin once daily for 3 to 7 days, then 20 mg once daily. In
syndrome, skeletal pain, skin discoloration, skin pho- adults ≤60 years, may gradually increase dose
tosensitivity, stomatitis, stupor, syncope, thrombocyto- based on response and tolerability in 10 to 20 mg
penia, thrombosis, tinnitus, tonic-clonic seizures, increments at intervals ≥1 week to a maximum of
torsades de pointes, toxic epidermal necrolysis, tran- 40 mg/day; for adults >60 years of age, do not
sient ischemic attacks, urinary incontinence, urinary exceed the maximum dose of 20 mg/day. Daily
retention, urticaria, vaginal hemorrhage, ventricular doses that exceeded these limits have been studied
arrhythmia, vertigo, withdrawal syndrome, xeroderma but are not recommended due to safety considera-
Dosing tions (APA 2009b; Leinonen 2000; Perna 2001;
Adult Note: Maximum daily dose: Due to the risk of Seedat 2003; Stahl 2003; Wade 1997).
QT prolongation, the maximum recommended daily Posttraumatic stress disorder (off-label use): Oral:
dose for all indications is 40 mg. A lower maximum Initial: 20 mg once daily. In adults ≤60 years of age,
daily dose of 20 mg is recommended in patients >60 may gradually increase dose based on response and
years of age, those with significant hepatic impair- tolerability in 10 to 20 mg increments at intervals ≥1
ment, and patients who are concurrently receiving week to a maximum dose of 40 mg once daily; for
medications that significantly increase citalopram lev- adults >60 years of age, do not exceed the maximum
els (eg, cimetidine, omeprazole) or known poor dose of 20 mg/day. Daily doses that exceeded these
metabolizers of CYP2C19 substrates. Initial dose limits have been studied but are not recommended
and titration: In patients sensitive to side effects, due to safety considerations (English 2006;
some experts suggest a lower starting dose of Tucker 2003).
10 mg daily and gradual titration in increments of no Premature ejaculation (off-label use): Oral: Initial:
more than 10 mg, particularly in patients with anxiety 20 mg once daily. In adults ≤60 years of age, may
who are generally more sensitive to overstimulation gradually increase dose based on response and
effects (eg, anxiety, insomnia) with antidepressants tolerability at intervals of ≥1 week (some experts
(Hirsch 2018c; WFSBP [Bandelow 2012]). suggest 3- to 4-week titration intervals [Khera
Aggressive or agitated behavior associated with 2018]) up to a maximum of 40 mg/day (Althof
dementia (off-label use): Oral: Initial: 10 mg once 2014; Atmaca 2002a; Safarinejad 2006); for adults
daily; increase to 20 mg once daily after ≥3 days. In >60 years of age, do not exceed the maximum dose
adults ≤60 years, may further increase dose based of 20 mg/day.
on response and tolerability up to 30 mg/day (Pol- Premenstrual dysphoric disorder (PMDD) (off-
lock 2002; Pollock 2007; Porsteinsson 2014); for label use):
adults >60 years, do not exceed the maximum dose Continuous daily dosing regimen: Oral: Initial:
of 20 mg/day. 10 mg once daily; over the first month increase to
Binge eating disorder (off-label use): Oral: Initial: usual effective dose of 20 mg once daily; in sub-
20 mg once daily. In adults ≤60 years of age, may sequent menstrual cycles, further dose increases
gradually increase dose based on response and (eg, in 10 mg increments per menstrual cycle) up to
314
CITALOPRAM
40 mg/day may be necessary in some patients for Switching antidepressants: Evidence for ideal anti-
optimal response (Casper 2018; Freeman 2002; depressant switching strategies is limited; strategies
Wikander 1998). include cross-titration (gradually discontinuing the
Intermittent regimens: first antidepressant while at the same time gradually
Luteal phase dosing regimen: Oral: Initial: 10 mg
increasing the new antidepressant) and direct switch
once daily during the luteal phase of menstrual
cycle only (ie, beginning therapy 14 days before (abruptly discontinuing the first antidepressant and
anticipated onset of menstruation and continued then starting the new antidepressant at an equivalent
to the onset of menses); over the first month dose or lower dose and increasing it gradually).
increase to usual effective dose of 20 mg once Cross-titration (eg, over 1 to 4 weeks depending
daily during the luteal phase; in a subsequent upon sensitivity to discontinuation symptoms and
menstrual cycle, a further increase to 30 mg/day adverse effects) is standard for most switches, but
during the luteal phase may be necessary in some
is contraindicated when switching to or from an
patients for optimal response (Casper 2018; Free-
man 2002; Wikander 1998). MAOI. A direct switch may be an appropriate
Symptom-onset dosing regimen: Oral: Initial: 10 mg approach when switching to another agent in the
once daily from the day of symptom onset until a same or similar class (eg, when switching between
few days after the start of menses; over the first two SSRIs), when the antidepressant to be discon-
month increase to usual effective dose of 20 mg tinued has been used for <1 week, or when the
once daily; in a subsequent menstrual cycle a discontinuation is for adverse effects. When choos-
further increase to 30 mg/day may be necessary
ing the switch strategy, consider the risk of discontin-
in some patients for optimal response (Casper
2018; Ravindran 2007). uation symptoms, potential for drug interactions,
Social anxiety disorder (off-label use): Oral: Initial: other antidepressant properties (eg, half-life, adverse
10 to 20 mg once daily. In adults ≤60 years of age, effects, pharmacodynamics), and the degree of
after ~6 weeks may gradually increase dose based symptom control desired (Hirsch 2018b; Ogle 2013;
on response and tolerability in 10 to 20 mg incre- WFSBP [Bauer 2013]).
ments at intervals ≥1 week up to maximum of Switching to or from an MAOI:
40 mg/day; for adults >60 years of age, do not
Allow 14 days to elapse between discontinuing an
exceed the maximum dose of 20 mg/day. Daily
doses that exceeded these limits have been studied MAOI and initiation of citalopram.
but are not recommended due to safety considera- Allow 14 days to elapse between discontinuing
tions (Atmaca 2002b; Furmark 2005; Stein 2019; citalopram and initiation of an MAOI.
WFSBP [Bandelow 2012]). Geriatric Note: For patients >60 years of age, the
Vasomotor symptoms associated with menopause maximum recommended dose is 20 mg/day due to
(alternative agent) (off-label use): Oral: Initial: the risk of QT prolongation.
10 mg once daily; may increase dose to 20 mg once
Generalized anxiety disorder (off-label use): Oral:
daily after 1 week. In adults ≤60 years of age, doses
as high as 40 mg/day have been studied; however, Initial: 10 mg once daily; may increase dose based
doses >20 mg/day have demonstrated little addi- on response and tolerability in 10 mg increments at
tional benefit and greater adverse effects (Barton intervals ≥1 week up to 20 mg/day. Doses up to
2010; Kalay 2007; NAMS 2015). For adults >60 40 mg/day have been studied; however, according
years of age, do not exceed the maximum dose of to the manufacturer, dosing should not exceed
20 mg/day. 20 mg/day. (Blank 2006; Lenze 2005)
Dosage adjustments: For concomitant therapy with Major depressive disorder (unipolar): Adults >60
moderate to strong CYP2C19 inhibitors or other years: Oral: Initial: 10 to 20 mg once daily (Marano
drugs that significantly increase citalopram levels 2015; VA/DoD 2016); maximum dose: 20 mg/day
(eg, cimetidine, omeprazole, voriconazole) and in
due to increased exposure and the risk of QT pro-
persons who are known to be poor metabolizers of
longation.
CYP2C19: Maximum dose: 20 mg/day.
Discontinuation of therapy: When discontinuing anti- Discontinuation of therapy: Refer to adult dosing.
depressant treatment that has lasted for >3 weeks, Switching antidepressants: Refer to adult dosing.
gradually taper the dose (eg, over 2 to 4 weeks) to Renal Impairment: Adult
minimize withdrawal symptoms and detect reemerg- Mild to moderate impairment: No dosage adjustment
ing symptoms (APA 2010; WFSBP [Bauer 2015]). necessary.
Reasons for a slower titration (eg, over 4 weeks)
Severe impairment: CrCl <20 mL/minute: No dosage
include use of a drug with a half-life <24 hours (eg,
paroxetine, venlafaxine), prior history of antidepres- adjustment provided in manufacturer's labeling (has
sant withdrawal symptoms, or high doses of antide- not been studied); use caution.
pressants (APA 2010; Hirsch 2019). If intolerable Hepatic Impairment: Adult Maximum recom-
withdrawal symptoms occur, resume the previously mended dose: 20 mg daily due to decreased clear-
prescribed dose and/or decrease dose at a more ance and the risk of QT prolongation
gradual rate (Shelton 2001). Select patients (eg,
Pediatric Note: Slower titration of dose every 2 to 4
those with a history of discontinuation syndrome)
on long-term treatment (>6 months) may benefit from weeks may minimize risk of SSRI associated behav-
tapering over >3 months (WFSBP [Bauer 2015]). ioral activation, which has been shown to increase risk
Evidence supporting ideal taper rates is limited of suicidal behavior. Doses >40 mg are not recom-
(Shelton 2001; WFSBP [Bauer 2015]). mended due to risk of QTc prolongation.
315
CITALOPRAM
Depression: Limited data available; efficacy results resume citalopram 24 hours after the last dose
variable: One randomized, placebo controlled trial of linezolid or IV methylene blue.
has shown citalopram to be effective for the treat- Renal Impairment: Pediatric Specific recommenda-
ment of depression in pediatric patients (Wagner tions in pediatric patients are not available; based on
2004); other controlled pediatric trials have not experience in adult patients, in mild to moderate
shown benefit (Sharp 2006; von Knorring 2006; impairment, no adjustment needed, and in severe
Wagner 2005). Some experts recommend the fol- impairment, use with caution (has not been studied).
lowing doses (Dopheide 2006): Oral: Hepatic Impairment: Pediatric Specific recommen-
Children 7 to ≤11 years: Initial: 10 mg/day given dations in pediatric patients are not available; based
once daily; increase dose slowly by 5 mg/day on experience in adult patients, consider reduced daily
every 2 weeks as clinically needed; dosage range: doses due to increased serum concentrations and the
20 to 40 mg/day risk of QT prolongation.
Children and Adolescents ≥12 years: Initial: Mechanism of Action A racemic bicyclic phthalane
20 mg/day given once daily; increase dose slowly derivative, citalopram selectively inhibits serotonin
by 10 mg/day every 2 weeks as clinically needed; reuptake in the presynaptic neurons and has minimal
dosage range: 20 to 40 mg/day effects on norepinephrine or dopamine. Uptake inhib-
Obsessive-compulsive disorder: Limited data ition of serotonin is primarily due to the S-enantiomer of
available: Several open label trials have been pub- citalopram. Displays little to no affinity for serotonin,
lished (Mukaddes 2003; Thomsen 1997; Thomsen dopamine, adrenergic, histamine, GABA, or muscarinic
2001). Some experts recommend the following receptor subtypes.
doses: Oral: Contraindications
Children 7 to ≤11 years: Initial: 5 to 10 mg/day Hypersensitivity to citalopram or any component of the
given once daily; increase dose slowly by formulation; use of MAO inhibitors intended to treat
5 mg/day every 2 weeks as clinically needed; psychiatric disorders (concurrently or within 14 days of
dosage range: 10 to 40 mg/day discontinuing either citalopram or the MAO inhibitor);
Children and Adolescents ≥12 years: Initial: 10 to initiation of citalopram in a patient receiving linezolid or
20 mg/day given once daily; increase dose slowly intravenous methylene blue; concomitant use with
by 10 mg/day every 2 weeks as clinically needed; pimozide
dosage range: 10 to 40 mg/day Canadian labeling: Additional contraindications (not in
Note: Higher mg/kg doses are needed in children US labeling): Known QT interval prolongation or con-
compared to adolescents. genital long QT syndrome
Discontinuation of therapy: Upon discontinuation Warnings/Precautions [US Boxed Warning]: Anti-
of antidepressant therapy, gradually taper the dose depressants increase the risk of suicidal thinking
to minimize the incidence of withdrawal symptoms and behavior in children, adolescents, and young
and allow for the detection of reemerging symp- adults (18 to 24 years of age) with major depressive
toms. Evidence supporting ideal taper rates is disorder (MDD) and other psychiatric disorders;
limited. APA and NICE guidelines suggest tapering consider risk prior to prescribing. Short-term studies
therapy over at least several weeks with consider- did not show an increased risk in patients >24 years
ation to the half-life of the antidepressant; antide- of age and showed a decreased risk in patients ≥65
pressants with a shorter half-life may need to be years. Closely monitor patients for clinical worsening,
tapered more conservatively. In addition for long- suicidality, or unusual changes in behavior, particularly
term treated patients, WFSBP guidelines recom- during the initial 1 to 2 months of therapy or during
mend tapering over 4-6 months. If intolerable with- periods of dosage adjustments (increases or
drawal symptoms occur following a dose reduction, decreases); the patient's family or caregiver should be
consider resuming the previously prescribed dose instructed to closely observe the patient and communi-
and/or decrease dose at a more gradual rate (APA cate condition with health care provider. A medication
2010; Bauer 2002; Haddad 2001; NCCMH 2010; guide concerning the use of antidepressants should be
Schatzberg 2006; Shelton 2001; Warner 2006). dispensed with each prescription. Citalopram is not
MAO inhibitor recommendations: FDA approved for use in children.
Switching to or from an MAO inhibitor intended to
treat psychiatric disorders: The possibility of a suicide attempt is inherent in major
Allow 14 days to elapse between discontinuing an depression and may persist until remission occurs. Use
MAO inhibitor intended to treat psychiatric dis- caution in high-risk patients. Worsening depression and
orders and initiation of citalopram. severe abrupt suicidality that are not part of the pre-
Allow 14 days to elapse between discontinuing senting symptoms may require discontinuation or mod-
citalopram and initiation of an MAO inhibitor ification of drug therapy. The patient's family or
intended to treat psychiatric disorders. caregiver should be alerted to monitor patients for the
Use with other MAO inhibitors (linezolid or IV meth- emergence of suicidality and associated behaviors
ylene blue): (such as agitation, irritability, hostility, impulsivity, and
Do not initiate citalopram in patients receiving hypomania) and call health care provider.
linezolid or IV methylene blue; consider other
May worsen psychosis in some patients or precipitate a
interventions for psychiatric condition.
shift to mania or hypomania in patients with bipolar
If urgent treatment with linezolid or IV methylene
disorder. Patients presenting with depressive symptoms
blue is required in a patient already receiving
should be screened for bipolar disorder. Monotherapy in
citalopram and potential benefits outweigh
patients with bipolar disorder should be avoided. Cit-
potential risks, discontinue citalopram promptly
alopram is not FDA approved for the treatment of
and administer linezolid or IV methylene blue.
bipolar depression.
Monitor for serotonin syndrome for 2 weeks or
until 24 hours after the last dose of linezolid or IV Potentially life-threatening serotonin syndrome (SS)
methylene blue, whichever comes first. May has occurred with serotonergic agents (eg, SSRIs,
316
CITALOPRAM
SNRIs), particularly when used in combination with of treatment, and abrupt discontinuation. For antide-
other serotonergic agents (eg, triptans, TCAs, fentanyl, pressants of short or intermediate half-lives, symptoms
lithium, tramadol, buspirone, St John's wort, tryptophan) may emerge within 2 to 5 days after treatment discon-
or agents that impair metabolism of serotonin (eg, MAO tinuation and last 7 to 14 days (APA 2010; Fava 2006;
inhibitors intended to treat psychiatric disorders, other Haddad 2001; Shelton 2001; Warner 2006).
MAO inhibitors [ie, linezolid and intravenous methylene Warnings: Additional Pediatric Considerations
blue]). Discontinue treatment (and any concomitant Selective serotonin reuptake inhibitor (SSRI)-associ-
serotonergic agent) immediately if signs/symptoms ated behavioral activation (ie, restlessness, hyperkine-
arise. May increase the risks associated with electro- sis, hyperactivity, agitation) is two- to threefold more
convulsive therapy. Has a low potential to impair cog- prevalent in children compared to adolescents; it is
nitive or motor performance; caution operating more prevalent in adolescents compared to adults.
hazardous machinery or driving. Bone fractures have Somnolence (including sedation and drowsiness) is
been associated with antidepressant treatment. Con- more common in adults compared to children and
sider the possibility of a fragility fracture if an antide- adolescents (Safer, 2006). SSRI-associated vomiting
pressant-treated patient presents with unexplained is two- to threefold more prevalent in children compared
bone pain, point tenderness, swelling, or bruising to adolescents and is more prevalent in adolescents
(Rabenda 2013; Rizzoli 2012). compared to adults (Safer, 2006).
Drug Interactions
Citalopram causes dose-dependent QTc prolongation;
Metabolism/Transport Effects Substrate of
torsades de pointes, ventricular tachycardia, and sud-
CYP2C19 (major), CYP2D6 (minor), CYP3A4 (major);
den death have been reported. Use is not recom-
Note: Assignment of Major/Minor substrate status
mended in patients with congenital long QT syndrome,
based on clinically relevant drug interaction potential;
bradycardia, recent MI, uncompensated heart failure,
Inhibits CYP2D6 (weak)
hypokalemia, and/or hypomagnesemia, or patients
receiving concomitant medications which prolong the
Avoid concomitant use of Citalopram with any of the
QT interval; if use is essential and cannot be avoided in
following: Bromopride; Dapoxetine; Dosulepin; Escita-
these patients, ECG monitoring is recommended. Dis-
lopram; Methylene Blue; Monoamine Oxidase Inhib-
continue therapy in any patient with persistent QTc
itors; Pimozide; QT-prolonging Agents (Highest Risk);
measurements >500 msec. Serum electrolytes, partic-
Tryptophan; Urokinase
ularly potassium and magnesium, should be monitored
prior to initiation and periodically during therapy in any Increased Effect/Toxicity
patient at increased risk for significant electrolyte dis- Citalopram may increase the levels/effects of: Agents
turbances; hypokalemia and/or hypomagnesemia with Antiplatelet Properties; Anticoagulants; Antipsy-
should be corrected prior to use. Due to the QT chotic Agents; Apixaban; ARIPiprazole; Aspirin; Blood
prolongation risk, doses >40 mg/day are not recom- Glucose Lowering Agents; Brexanolone; BusPIRone;
mended. In a scientific statement from the American Cephalothin; Collagenase (Systemic); Dabigatran
Heart Association, citalopram has been determined to Etexilate; Deoxycholic Acid; Desmopressin; Dextro-
be an agent that may exacerbate underlying myocardial methorphan; Domperidone; Dosulepin; Doxepin-Con-
dysfunction (magnitude: major) (AHA [Page 2016]). taining Products; Edoxaban; Gilteritinib; Haloperidol;
Additionally, the maximum daily dose should not exceed Ibritumomab Tiuxetan; Lofexidine; Methylene Blue;
20 mg/day in certain populations (eg, CYP2C19 poor Mexiletine; Nonsteroidal Anti-Inflammatory Agents
metabolizers, patients with hepatic impairment, elderly (COX-2 Selective); Nonsteroidal Anti-Inflammatory
patients). Potentially significant interactions may exist, Agents (Nonselective); Obinutuzumab; Perhexiline;
requiring dose or frequency adjustment, additional mon- QT-prolonging Kinase Inhibitors (Moderate Risk);
itoring, and/or selection of alternative therapy. QT-prolonging Miscellaneous Agents (Moderate Risk);
QT-prolonging Moderate CYP3A4 Inhibitors (Moder-
Use with caution in patients with a previous seizure ate Risk); QT-prolonging Strong CYP3A4 Inhibitors
disorder or condition predisposing to seizures such as (Moderate Risk); Rivaroxaban; Salicylates; Serotonin
brain damage or alcoholism. May cause or exacerbate Modulators; Serotonin Reuptake Inhibitor/Antagonists;
sexual dysfunction. Pharmacokinetics are altered in Thiazide and Thiazide-Like Diuretics; Thrombolytic
patients >60 years of age; a lower maximum dose of Agents; TraMADol; Tricyclic Antidepressants; Uroki-
20 mg/day is recommended in this population because nase; Vitamin K Antagonists; Voriconazole
of the risk of QT prolongation. May cause mild pupillary
dilation, which in susceptible individuals can lead to an The levels/effects of Citalopram may be increased by:
episode of narrow-angle glaucoma. Consider evaluat- Alcohol (Ethyl); Antiemetics (5HT3 Antagonists); Anti-
ing patients who have not had an iridectomy for narrow- psychotic Agents; Bromopride; BuPROPion; BusPIR-
one; Cimetidine; CNS Depressants; CYP2C19
angle glaucoma risk factors. Citalopram is not FDA-
Inhibitors (Moderate); Dapoxetine; Escitalopram; Eso-
approved for use in children; however, if used, monitor
meprazole; Fat Emulsion (Fish Oil Based); Flucona-
weight and growth regularly during therapy due to the
zole; Glucosamine; Herbs (Anticoagulant/Antiplatelet
potential for decreased appetite and weight loss with
Properties); Ibrutinib; Inotersen; Limaprost; Linezolid;
SSRI use.
Lithium; Lofexidine; Metaxalone; Methylene Blue;
Abrupt discontinuation or interruption of antidepressant Methylphenidate; Metoclopramide; MetyroSINE;
therapy has been associated with a discontinuation Monoamine Oxidase Inhibitors; Multivitamins/Fluoride
syndrome. Symptoms arising may vary with antidepres- (with ADE); Multivitamins/Minerals (with ADEK,
sant however commonly include nausea, vomiting, Folate, Iron); Multivitamins/Minerals (with AE, No
diarrhea, headaches, light-headedness, dizziness, Iron); Omega-3 Fatty Acids; Omeprazole; Ondanse-
diminished appetite, sweating, chills, tremors, paresthe- tron; Opioid Agonists; Pentamidine (Systemic); Pento-
sias, fatigue, somnolence, and sleep disturbances (eg, san Polysulfate Sodium; Pentoxifylline; Pimozide;
vivid dreams, insomnia). Greater risks for developing a Prostacyclin Analogues; QT-prolonging Agents (High-
discontinuation syndrome have been associated with est Risk); QT-prolonging Antipsychotics (Moderate
antidepressants with shorter half-lives, longer durations Risk); QT-prolonging Class IC Antiarrhythmics
317
CITALOPRAM
(Moderate Risk); QT-prolonging Moderate CYP3A4 Treatment algorithms have been developed by the
Inhibitors (Moderate Risk); QT-prolonging Quinolone ACOG and the APA for the management of depression
Antibiotics (Moderate Risk); QT-prolonging Strong in women prior to conception and during pregnancy
CYP3A4 Inhibitors (Moderate Risk); Tedizolid; Tipra- (ACOG 2008; APA 2010; Yonkers 2009).
navir; TraMADol; Tricyclic Antidepressants; Trypto-
phan; Vitamin E (Systemic); Voriconazole
Decreased Effect Pregnancy Registry for Antidepressants (NPRAD).
Citalopram may decrease the levels/effects of: Ioflu- Women 18 to 45 years of age or their health care
pane I 123; Thyroid Products providers may contact the registry by calling
The levels/effects of Citalopram may be decreased by: 844-405-6185. Enrollment should be done as early in
Bosentan; CarBAMazepine; CYP2C19 Inducers pregnancy as possible.
(Moderate); CYP2C19 Inducers (Strong); CYP3A4 Breastfeeding Considerations
Inducers (Moderate); CYP3A4 Inducers (Strong); Citalopram and its active metabolites are present in
Cyproheptadine; Dabrafenib; Deferasirox; Enzaluta- breast milk.
mide; Gilteritinib; Lorlatinib; Mitotane; Nonsteroidal The relative infant dose (RID) of citalopram has been
Anti-Inflammatory Agents (COX-2 Selective); Nonster- evaluated in numerous studies; the reported RID of
oidal Anti-Inflammatory Agents (Nonselective); Pitoli- citalopram ranges from 3% to 10% of the weight-
sant; RifAMPin; Sarilumab; Siltuximab; St John's adjusted maternal dose (maternal dose not stated;
Wort; Tocilizumab Berle 2011), and may be higher (Berle 2011; Sriraman
Dietary Considerations May be taken without regard 2015). In general, breastfeeding is considered accept-
to food. able when the RID is <10% (Anderson 2016; Ito
Pharmacodynamics/Kinetics 2000); however, some sources note breastfeeding
Onset of Action Depression: The onset of action is 1 should only be considered if the RID is <5% for
to 4 weeks; however, individual response varies psychotropic agents (Larsen 2015). When an RID is
greatly and full response may not be seen until 8 to >25% breastfeeding should generally be avoided
12 weeks after initiation of treatment. (Anderson 2016; Ito 2000). Active metabolites of cit-
Duration of Action 1 to 2 days alopram can also be detected in breast milk. Peak milk
Half-life Elimination 24 to 48 hours (average: 35 concentrations of citalopram and desmethylcitalopram
hours); doubled with hepatic impairment and occur 4 and 6 hours, respectively, after the maternal
increased by 30% (following multiple doses) to 50% dose in women on chronic therapy (Rampono 2000).
(following single dose) in elderly patients (≥60 years) However, avoiding breastfeeding during the expected
Time to Peak Serum: 1 to 6 hours, average within 4 peak concentrations will generally not decrease infant
hours exposure significantly for antidepressants with long
Pregnancy Risk Factor C half-lives (Berle 2011). Although the absolute infant
plasma concentrations are generally negligible, in
some cases the infant plasma concentration of citalo-
pram was up to 10% of the maternal concentration
duction studies. Citalopram and its metabolites cross
(Berle 2011).
the human placenta (Heikkinen, Ekblad, Kero 2002). An
Excessive somnolence, decreased feeding, and weight
increased risk of teratogenic effects, including cardio-
loss have been noted in infants exposed to citalopram
vascular defects, may be associated with maternal use
from breast milk. Infants of mothers using psycho-
of citalopram or other SSRIs; however, available infor-
tropic medications should be monitored daily for
mation is conflicting. Nonteratogenic effects in the new-
changes in sleep, feeding patterns, and behavior
born following SSRI/SNRI exposure late in the third
(Bauer 2013) as well as infant growth and neuro-
trimester include respiratory distress, cyanosis, apnea,
development (Sachs 2013; Sriraman 2015). Maternal
seizures, temperature instability, feeding difficulty, vom-
use of an SSRI during pregnancy may cause delayed
iting, hypoglycemia, hypo- or hypertonia, hyper-reflexia,
lactogenesis (Marshall 2010).
jitteriness, irritability, constant crying, and tremor. Symp-
When first initiating an antidepressant in a breastfeed-
toms may be due to the toxicity of the SSRIs/SNRIs or a
ing woman, agents other than citalopram are pre-
discontinuation syndrome and may be consistent with
ferred. Women successfully treated with citalopram
serotonin syndrome associated with SSRI treatment.
during pregnancy may continue use while breastfeed-
Persistent pulmonary hypertension of the newborn
ing if there are no other contraindications (Berle 2011;
(PPHN) has also been reported with SSRI exposure.
Sriraman 2015). According to the manufacturer, the
The long-term effects of in utero SSRI exposure on
decision to continue or discontinue breastfeeding dur-
infant development and behavior are not known.
ing therapy should take into account the risk of infant
Due to pregnancy-induced physiologic changes, exposure, the benefits of breastfeeding to the infant,
women who are pregnant may require adjusted doses and benefits of treatment to the mother.
of citalopram to achieve euthymia (Heikkinen, Ekblad, Dosage Forms: US
Kero 2002). The ACOG recommends that therapy with Solution, Oral:
SSRIs or SNRIs during pregnancy be individualized; Generic: 10 mg/5 mL (240 mL)
treatment of depression during pregnancy should incor- Tablet, Oral:
porate the clinical expertise of the mental health clini- CeleXA: 10 mg, 20 mg, 40 mg
cian, obstetrician, primary health care provider, and Generic: 10 mg, 20 mg, 40 mg
pediatrician. According to the American Psychiatric Dental Health Professional Considerations Prob-
Association (APA), the risks of medication treatment lems with SSRI-induced bruxism have been reported
should be weighed against other treatment options and may preclude their use; clinicians attempting to
and untreated depression. For women who discontinue evaluate any patient with bruxism or involuntary muscle
antidepressant medications during pregnancy and who movement, who is simultaneously being treated with an
may be at high risk for postpartum depression, the SSRI drug, should be aware of the potential associa-
medications can be restarted following delivery. tion.
318
CLADRIBINE
Also see Local Anesthetic/Vasoconstrictor Precautions Infection: Fungal infection (6%), herpes virus infection
(PO: 6%), serious infection (IV: 6%), viral infection
(IV: 6%), herpes zoster infection (2% to 4%)
Cladribine (KLA dri been)
Neuromuscular & skeletal: Back pain (8%), arthralgia
Brand Names: US Mavenclad (10 Tabs); Mavenclad (4 (≤7%), arthritis (PO: ≤7%), asthenia (IV: 6%), myal-
Tabs); Mavenclad (5 Tabs); Mavenclad (6 Tabs); gia (IV: 6%)
Mavenclad (7 Tabs); Mavenclad (8 Tabs); Mavenclad Respiratory: Cough (IV: 7%), bronchitis (PO: 5%),
(9 Tabs) dyspnea (IV: 5%), abnormal breath sounds (IV:
Brand Names: Canada Cladribine Injection; Maven- 4%), rales (IV: 1%)
clad Frequency not defined:
Cardiovascular: Edema (IV), phlebitis (IV)
Dermatologic: Cellulitis (IV), erythema of skin (IV),
metabolite; Antineoplastic Agent, Antimetabolite
erythematous rash (IV), macular eruption (IV), mac-
(Purine Analog); Immunosuppressant Agent
ulopapular rash (IV), papular rash (IV), pruritic rash
Use
(IV), pustular rash (IV)
Hairy cell leukemia (injection only): Treatment of
Hematologic & oncologic: Malignant neoplasm of
active hairy cell leukemia as defined by clinically
ovary (PO), purpuric disease (IV)
significant anemia, neutropenia, thrombocytopenia,
Infection: Bacteremia (IV), coccidioidomycosis (PO),
or disease-related symptoms.
localized infection (IV), septicemia (IV)
Multiple sclerosis, relapsing (oral tablet only): Treat-
Local: Bleeding at injection site (IV), localized
ment of relapsing forms of multiple sclerosis (MS), edema (IV)
including relapsing-remitting (RRMS) and active sec- Renal: Pyelonephritis (PO)
ondary progressive disease in adults who have had <1%, postmarketing, and/or case reports: Acute renal
inadequate response or are intolerant to other thera- failure, aplastic anemia, autoimmune hemolytic ane-
pies for multiple sclerosis. mia, basal cell carcinoma, cardiac failure, cervical
Limitations of use: Not recommended for patients with carcinoma, confusion, conjunctivitis, diplopia, disori-
clinically isolated syndrome. entation, eosinophilia, graft versus host disease,
Local Anesthetic/Vasoconstrictor Precautions hemolytic anemia, hepatic injury, impaired conscious-
No information available to require special precautions ness, increased serum bilirubin, increased serum
Effects on Dental Treatment No significant effects or transaminases, interstitial pulmonary disease, malig-
complications reported nant melanoma, mucous membrane ulceration, mye-
Effects on Bleeding The major dose-limiting adverse lodysplastic syndrome, myocarditis, opportunistic
effect of cladribine is bone marrow suppression includ- infection, pancreatic adenocarcinoma, pancytopenia,
ing severe (grade 4) thrombocytopenia in ~12% of paralysis, paraplegia, peripheral sensory neuropathy,
patients receiving repeated courses of therapy; recov- pharyngeal edema, pneumonia, pneumonitis, poly-
ery is usually by day 12. neuropathy, progressive multifocal leukoencephalop-
Adverse Reactions athy, pulmonary fibrosis, pulmonary infiltrates, renal
>10%: failure syndrome, renal insufficiency, respiratory tract
Central nervous system: Fatigue (IV: 31%), headache infection, seizure, septic shock, severe neurotoxicity,
(PO: 25%; IV: 14%), high fever (IV: 11%) status epilepticus, Stevens-Johnson syndrome, tuber-
Dermatologic: Skin rash (IV: 16%; PO: <1%) culosis, tumor lysis syndrome, urticaria, vertigo, viral
Gastrointestinal: Nausea (IV: 22%; PO: 10%) skin infection
Hematologic & oncologic: Lymphocytopenia (4% to Mechanism of Action Cladribine is a purine nucleo-
87%), severe neutropenia (IV: 70%), severe anemia side analogue; it is a prodrug which is activated by
(IV: 37%), bone marrow depression (34%), phosphorylation and converted into the active moiety,
decreased hemoglobin (oral: 26%), thrombocytope- Cd-ATP. This active form incorporates into DNA to
nia (11% to 12%) result in the breakage of DNA strand and shutdown of
Hypersensitivity: Hypersensitivity reaction (11%) DNA synthesis and repair. This also results in a deple-
Infection: Infection (PO: 49%; IV: 6% to 28%), bacte- tion of nicotinamide adenine dinucleotide and adeno-
rial infection (IV: 12%) sine triphosphate (ATP). Cladribine is cell-cycle
Local: Injection site reaction (IV: 11%) nonspecific. The mechanism of cladribine in treating
Respiratory: Upper respiratory tract infection multiple sclerosis (MS) is unknown, but may involve
(PO: 38%) cytotoxic effects on B and T lymphocytes that result
Miscellaneous: Fever (IV: 33% to 69%; PO: 5%) from the shutdown of DNA synthesis, leading to a
1% to 10%: depletion of lymphocytes.
Cardiovascular: Hypertension (PO: 5%), peripheral Pharmacodynamics/Kinetics
edema (IV: 2%), tachycardia (IV: 2%) Half-life Elimination Children 8 months to 18 years:
Central nervous system: Dizziness (IV: 6%), pain (IV: IV: 19.7 ± 3.4 hours (Kearns 1994); Adults: After a 2-
6%), insomnia (3% to 6%), depression (PO: 5%), hour infusion (with normal renal function): 5.4 hours;
malaise (IV: 5%), chills (IV: 2%), anxiety (IV: 1%), Oral: ~24 hours
myasthenia (IV: 1%) Time to Peak Oral: Median 0.5 hour (range 0.5 to 1.5
Dermatologic: Alopecia (PO: 3%), hyperhidrosis (IV: hours) (fasting); 1.5 hours (range 1 to 3 hours) (with
3%), ecchymosis (IV: 2%), pruritus (IV: 2%) high-fat meal)
Gastrointestinal: Vomiting (IV: 9%), decreased appe- Pregnancy Considerations
tite (IV: 8%), diarrhea (IV: 7%), abdominal pain (IV: Based on the mechanism of action and data from
4%), constipation (IV: 4%), oral herpes simplex animal reproduction studies, in utero exposure to cla-
infection (oral: 3%), flatulence (IV: 1%) dribine is expected to cause fetal harm. Females of
Hematologic & oncologic: Febrile neutropenia (IV: reproductive potential should use highly effective con-
8%), neutropenia (PO: 4%), petechia (IV: 2%), ane- traception during therapy regardless of the route of
mia (IV: 1%), bruise (IV: 1%) administration/indication for treatment.
319
CLADRIBINE
[US Boxed Warning]: Oral tablet: Cladribine is con- Mycobacterial infections, disseminated: Prophylaxis
traindicated for use in pregnant women and in and treatment of disseminated mycobacterial infec-
women and men of reproductive potential who do tions due to Mycobacterium avium complex (MAC) in
not plan to use effective contraception because of patients with advanced HIV infection.
the potential for fetal harm. Malformations and Otitis media: Treatment of acute otitis media in pedia-
embryolethality occurred in animals. Exclude preg- tric patients due to susceptible H. influenzae, M.
nancy before the start of treatment with cladribine catarrhalis, or S. pneumoniae.
in females of reproductive potential. Advise females Pharyngitis/tonsillitis: Treatment of pharyngitis/tonsil-
and males of reproductive potential to use effective litis due to susceptible Streptococcus pyogenes (alter-
contraception during cladribine dosing and for 6 native agent).
months after the last dose in each treatment Pneumonia, community-acquired: Treatment of com-
course. Stop cladribine if the patient becomes preg- munity-acquired pneumonia due to susceptible Myco-
nant. Pregnancy should be excluded in females of plasma pneumoniae, S. pneumoniae, or
reproductive potential prior to each course of cladribine. Chlamydophila pneumoniae (adult and pediatric
The effect of cladribine on hormonal contraceptives is patients) and H. influenzae, H. parainfluenzae, or M.
not known, use of a barrier method is recommended in catarrhalis (adults).
addition to systemic hormonal contraceptives during Skin/skin structure infections: Treatment of uncom-
therapy and for 4 weeks after the last cladribine dose. plicated skin/skin structure infection due to susceptible
Staphylococcus aureus or S. pyogenes.
Information related to the use of cladribine for the
treatment of hairy cell leukemia in pregnancy is limited
Clarithromycin is one of the drugs confirmed to prolong
(Daver 2013).
A pregnancy registry is available for all cancers diag- causing torsade de pointes. In terms of epinephrine, it
nosed during pregnancy at Cooper Health is not known what effect vasoconstrictors in the local
(877-635-4499). anesthetic regimen will have in patients with a known
Product Availability Mavenclad: FDA approved March history of congenital prolonged QT interval or in patients
2019; anticipated availability is currently unknown. Con- taking any medication that prolongs the QT interval.
sult the prescribing information for additional informa- Until more information is obtained, it is suggested that
tion. the clinician consult with the physician prior to the use of
a vasoconstrictor in suspected patients, and that the
vasoconstrictor (epinephrine, mepivacaine and levonor-
Clarithromycin (kla RITH roe mye sin)
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used
Related Information with caution. See Dental Health Professional Consid-
erations.
Antibiotic Prophylaxis on page 1502
Bacterial Infections on page 1525
related to dental treatment: Abnormal taste.
Clinical Risk Related to Drugs Prolonging QT Interval
on page 1462
Gastrointestinal Disorders on page 1465
Adverse Reactions
Brand Names: US Biaxin [DSC] 1% to 10%:
Brand Names: Canada Accel-Clarithromycin; Apo- Central nervous system: Headache (2%), insomnia
Clarithromycin; Apo-Clarithromycin XL; Biaxin; Biaxin Dermatologic: Skin rash (children 3%)
BID; Biaxin XL; Dom-Clarithromycin; Mylan-Clarithro- Gastrointestinal: Dysgeusia (adults 3% to 7%), vomit-
mycin; PMS-Clarithromycin; RAN-Clarithromycin; ing (children 6%), diarrhea (3% to 6%), nausea
Riva-Clarithromycin; Sandoz-Clarithromycin; Teva- (adults 3%), abdominal pain (2% to 3%), dyspepsia
Clarithromycin (adults 2%)
Generic Availability (US) Yes Hematologic & oncologic: Prolonged prothrombin time
Pharmacologic Category Antibiotic, Macrolide (adults 1%)
Dental Use Alternate oral antibiotic for prevention of Hepatic: Abnormal hepatic function tests
infective endocarditis in individuals allergic to penicillins Hypersensitivity: Anaphylactoid reaction
or ampicillin, when amoxicillin cannot be used Infection: Candidiasis (including oral)
Use Renal: Increased blood urea nitrogen (4%)
Bronchitis, acute bacterial exacerbation: Treatment <1%, postmarketing, and/or case reports: Abdominal
of acute bacterial exacerbation of chronic bronchitis in distension, abnormal albumin-globulin ratio, acne vul-
adults due to susceptible Haemophilus influenzae, H. garis, acute generalized exanthematous pustulosis,
parainfluenzae, Moraxella catarrhalis, or Streptococ- ageusia, agranulocytosis, altered sense of smell, ana-
cus pneumoniae. phylaxis, angioedema, anorexia, anosmia, anxiety,
Helicobacter pylori eradication: Eradication of Heli- asthma, atrial fibrillation, behavioral changes, bullous
cobacter pylori to reduce the risk of duodenal ulcer dermatitis, cellulitis, chest pain, chills, cholestasis,
recurrence as a component of combination therapy cholestatic hepatitis, Clostridioides (formerly Clostri-
(triple therapy) in adults with H. pylori infection and dium) difficile-associated diarrhea, Clostridioides (for-
duodenal ulcer disease (active or 5 year history of merly Clostridium) difficile (colitis), confusion,
duodenal ulcer). constipation, dark urine (abnormal urine color associ-
Limitations of use: Regimens that contain clarithromy- ated with liver injury), decreased appetite, decreased
cin as the single antibacterial agent are more likely to white blood cell count, dental discoloration (reversible
be associated with the development of clarithromycin with dental cleaning), depersonalization, depression,
resistance. Clarithromycin-containing regimens disorientation, dizziness, DRESS syndrome, drowsi-
should not be used in patients with known or sus- ness, dyskinesia, eosinophilia, epistaxis, eructation,
pected clarithromycin-resistant isolates (efficacy is esophagitis, extrasystoles, fatigue, fever, flatulence,
reduced). gastritis, gastroenteritis, gastroesophageal reflux
320
CLARITHROMYCIN
disease, glossitis, hallucination, hearing loss (reversi- either metronidazole or tinidazole 500 mg twice
ble), hemorrhage, hepatic failure, hepatic insuffi- daily; continue treatment for 10 to 14 days.
ciency, hepatitis, hepatotoxicity (idiosyncratic) Sequential regimen: Amoxicillin 1 g twice daily plus
(Chalasani 2014), hyperhidrosis, hypersensitivity a standard-dose proton pump inhibitor twice daily
reaction, hypoglycemia, IgA vasculitis, increased for 5 to 7 days; then follow with clarithromycin
gamma-glutamyl transferase, increased INR, 500 mg twice daily, and a standard-dose proton
increased lactate dehydrogenase, increased serum pump inhibitor twice daily, and either metronida-
alkaline phosphatase, increased serum ALT, zole or tinidazole 500 mg twice daily for 5 to
increased serum AST, increased serum bilirubin, 7 days.
increased serum creatinine, infection, interstitial neph- Hybrid regimen: Amoxicillin 1 g twice daily plus a
ritis, jaundice, leukopenia, loss of consciousness, standard-dose proton pump inhibitor twice daily
maculopapular rash, malaise, manic behavior, muscle for 7 days; then follow with amoxicillin 1 g twice
spasm, myalgia, myopathy, neck stiffness, nervous- daily, clarithromycin 500 mg twice daily, a stand-
ness, neutropenia, nightmares, palpitations, pancrea- ard-dose PPI twice daily, and either metronidazole
titis, parasomnias, paresthesia, prolonged QT interval or tinidazole 500 mg twice daily for 7 days.
on ECG, pruritus, pseudomembranous colitis, psycho- Lyme disease (off-label use): Oral: 500 mg twice
sis, pulmonary embolism, rectal pain, renal failure, daily for 14 to 21 days (not recommended for preg-
rhabdomyolysis, seizure, Stevens-Johnson syndrome, nant women) (Wormser 2006)
stomatitis, thrombocytopenia, tinnitus, tongue discol- Mycobacterial infection, disseminated (prophy-
oration, torsades de pointes, toxic epidermal necrol- laxis and treatment): Oral:
ysis, tremor, urticaria, vaginal infection, ventricular Manufacturer's labeling: 500 mg twice daily (use with
arrhythmia, ventricular tachycardia, vertigo, weak- other antimycobacterial drugs, eg, ethambutol or
ness, xerostomia rifampin). Continue therapy if clinical response is
Dental Usual Dosage Prophylaxis against infective observed; may discontinue when patient is consid-
endocarditis (off-label use): Oral: ered at low risk of disseminated infection.
Children: 15 mg/kg 30-60 minutes before procedure Alternate dosing: Mycobacterium avium complex dis-
Adults: 500 mg 30-60 minutes prior to procedure ease (MAC) in HIV-infected patients (HHS [OI adult
Dosing 2017]):
Adult & Geriatric Primary prophylaxis (patients with CD4 count <50
cells/mm3): 500 mg twice daily; may discontinue
Usual dosage range: Oral: 250 to 500 mg every 12
when CD4 count >100 cells/mm3 for ≥3 months in
hours or 1000 mg (two 500 mg extended-release
response to ART. Note: If effective ART is initiated
tablets) once daily for 7 to 14 days
immediately and viral suppression is achieved,
Bronchitis, acute bacterial exacerbation: Oral:
some experts do not recommend routine initiation
M. catarrhalis and S. pneumoniae: 250 mg every 12
of MAC primary prophylaxis, regardless of initial
hours for 7 to 14 days or 1,000 mg (two 500 mg
CD4 count (IAS-USA [Gunthard 2016]).
extended-release tablets) once daily for 7 days
Treatment and chronic maintenance therapy:
H. influenzae: 500 mg every 12 hours for 7 to 14
500 mg twice daily plus ethambutol; consider
days or 1,000 mg (two 500 mg extended-release additional agents (eg, rifabutin, aminoglycoside,
tablets) once daily for 7 days fluoroquinolone) for CD4 <50 cells/mm3, high
H. parainfluenzae: 500 mg every 12 hours for 7 days mycobacterial load, or ineffective antiretroviral
or 1,000 mg (two 500 mg extended-release tab- therapy; may discontinue chronic maintenance if
lets) once daily for 7 days no signs/symptoms of MAC disease, have main-
Bartonellosis in HIV-infected patients (excluding tained a CD4 count >100 cells/mm3 for >6 months
CNS infections and endocarditis) (off-label use; in response to ART, and completed at least 12
HHS [OI adult 2015]): Oral: months of therapy
Treatment (alternative to preferred): 500 mg twice Pertussis (off-label use): Oral: 500 mg twice daily for
daily for at least 3 months 7 days (CDC 2005)
Long-term suppressive therapy: 500 mg twice daily; Pneumonia, community-acquired: Oral:
may discontinue if completed 3 to 4 months therapy Manufacturer's labeling:
and CD4 >200 cells/mm3 for at least 6 months. C. pneumoniae, M. pneumoniae, and S. pneumo-
Note: Some clinicians would discontinue only if niae: 250 mg every 12 hours for 7 to 14 days or
Bartonella titers have also decreased four-fold 1,000 mg (two 500 mg extended-release tablets)
H. pylori eradication: Oral: once daily for 7 days
American College of Gastroenterology guidelines H. influenzae: 250 mg every 12 hours for 7 days or
(Chey 2007; Chey 2017): 1,000 mg (two 500 mg extended-release tablets)
Clarithromycin triple therapy: 500 mg twice daily, in once daily for 7 days
combination with a standard-dose or double-dose H. parainfluenzae and M. catarrhalis: 1000 mg (two
proton pump inhibitor, and either amoxicillin 1 g 500 mg extended-release tablets) once daily for
twice daily or metronidazole 500 mg three times 7 days
daily; continue regimen for 14 days. Note: Avoid Alternate dosing:
use of clarithromycin triple therapy in patients with Outpatient empiric therapy: 500 mg twice daily for 5
risk factors for macrolide resistance (eg, prior days, in combination with a beta-lactam (Lim
macrolide exposure, local clarithromycin resist- 2009; Mandell 2007)
ance rates ≥15%, eradication rates with clarithro- Prophylaxis against infective endocarditis (off-
mycin-based regimens ≤85%) (ACG [Chey 2017]; label use): Oral: 500 mg 30 to 60 minutes prior to
Fallone 2016). procedure. Note: American Heart Association (AHA)
Concomitant regimen: 500 mg twice daily in combi- guidelines now recommend prophylaxis only in
nation with amoxicillin 1 g twice daily, and a stand- patients undergoing invasive procedures and in
ard-dose proton pump inhibitor twice daily, and whom underlying cardiac conditions may predispose
321
CLARITHROMYCIN
to a higher risk of adverse outcomes should infection Helicobacter pylori eradication: Children and Ado-
occur. As of April 2007, routine prophylaxis for GI/GU lescents: Oral: 20 mg/kg/day divided every 12
procedures is no longer recommended by the AHA hours for 7 to 14 days. Note: Duration dependent
(Wilson 2007). on regimen used; maximum single dose: 500 mg.
Skin and skin structure infection, uncomplicated: Administer as part of triple or quadruple combina-
Oral: 250 mg every 12 hours for 7 to 14 days tion regimens with amoxicillin and proton pump
Streptococcal pharyngitis (group A) (alternative inhibitor with or without metronidazole
agent for severely penicillin-allergic patients): (Koletzko 2011)
Oral: 250 mg every 12 hours for 10 days (IDSA Lyme disease: Limited data available: Infants, Chil-
[Shulman 2012]). dren, and Adolescents: Oral: 7.5 mg/kg twice daily
Dosage adjustment for concomitant therapy: Ata- for 14 to 21 days; maximum single dose: 500 mg
zanavir: Decrease clarithromycin dose by 50%. (IDSA [Wormser 2006])
Mycobacterium avium complex infection (MAC)
(HIV-exposed/-positive):
CrCl ≥30 mL/minute: No dosage adjustment neces-
Infants and Children (DHHS [pediatric] 2013)
sary.
Prophylaxis:
CrCl <30 mL/minute: Decrease clarithromycin dose
Primary prophylaxis: Oral: 15 mg/kg/day divided
by 50%
Hemodialysis: Administer after HD session is com- every 12 hours; maximum single dose: 500 mg;
pleted (Aronoff 2007). to prevent first episode begin therapy at the
In combination with atazanavir or ritonavir: following CD4 + T-lymphocyte counts (see
CrCl 30 to 60 mL/minute: Decrease clarithromycin below):
dose by 50%. Infants <12 months: <750 cells/mm3
CrCl <30 mL/minute: Decrease clarithromycin dose Children 1 to <2 years: <500 cells/mm3
by 75%. Children 2 to 5 years: <75 cells/mm3
Hepatic Impairment: Adult No dosage adjustment Children ≥6 years: <50 cells/mm3
necessary if renal function is normal; however, in Secondary prophylaxis: Oral: 15 mg/kg/day div-
patients with hepatic impairment and concomitant ided every 12 hours; maximum single dose:
severe renal impairment, a dosage reduction or pro- 500 mg; use in combination with ethambutol
longed dosing intervals may be appropriate. with or without rifabutin
Pediatric Treatment: Oral: 15 to 30 mg/kg/day divided every
Note: All pediatric dosing recommendations based on 12 hours; maximum single dose: 500 mg; use in
immediate release product formulations (tablet and combination with ethambutol and if severe infec-
oral suspension): tion, rifabutin; follow with chronic suppressive
General dosing, susceptible infection, mild to therapy
moderate infection: Infants, Children, and Adoles- Adolescents (DHHS [adult] 2013):
cents: Oral: 15 mg/kg/day divided every 12 hours; Prophylaxis:
maximum single dose: 500 mg (Red Book Primary prophylaxis: Oral: 500 mg twice daily
[AAP 2012]) Secondary prophylaxis: Oral: 500 mg twice daily
Bartonellosis, treatment and secondary prophy- plus ethambutol; consider additional agents
laxis in HIV-exposed/-positive patients (exclud- (eg, rifabutin, aminoglycoside, fluoroquinolone)
ing CNS infections and endocarditis): Limited for CD4 <50 cells/mm3, high mycobacterial
data available: Oral: load, or ineffective antiretroviral therapy.
Infants and Children: 15 mg/kg/day divided every Treatment: Oral: 500 mg twice daily in combina-
12 hours for at least 3 months; maximum single tion with ethambutol: Consider additional agents
dose: 500 mg (CDC 2009) (eg, rifabutin, aminoglycoside, fluoroquinolone)
Adolescents: 500 mg twice daily administered for at for CD4 <50 cells/mm3, high mycobacterial load,
least 3 months (DHHS [adult] 2013) or ineffective antiretroviral therapy.
Endocarditis, prophylaxis: Note: AHA guidelines Otitis media, acute (AOM): Infants ≥6 months and
(Baltimore 2015) limit the use of prophylactic anti- Children: Oral: 15 mg/kg/day divided every 12
biotics to patients at the highest risk for infective hours for 10 days; maximum single dose: 500 mg;
endocarditis (IE) or adverse outcomes (eg, pros- Note: Due to increased S. pneumoniae and H.
thetic heart valves, patients with previous IE, unre- influenzae resistance, clarithromycin is not routinely
paired cyanotic congenital heart disease, repaired recommended as a treatment option (AAP [Lieber-
congenital heart disease with prosthetic material or thal 2013])
device during first 6 months after procedure, Peritonitis (peritoneal dialysis), prophylaxis for
repaired congenital heart disease with residual patients requiring invasive dental procedures:
defects at the site or adjacent to site of prosthetic Infants, Children, and Adolescents: Oral: 15 mg/kg
patch or device, heart transplant recipients with 30 to 60 minutes before dental procedure; max-
cardiac valvulopathy): imum single dose: 500 mg (Warady [ISPD 2012])
Dental procedures in patients allergic to penicillins: Pertussis: Infants, Children, and Adolescents: Oral:
Limited data available: Infants, Children, and Ado- 15 mg/kg/day divided every 12 hours for 7 days;
lescents: Oral: 15 mg/kg; maximum single dose: maximum single dose: 500 mg (CDC [Tiwari 2005])
500 mg; administer 30 to 60 minutes before pro- Pneumonia, community-acquired (CAP); pre-
cedure (AHA [Wilson 2007]). sumed atypical pneumonia (M. pneumoniae, C.
Group A streptococcal infection; rheumatic pneumoniae, C. trachomatis); mild infection or
fever, primary prevention and treatment of step-down therapy: Infants >3 months, Children,
streptococcal tonsillopharyngitis: Infants, Chil- and Adolescents: Oral: 15 mg/kg/day every 12
dren, and Adolescents: Oral: 15 mg/kg/day divided hours for 10 days; shorter courses may be appro-
every 12 hours for 10 days; maximum single dose: priate for mild disease; maximum single dose:
250 mg (Gerber 2009; IDSA [Shulman 2012]) 500 mg; Note: A beta-lactam antibiotic should be
322
CLARITHROMYCIN
added if typical bacterial pneumonia cannot be been reported; usually reversible after discontinuation
ruled out (Bradley 2011). of clarithromycin. May lead to hepatic failure or death
Renal Impairment: Pediatric (rarely), especially in the presence of preexisting dis-
Infants, Children, and Adolescents: The following eases and/or concomitant use of medications. Discon-
adjustments have been recommended (Aronoff tinue immediately if symptoms of hepatitis (eg,
2007). Note: Renally adjusted dose recommenda- anorexia, jaundice, abdominal tenderness, pruritus,
tions are based on a dose 15 mg/kg/day divided dark urine) occur. Use with caution in patients with
twice daily. myasthenia gravis; exacerbation of symptoms and
GFR ≥30 mL/minute/1.73 m2: No dosage adjust- new onset of symptoms has occurred. Use with caution
ment necessary in severe renal impairment; dosage adjustment
GFR 10 to 29 mL/minute/1.73 m2: 4 mg/kg/dose required.
every 12 hours Potentially significant drug-drug interactions may exist,
GFR <10 mL/minute/1.73 m2: 4 mg/kg/dose once requiring dose or frequency adjustment, additional mon-
daily itoring, and/or selection of alternative therapy. Pro-
Hemodialysis: Administer after HD session is com- longed use may result in fungal or bacterial
pleted: 4 mg/kg/dose once daily superinfection, including C. difficile-associated diarrhea
Peritoneal dialysis: 4 mg/kg/dose once daily (CDAD) and pseudomembranous colitis; CDAD has
Hepatic Impairment: Pediatric Infants, Children, been observed >2 months postantibiotic treatment.
and Adolescents: No dosage adjustment necessary Decreased H. pylori eradication rates have been
if renal function is normal; however, in patients with observed with short-term (≤7 days) combination ther-
hepatic impairment and concomitant severe renal apy. Current guidelines recommend 10 to 14 days of
impairment, a dosage reduction or prolonged dosing therapy (triple or quadruple) for eradication of H. pylori
intervals may be appropriate. in pediatric and adult patients (Chey 2007; NASPHGAN
Mechanism of Action Exerts its antibacterial action by [Koletzko 2011]). Decreased survival has been
binding to 50S ribosomal subunit resulting in inhibition observed in HIV patients with Mycobacterium avium
of protein synthesis. The 14-OH metabolite of clarithro- complex (MAC) receiving clarithromycin doses above
mycin is twice as active as the parent compound the maximum recommended dose; maximum recom-
against certain organisms. mended dosing should not be exceeded in this popula-
Contraindications tion. Development of resistance to clarithromycin has
Hypersensitivity to clarithromycin, erythromycin, any of been observed when used as prophylaxis and treat-
the macrolide antibiotics, or any component of the ment of MAC infection (Biaxin Canadian product
formulation; history of cholestatic jaundice/hepatic labeling).
dysfunction associated with prior use of clarithromy-
cin; concomitant use with cisapride, pimozide, ergot Severe acute reactions have (rarely) been reported,
alkaloids (eg, ergotamine, dihydroergotamine), or including anaphylaxis, Stevens-Johnson syndrome
HMG-CoA reductase inhibitors extensively metabo- (SJS), toxic epidermal necrolysis (TEN), drug rash with
lized by CYP3A4 (eg, lovastatin, simvastatin); con- eosinophilia and systemic symptoms (DRESS),
comitant use with colchicine in patients with renal or Henoch-Schönlein purpura (IgA vasculitis), and acute
hepatic impairment generalized exanthematous pustulosis; discontinue
Canadian labeling: Additional contraindications (not in therapy and initiate treatment immediately for severe
US labeling): Severe hepatic failure in combination acute hypersensitivity reactions. The presence of ER
with renal impairment; history of QT prolongation tablets in the stool has been reported, particularly in
(congenital or documented acquired QT prolongation patients with anatomic (eg, ileostomy, colostomy) or
or ventricular cardiac arrhythmia, including torsades functional GI disorders with decreased transit times.
de pointes; hypokalemia; concomitant use with saqui- Consider alternative dosage forms (eg, suspension) or
navir, midazolam (oral), colchicine (regardless of hep- an alternative antimicrobial for patients with tablet res-
atic/renal impairment), ticagrelor; concomitant use idue in the stool and no signs of clinical improvement.
with astemizole, domperidone, terfenadine, or ranola- Some dosage forms may contain propylene glycol.
zine (not available in Canada) Large amounts are potentially toxic and have been
associated hyperosmolality, lactic acidosis, seizures,
Warnings/Precautions Use has been associated with
and respiratory depression; use caution (AAP 1997;
QT prolongation and infrequent cases of arrhythmias,
Zar 2007).
including torsade de pointes (may be fatal). Use with
Drug Interactions
caution in elderly patients; may be at increased risk of
torsades de pointes. Avoid use in patients with known
CYP3A4 (major); Note: Assignment of Major/Minor
prolongation of the QT interval, ventricular cardiac
substrate status based on clinically relevant drug
arrhythmia (including torsades de pointes), uncorrected
interaction potential; Inhibits CYP3A4 (strong),
hypokalemia or hypomagnesemia, clinically significant
OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/
bradycardia, and patients receiving Class IA (eg, quini-
ABCB1
dine, procainamide) or Class III (eg, amiodarone, dofe-
tilide, sotalol) antiarrhythmic agents or other drugs
Avoid concomitant use of Clarithromycin with any of
known to prolong the QT interval. Use caution in
the following: Acalabrutinib; Ado-Trastuzumab Emtan-
patients with coronary artery disease. A clinical trial in
sine; Alfuzosin; Aprepitant; Astemizole; Asunaprevir;
patients with CAD demonstrated an increase in risk of
Avanafil; Axitinib; Barnidipine; BCG (Intravesical); Blo-
all-cause mortality ≥1 year after the end of treatment in
nanserin; Bosutinib; Bromocriptine; Budesonide (Sys-
patients randomized to receive clarithromycin. Other
temic); Cholera Vaccine; Cisapride; Cobimetinib;
epidemiologic studies evaluating this risk have variable
Conivaptan; Dabrafenib; Dapoxetine; Dihydroergot-
results.
amine; Domperidone; Dronedarone; Elagolix; Eletrip-
Elevated liver function tests and hepatitis (hepatocellu- tan; Eplerenone; Ergotamine; Everolimus; Flibanserin;
lar and/or cholestatic with or without jaundice) have Fluticasone (Nasal); Fosaprepitant; Fusidic Acid
323
CLARITHROMYCIN
(Systemic); Grazoprevir; Halofantrine; Ibrutinib; Idela- PredniSONE; Protease Inhibitors; Prucalopride; QT-
lisib; Irinotecan Products; Isavuconazonium Sulfate; prolonging Antidepressants (Moderate Risk); QT-pro-
Ivabradine; Lapatinib; Lercanidipine; Lomitapide; Lopi- longing Miscellaneous Agents (Moderate Risk); QUE-
navir; Lovastatin; Lurasidone; Macitentan; Mizolas- t i a p i n e ; R a d o t i n i b ; Ra m e l t e o n ; R a n o l a z i n e ;
tine; Naloxegol; Neratinib; NiMODipine; Nisoldipine; Reboxetine; Red Yeast Rice; Regorafenib; Repagli-
Palbociclib; PAZOPanib; Pimozide; QT-prolonging nide; Retapamulin; Revefenacin; Ribociclib; RifAXI-
Agents (Highest Risk); QT-prolonging Miscellaneous M in; Ri lpi vi rin e; Riv aro xa ba n; Rom iDEPs in ;
Agents (Moderate Risk); Radotinib; Ranolazine; Red Rupatadine; Ruxolitinib; Salmeterol; Saquinavir; SAX-
Yeast Rice; Regorafenib; Revefenacin; Rupatadine; agliptin; Sildenafil; Silodosin; Simeprevir; Simvastatin;
Salmeterol; Saquinavir; Silodosin; Simeprevir; Sim- Sirolimus; Sonidegib; SORAfenib; SUFentanil; Suvor-
vastatin; Sonidegib; Suvorexant; Tamsulosin; Terfena- exant; Tacrolimus (Systemic); Tacrolimus (Topical);
dine; Ticagrelor; Tolvaptan; Topotecan; Trabectedin; Tadalafil; Talazoparib; Tamsulosin; Tasimelteon; Tem-
Triazolam; Udenafil; Ulipristal; VinCRIStine (Liposo- sirolimus; Terfenadine; Tetrahydrocannabinol; Tetra-
mal); Vinflunine; Vorapaxar; Voxilaprevir hydrocannabinol and Cannabidiol; Tezacaftor;
Increased Effect/Toxicity Theophylline Derivatives; Ticagrelor; Tofacitinib; Tol-
Clarithromycin may increase the levels/effects of: terodine; Tolvaptan; Topotecan; Toremifene; Trabecte-
Abemaciclib; Acalabrutinib; Ado-Trastuzumab Emtan- din; TraMADol; TraZODone; Triazolam; Udenafil;
sine; Afatinib; Alfuzosin; Alitretinoin (Systemic); Almo- Ulipristal; Valbenazine; Vardenafil; Vemurafenib; Ven-
triptan; Alosetron; ALPRAZolam; Antineoplastic etoclax; Vilazodone; VinCRIStine (Liposomal); Vinflu-
Agents (Vinca Alkaloids); Apixaban; Aprepitant; ARI- nine; Vitamin K Antagonists; Vorapaxar; Voriconazole;
Piprazole; ARIPiprazole Lauroxil; Astemizole; Asu- Voxilaprevir; Zidovudine; Zopiclone; Zuclopenthixol
n a p r e v i r ; A t o r v a S TATi n ; A v a n a f i l ; A x i t i n i b ; The levels/effects of Clarithromycin may be increased
Barnidipine; Benperidol; Benzhydrocodone; Betame- by: Antihepaciviral Combination Products; Bosentan;
thasone (Ophthalmic); Betrixaban; Bictegravir; Bilas- CarBAMazepine; Ceritinib; Citalopram; Cobicistat;
tine; Blonanserin; Bortezomib; Bosentan; Bosutinib; Conivaptan; Crizotinib; CYP3A4 Inducers (Moderate);
Brentuximab Vedotin; Brexpiprazole; Brigatinib; Brin- CYP3A4 Inducers (Strong); CYP3A4 Inhibitors (Mod-
zolamide; Bromocriptine; Budesonide (Nasal); Bude- erate); CYP3A4 Inhibitors (Strong); Dasatinib; Efavir-
sonide (Oral Inhalation); Budesonide (Systemic); en z; Enc oraf en ib; Eryth rom yc in (S ys tem ic );
Budesonide (Topical); Buprenorphine; BusPIRone; Fluconazole; FLUoxetine; Fosnetupitant; Fusidic Acid
Cabazitaxel; Cabergoline; Cabozantinib; Calcifediol; (Systemic); Idelalisib; Lopinavir; MiFEPRIStone; Netu-
Calcium Channel Blockers; Cannabidiol; Cannabis; pitant; Nilotinib; Osimertinib; Pentamidine (Systemic);
CarBAMazepine; Cardiac Glycosides; Cariprazine; Pimozide; Protease Inhibitors; QT-prolonging Agents
Celiprolol; Ceritinib; Cilostazol; Cinacalcet; Cisapride; (Highest Risk); QT-prolonging Antipsychotics (Moder-
Citalopram; CloZAPine; Cobicistat; Cobimetinib; ate Risk); QT-prolonging Class IC Antiarrhythmics
Codeine; Colchicine; Conivaptan; Copanlisib; Cortico- (Moderate Risk); QT-prolonging Quinolone Antibiotics
steroids (Orally Inhaled); Corticosteroids (Systemic); (Moderate Risk); QUEtiapine; Ribociclib; Saquinavir;
Crizotinib; CycloSPORINE (Systemic); CYP3A4 Stiripentol; Toremifene; TraZODone; Vemurafenib;
Inducers (Strong); CYP3A4 Substrates (High risk with Vilanterol; Voriconazole
Inhibitors); Dabigatran Etexilate; Dabrafenib; Dacla- Decreased Effect
tasvir; Dapoxetine; Dasatinib; Deflazacort; Dexame- Clarithromycin may decrease the levels/effects of:
thasone (Ophthalmic); Dienogest; BCG (Intravesical); BCG Vaccine (Immunization);
Dihydroergotamine; DOCEtaxel; Domperidone; DOX- Cholera Vaccine; Doxercalciferol; Ifosfamide; Lacto-
Orubicin (Conventional); Dronabinol; Dronedarone; bacillus and Estriol; Sincalide; Sodium Picosulfate;
Drospirenone; Dutasteride; Duvelisib; Edoxaban; Ela- Ticagrelor; Typhoid Vaccine; Zidovudine
golix; Eletriptan; Eliglustat; Encorafenib; Eplerenone;
Ergot Derivatives; Ergotamine; Erlotinib; Estazolam; The levels/effects of Clarithromycin may be decreased
Estrogen Derivatives; Eszopiclone; Etizolam; Everoli- by: Bosentan; CarBAMazepine; CYP3A4 Inducers
mus; Evogliptin; FentaNYL; Fesoterodine; Flibanserin; (Moderate); CYP3A4 Inducers (Strong); Deferasirox;
FLUoxetine; Fluticasone (Nasal); Fluticasone (Oral Efavirenz; Enzalutamide; Lopinavir; Lorlatinib; Mito-
Inhalation); Fosaprepitant; Fostamatinib; Galant- tane; Pitolisant; Protease Inhibitors; Sarilumab; Siltux-
amine; Gefitinib; Gilteritinib; Glasdegib; GlipiZIDE; imab; St John's Wort; Tocilizumab
GlyBURIDE; Grazoprevir; GuanFACINE; Halofantrine; Food Interactions Immediate release: Food delays
HYDROcodone; Ibrutinib; Iloperidone; Imatinib; Imida- rate, but not extent of absorption; Extended release:
fenacin; Irinotecan Products; Isavuconazonium Sul- Food increases clarithromycin AUC by ~30% relative to
fate; Ivabradine; Ivacaftor; Ixabepilone; Lacosamide; fasting conditions. Management: Administer immediate
Lapatinib; Larotrectinib; Lercanidipine; Levobupiva- release products without regard to meals. Administer
caine; Levomilnacipran; Lomitapide; Lopinavir; Lorla- extended release products with food.
tinib; Lovastatin; Lumefantrine; Lurasidone; Pharmacodynamics/Kinetics
Macitentan; Manidipine; Maraviroc; MedroxyPRO- Half-life Elimination Immediate release: Clarithro-
GESTERone; MethylPREDNISolone; Midazolam; mycin: 3-7 hours; 14-OH-clarithromycin: 5-9 hours
Midostaurin; MiFEPRIStone; Mirodenafil; Mizolastine; Time to Peak Immediate release: 2-3 hours; Extended
Naldemedine; Nalfurafine; Naloxegol; Neratinib; Nilo- release: 5-8 hours
tinib; NiMODipine; Nintedanib; Nisoldipine; Olaparib; Pregnancy Considerations
Ondansetron; Ospemifene; Oxybutynin; OxyCO- Clarithromycin crosses the placenta (Witt 2003).
DONE; Palbociclib; Panobinostat; Parecoxib; Parical-
citol; PARoxetine; PAZOPanib; P-glycoprotein/ABCB1 The manufacturer recommends that clarithromycin not
Substrates; Pimavanserin; Pimecrolimus; Pimozide; be used in a pregnant woman unless there are no
Piperaquine; Pitavastatin; PONATinib; Pranlukast; alternative therapies. Clarithromycin is not recom-
Pravastatin; Praziquantel; PrednisoLONE (Systemic); mended as a first-line agent for the treatment or pro-
phylaxis of Mycobacterium avium complex or for
324
CLEVIDIPINE
treatment of bacterial respiratory disease in HIV- children ≥12 years of age and adults (tablets and
infected pregnant patients (HHS [OI adult 2017]). syrup) and in children 6 to 12 years (syrup only)
Breastfeeding Considerations Urticaria/angioedema: Relief of mild, uncomplicated
Clarithromycin and its active metabolite (14-hydroxy allergic skin manifestations of urticaria and angioe-
clarithromycin) are present in breast milk. dema in children ≥12 years of age and adults (tablets
The relative infant dose (RID) of clarithromycin is <1% and syrup) and in children 6 to 12 years (syrup only)
when calculated using the highest mean breast milk
concentration located and compared to an infant ther- OTC Labeling: Common cold/hay fever/upper res-
apeutic dose of 15 mg/kg/day. piratory allergies: Relief of symptoms associated
In general, breastfeeding is considered acceptable with the common cold (eg, rhinorrhea, sneezing,
when the RID is <10% (Anderson 2016; Ito 2000). throat/nose pruritus, lacrimation) in children ≥12 years
Using the highest mean milk concentrations (clarithro- of age and adults
mycin: 0.85 mg/L; 14-hydroxy clarithromycin: Local Anesthetic/Vasoconstrictor Precautions
0.63 mg/L), the estimated daily infant dose via breast No information available to require special precautions
milk was calculated to be 136 mcg/kg/day. This milk Effects on Dental Treatment Key adverse event(s)
concentration was obtained following maternal admin- related to dental treatment: Xerostomia (normal salivary
istration of oral clarithromycin 250 mg twice daily; the flow resumes upon discontinuation).
half-lives of clarithromycin and 14-hydroxy clarithro- Effects on Bleeding No information available to
mycin in breast milk were 4.3 ± 0.3 hours and 9 ± 1.2 require special precautions
hours, respectively (Sedlmayr 1993). Adverse Reactions Frequency not defined.
Decreased appetite, diarrhea, rash, and somnolence Cardiovascular: Hypotension, palpitations, tachycardia
have been reported in breastfed infants exposed to Central nervous system: Ataxia, confusion, dizziness,
macrolide antibiotics (Goldstein 2009). In general, drowsiness (slight to moderate), fatigue, headache,
antibiotics that are present in breast milk may cause insomnia, irritability, nervousness, restlessness,
non-dose-related modification of bowel flora. Monitor sedation
infants for GI disturbances, such as thrush and diar- Dermatologic: Skin photosensitivity, skin rash
rhea (WHO 2002). In addition, an increased risk for Gastrointestinal: Constipation, diarrhea, epigastric dis-
infantile hypertrophic pyloric stenosis (IHPS) may be tress, nausea, vomiting, xerostomia
present in infants who are exposed to macrolides via Genitourinary: Difficulty in micturition, urinary fre-
breast milk, especially during the first two weeks of life quency, urinary retention
(Lund 2014); however, data are conflicting (Goldstein Hematologic & oncologic: Agranulocytosis, hemolytic
2009). According to the manufacturer, the decision to anemia, thrombocytopenia
breastfeed during therapy should consider the risk of Hypersensitivity: Anaphylaxis
infant exposure, the benefits of breastfeeding to the
Ophthalmic: Blurred vision
infant, and benefits of treatment to the mother.
Otic: Tinnitus
Dosage Forms: US Respiratory: Thickening of bronchial secretions
Mechanism of Action Competes with histamine for
Generic: 125 mg/5 mL (50 mL, 100 mL); 250 mg/5 mL
H1-receptor sites on effector cells in the gastrointestinal
(50 mL, 100 mL)
tract, blood vessels, and respiratory tract; anticholiner-
Tablet, Oral:
gic and sedative effects are also seen.
Tablet Extended Release 24 Hour, Oral:
Generic: 500 mg Onset of Action 2 hours after administration; Peak
effect: Therapeutic: 5 to 7 hours
FDA issued a special alert in December 2005 stating Duration of Action 10 to 12 hours; may persist for up
that short-term therapy with clarithromycin in patients to 24 hours
with stable coronary artery disease may cause signifi- Half-life Elimination ~21 hours (range: 10 to 33
cantly higher cardiovascular mortality. The use of hours) (Sharma 2003)
500 mg clarithromycin daily for 14 days in patients with Time to Peak 2 to 4 hours
the above condition resulted in significantly higher all- Pregnancy Risk Factor B
cause mortality compared to patients taking placebo. Pregnancy Considerations Maternal clemastine use
This information is provided to the dental practitioner on has generally not resulted in an increased risk of birth
the possible association between short-term use of defects. Antihistamines are recommended for the treat-
clarithromycin for infections and increases in mortality ment of rhinitis, urticaria, and pruritus with rash in
in patients with a history of stable coronary artery pregnant women (although second generation antihist-
disease. amines may be preferred). Antihistamines are not rec-
Also see Local Anesthetic/Vasoconstrictor Precautions ommended for treatment of pruritus associated with
intrahepatic cholestasis in pregnancy.
Clemastine (KLEM as teen)

Clevidipine (klev ID i peen)
Brand Names: US Dayhist Allergy 12 Hour Relief
[OTC]; Tavist Allergy [OTC] [DSC] Related Information
Pharmacologic Category Ethanolamine Derivative; Calcium Channel Blockers and Gingival Hyperplasia on
Histamine H1 Antagonist; Histamine H1 Antagonist, page 1601
First Generation Brand Names: US Cleviprex
Use Brand Names: Canada Cleviprex
Allergic rhinitis: Relief of symptoms associated with Pharmacologic Category Antihypertensive; Calcium
allergic rhinitis or other upper respiratory allergies (eg, Channel Blocker; Calcium Channel Blocker, Dihydro-
sneezing, rhinorrhea, pruritus, and lacrimation) in pyridine
325
CLEVIDIPINE
Use Hypertension: Management of hypertension when or ampicillin, when amoxicillin cannot be used; alternate
oral therapy is not feasible or not desirable. IM or IV antibiotic for prevention of infective endocarditis
Local Anesthetic/Vasoconstrictor Precautions in patients allergic to penicillins or ampicillin and unable
No information available to require special precautions to take oral medication; alternate oral antibiotic for
Effects on Dental Treatment Key adverse event(s) prophylaxis for dental patients with total joint replace-
related to dental treatment: Although other calcium ment who are allergic to penicillin; alternate IV antibiotic
channel blockers (eg, nifedipine, diltiazem) have been for prophylaxis for dental patients with total joint
associated with gingival hyperplasia, there are no replacement who are allergic to penicillin and unable
reports that clevidipine has caused this adverse effect. to take oral medications; alternate antibiotic in the treat-
Effects on Bleeding No information available to ment of common orofacial infections caused by aerobic
require special precautions gram-positive cocci and susceptible anaerobes; treat-
Adverse Reactions ment of periodontal disease
>10%: Use
Cardiovascular: Atrial fibrillation (21%) Bone and joint infections: Treatment of bone and joint
Central nervous system: Insomnia (12%) infections, including acute hematogenous osteomyeli-
Gastrointestinal: Nausea (5% to 21%) tis caused by Staphylococcus aureus and as adjunc-
Miscellaneous: Fever (19%) tive therapy in the surgical treatment of chronic bone
1% to 10%: and joint infections caused by susceptible organisms.
Central nervous system: Headache (6%) Gynecological infections: Treatment of gynecologic
Gastrointestinal: Vomiting (3%) infections, including endometritis, nongonococcal
Hematologic & oncologic: Postprocedural hemor- tubo-ovarian abscess, pelvic cellulitis, and postsurgi-
rhage (3%) cal vaginal cuff infection caused by susceptible anae-
Renal: Acute renal failure (9%) robes.
Intraabdominal infections: Treatment of intraabdomi-
Respiratory: Pneumonia (3%), respiratory failure (3%)
nal infections, including peritonitis and intraabdominal
<1%, postmarketing, and/or case reports: Dyspnea,
abscess caused by susceptible anaerobic organisms.
hypersensitivity reaction, hypotension, increased
serum triglycerides, intestinal obstruction, myocardial
lower respiratory tract infections, including pneumo-
infarction, oxygen saturation decreased, syncope,
nia, empyema, and lung abscess caused by suscep-
tachycardia (reflex), thrombophlebitis
tible anaerobes, Streptococcus pneumoniae, other
Mechanism of Action Dihydropyridine calcium chan- streptococci (except Enterococcus faecalis), and S.
nel blocker with potent arterial vasodilating activity.
aureus.
Inhibits calcium ion influx through the L-type calcium
Septicemia: Treatment of septicemia caused by S.
channels during depolarization in arterial smooth aureus, streptococci (except E. faecalis), and suscep-
muscle, producing a decrease in mean arterial pressure tible anaerobes.
(MAP) by reducing systemic vascular resistance. Skin and skin structure infections: Treatment of skin
Pharmacodynamics/Kinetics and skin structure infections caused by Streptococcus
Onset of Action 2 to 4 minutes after start of infusion pyogenes, S. aureus, and susceptible anaerobes.
Duration of Action IV: 5 to 15 minutes Local Anesthetic/Vasoconstrictor Precautions
Half-life Elimination Biphasic: Initial: 1 minute (pre- No information available to require special precautions
dominant); Terminal: ~15 minutes Effects on Dental Treatment No significant effects or
Pregnancy Risk Factor C complications reported (See Dental Health Professional
Pregnancy Considerations Adverse events have Considerations)
been observed in animal reproduction studies. Effects on Bleeding No information available to
Untreated chronic maternal hypertension is associated require special precautions
with adverse events in the fetus, infant, and mother. If Adverse Reactions Frequency not defined.
treatment for hypertension during pregnancy is needed, Cardiovascular: Hypotension (rare; IV administration),
other agents are preferred (ACOG 2013). thrombophlebitis (IV)
Central nervous system: Metallic taste (IV)
Clindamycin (Systemic) (klin da MYE sin) Dermatologic: Acute generalized exanthematous pus-
tulosis, erythema multiforme (rare), exfoliative derma-
Related Information titis (rare), maculopapular rash, pruritus, skin rash,
Antibiotic Prophylaxis on page 1502 Stevens-Johnson syndrome (rare), toxic epidermal
Bacterial Infections on page 1525 necrolysis, urticaria, vesiculobullous dermatitis
Osteonecrosis of the Jaw on page 1486 Gastrointestinal: Abdominal pain, antibiotic-associated
Periodontal Diseases on page 1534 colitis, Clostridioides (formerly Clostridium) difficile-
Related Sample Prescriptions associated diarrhea, diarrhea, esophageal ulcer,
esophagitis, nausea, pseudomembranous colitis,
Bacterial Infections and Periodontal Diseases - Sample
unpleasant taste (IV), vomiting
Prescriptions on page 36
Genitourinary: Azotemia, oliguria, proteinuria, vaginitis
Prevention of Endocarditis and to Reduce the Risk of Hematologic & oncologic: Agranulocytosis, eosinophilia
Late Infections of Joint Prostheses - Sample Prescrip- (transient), neutropenia (transient), thrombocytopenia
tions on page 41 Hepatic: Abnormal hepatic function tests, jaundice
Brand Names: US Cleocin; Cleocin in D5W [DSC]; Hypersensitivity: Anaphylactic shock, anaphylactoid
Cleocin Phosphate; CLIN Single Use reaction (rare), anaphylaxis, angioedema, hypersensi-
Brand Names: Canada Clindamycine; Dalacin C tivity reaction
Generic Availability (US) May be product dependent Immunologic: DRESS syndrome
Pharmacologic Category Antibiotic, Lincosamide Local: Abscess at injection site (IM), induration at
Dental Use Alternate oral antibiotic for prevention of injection site (IM), irritation at injection site (IM), pain
infective endocarditis in individuals allergic to penicillins at injection site (IM)
326
CLINDAMYCIN (SYSTEMIC)
Neuromuscular & skeletal: Polyarthritis (rare) should be treated for systemic involvement (CDC
Renal: Renal insufficiency (rare) [Hendricks 2014]).
Dental Usual Dosage Systemic, meningitis excluded: IV: 900 mg every 8
Orofacial infection: hours in combination with other appropriate agents
Children: for at least 2 weeks or until clinically stable, which-
Oral: 10-20 mg/kg/day in 3-4 equally divided doses ever is longer (CDC [Hendricks 2014]).
IV: 15-25 mg/kg/day in 3-4 equally divided doses Meningitis (alternative agent): IV: 900 mg every 8
Adults: hours in combination with other appropriate agents
Oral: 150-450 mg/dose for 7 days; maximum dose: for at least 2 to 3 weeks or until clinically stable,
1.8 g/day whichever is longer (CDC [Hendricks 2014]).
IV: 600-900 mg every 8 hours Note: Following the course of IV combination ther-
Treatment of periodontal disease: Oral: 300 mg every 8 apy for systemic anthrax infection (including men-
hours for 8 days ingitis), patients exposed to aerosolized spores
Infective endocarditis prophylaxis: require oral monotherapy to complete a total anti-
Children: mi cro bi al c ou r se o f 60 da ys (CDC [H en -
Oral: 20 mg/kg 30-60 minutes before procedure dricks 2014]).
IM, IV: 20 mg/kg 30-60 minutes before procedure. Babesiosis (off-label use):
Note: Intramuscular injections should be avoided in Mild to moderate disease: Oral: 600 mg every 8
patients who are receiving anticoagulant therapy. In hours in combination with quinine for 7 to 10 days
these circumstances, orally administered regimens (IDSA [Wormser 2006])
should be given whenever possible. Intravenously Severe disease: IV: 600 mg every 6 hours for 7 to 10
administered antibiotics should be used for patients days in combination with quinine (IDSA [Wormser
who are unable to tolerate or absorb oral medica- 2006]; Krause 2019); a longer duration is needed
tions. for those at high risk for relapse (Krause 2008;
Adults: Sanchez 2016; Vannier 2012). Clindamycin can
Oral: 600 mg 30-60 minutes before procedure be given orally once symptoms have abated and
IM, IV: 600 mg 30-60 minutes before procedure. parasitemia is reduced (Krause 2019; San-
chez 2016).
Note: Intramuscular injections should be avoided
Bacterial vaginosis (alternative agent) (off-label
in patients who are receiving anticoagulant therapy.
use): Oral: 300 mg twice daily for 7 days (CDC
In these circumstances, orally administered regi-
[Workowski 2015])
mens should be given whenever possible. Intra-
Bite wound, prophylaxis or treatment, animal or
venously administered antibiotics should be used
human bite (alternative agent) (off-label use):
for patients who are unable to tolerate or absorb
Note: For animal bite, use in combination with an
oral medications.
appropriate agent for Pasteurella multocida. For
Prophylaxis in total joint replacement patients under-
human bite, use in combination with an appropriate
going dental procedures which produce bacteremia:
agent for Eikenella corrodens (IDSA [Stevens 2014]).
Adults:
Oral: 300 to 450 mg 3 times daily (Baddour 2019a;
Oral: 600 mg 1 hour prior to procedure Baddour 2019b; IDSA [Stevens 2014])
IV: 600 mg 1 hour prior to procedure (for patients IV: 600 mg every 6 to 8 hours (IDSA [Stevens 2014]).
unable to take oral medication) Note: In selected patients with high-risk wounds,
Note: In general, patients with prosthetic joint implants some experts recommend parenteral therapy be
do not require prophylactic antibiotics prior to dental given initially until infection is resolving, followed
procedures. In planning an invasive oral procedure, by oral therapy (Baddour 2019a; Baddour 2019b).
dental consultation with the patient's orthopedic sur- Note: For prophylaxis, duration is 3 to 5 days (IDSA
geon may be advised to review the risks of infection. [Stevens 2014]); for treatment of established infec-
Dosing tion, duration is typically 5 to 14 days and varies
Adult & Geriatric based on clinical response and patient-specific
Usual dose: factors (Baddour 2019a; Baddour 2019b).
Oral: 600 to 1,800 mg/day in 2 to 4 divided doses; up Diabetic foot infection, mild to moderate (alterna-
to 2,400 mg/day in 4 divided doses may be given tive agent) (off-label use): Oral: 300 to 450 mg
for severe infections every 6 to 8 hours (Bader 2008; IDSA [Lipsky
IM, IV: 600 to 2,700 mg/day in 2 to 4 divided doses; 2012]; Lipsky 1990; Weintrob 2018). Note: May be
according to the manufacturer, up to 4,800 mg/day used alone for empiric therapy of mild infections; if
IV (in divided doses) has been used in life-threat- there are risk factors for gram-negative bacilli, must
ening infections; however, data supporting this be used in combination with other appropriate
dose are lacking; maximum: 600 mg/dose IM agents. Duration of therapy should be tailored to
Anthrax (off-label use): Note: Consult public health individual clinical circumstances; most patients
officials for event-specific recommendations. respond to 1 to 2 weeks of therapy (IDSA [Lipsky
Inhalational exposure postexposure prophylaxis 2012]; Weintrob 2018).
(alternative agent): Oral: 600 mg every 8 hours for Endocarditis, prophylaxis (dental or invasive res-
60 days. Note: Anthrax vaccine should also be piratory tract procedures) (alternative agent for
administered to exposed individuals (CDC [Hen- penicillin-allergic patients) (off-label use):
dricks 2014]). Oral: 600 mg as a single dose 30 to 60 minutes prior
Cutaneous, without systemic involvement, empiric to procedure (AHA [Wilson 2007])
therapy (alternative agent): Oral: 600 mg every 8 IM, IV: 600 mg as a single dose 30 to 60 minutes
hours for 60 days following biological weapon- before procedure (only if unable to tolerate or
related event; duration is 7 to 10 days after naturally absorb oral therapy) (AHA [Wilson 2007])
acquired infection. Note: Patients with cutaneous Note: Only recommended for patients with cardiac
lesions of the head or neck or extensive edema conditions associated with the highest risk of an
327
adverse outcome from endocarditis and who are be given in combination with doxycycline to complete
undergoing a procedure likely to result in bacter- at least 14 days of therapy rather than giving dox-
emia with an organism that has the potential ability ycycline alone (CDC [Workowski 2015]).
to cause endocarditis. Perioperative prophylaxis (in combination with
Hidradenitis suppurativa (off-label use): Oral: other appropriate agents when coverage for
300 mg twice daily in combination with rifampin for MRSA is indicated or for gram-positive coverage
10 to 12 weeks (Dessinioti 2016; Gener 2009; Gul- in patients unable to tolerate cephalosporins)
liver 2016; Zouboulis 2015) (off-label use): IV: 900 mg started within 60 minutes
Malaria (off-label use): prior to initial surgical incision. Clindamycin doses
Uncomplicated malaria, treatment, chloroquine- may be repeated intraoperatively at 6-hour intervals
resistant or unknown resistance (alternative agent): if procedure is lengthy or if there is excessive blood
Oral: 20 mg/kg/day in divided doses every 8 hours loss (ASHP/IDSA/SIS/SHEA [Bratzler 2013]). In
for 7 days in combination with quinine sulfate. cases where an extension of prophylaxis is war-
Note: Quinine sulfate duration is region specific ranted postoperatively, total duration should be ≤24
(CDC 2013). hours (Anderson 2014; ASHP/IDSA/SIS/SHEA [Brat-
Severe malaria, treatment: IV: Loading dose: zler 2013]). For clean and clean-contaminated pro-
10 mg/kg followed by 5 mg/kg every 8 hours in cedures, continued prophylactic antibiotics beyond
combination with IV quinidine gluconate; may surgical incision closure is not recommended, even
switch to oral therapy (clindamycin plus quinine in the presence of a drain (CDC [Berríos-
sulfate) when tolerated. Note: Duration of clinda- Torres 2017]).
mycin is 7 days. Quinine sulfate duration is region Pneumocystis jirovecii pneumonia (PCP), treat-
specific (CDC 2013). ment (alternative agent) (off-label use):
Neutropenic fever, empiric therapy for low-risk Mild to moderate disease: Oral: 450 mg every 6
cancer patients (alternative agent for penicillin- hours or 600 mg every 8 hours with primaquine
allergic patients) (off-label use): Oral: 600 mg for 21 days (HHS [OI adult 2017])
every 8 hours (Rubenstein 1993); some experts Severe disease: IV: 600 mg every 6 hours or 900 mg
recommend 300 mg every 6 hours (Bow 2018) (data every 8 hours with primaquine for 21 days; follow-
on appropriate dose are limited). Use in combination ing clinical improvement, clindamycin can be given
with oral ciprofloxacin; continue until afebrile and orally at 450 mg every 6 hours or 600 mg every 8
neutropenia has resolved. Note: Avoid in patients hours (HHS [OI adult 2017]; Thomas 2018).
who have received fluoroquinolone prophylaxis.
Note: Patients with moderate or severe infection
Administer first dose in the health care setting (after
(PaO2 <70 mm Hg at room air or alveolar-arterial
blood cultures are drawn); observe patient for ≥4
oxygen gradient ≥35 mm Hg) should receive
hours before discharge (ASCO/IDSA [Taplitz 2018];
adjunctive glucocorticoids (HHS [OI adult 2017]).
IDSA [Freifeld 2011]).
Pneumonia due to MRSA (alternative agent) (off-
Odontogenic infection (alternative agent for pen-
label use): Oral, IV: 600 mg 3 times daily; duration is
icillin-allergic patients) (off-label use):
for a minimum of 7 days and varies based on disease
IV: 600 mg every 8 hours until improved, then tran-
severity and response to therapy (IDSA [Liu 2011])
sition to oral clindamycin (Bhagania 2018;
Postpartum endometritis: IV: 900 mg every 8 hours
Chow 2018).
Oral (initial therapy for mild infection or step-down plus gentamicin; treat until the patient is clinically
after parenteral treatment): 450 mg every 8 hours improved (no fundal tenderness) and afebrile for 24
to complete a 7- to 14-day course (Chow 2018); to 48 hours (Chen 2018; Gall 1996).
doses in the literature varied from 150 mg every 6 Prosthetic joint infection (off-label use):
hours (Tancawan 2015) to 300 mg every 6 hours Cutibacterium acnes, treatment (alternative agent for
(Cachovan 2011) to 600 mg every 8 hours (Bhaga- penicillin allergy):
nia 2018). IV: 600 to 900 mg every 8 hours for 4 to 6 weeks
Osteomyelitis: (IDSA [Osmon 2013])
Osteomyelitis due to MRSA (alternative agent): IV, Oral: 300 to 450 mg every 6 hours (IDSA [Osmon
Oral: 600 mg 3 times daily for a minimum of 8 2013]), following at least 2 weeks of parenteral
weeks; some experts combine with rifampin (IDSA therapy (Kanafani 2018)
[Liu 2011]). Methicillin-resistant staphylococci, treatment
Osteomyelitis, native vertebral due to staphylococci, (chronic suppression): Oral: 600 mg every 8 hours
methicillin-susceptible (alternative agent): (Berbari 2019)
IV: 600 to 900 mg every 8 hours for 6 weeks (IDSA Rhinosinusitis, acute bacterial (alternative agent
[Berbari 2015]) for penicillin-allergic patients able to tolerate
Oral: 300 to 450 mg 4 times daily (IDSA [Berbari cephalosporins with concern for pneumococcal
2015]) or 600 mg 3 times daily (IDSA [Liu 2011]) resistance) (off-label use): Oral: 300 mg every 6 to
for 6 weeks (IDSA [Berbari 2015]). Note: Clinda- 8 hours in combination with a third-generation ceph-
mycin may also be used as suppressive therapy in alosporin (eg, cefixime or cefpodoxime) for 5 to 7
selected patients (Osmon 2019). days (IDSA [Chow 2012]; Patel 2018; Rosenfeld
Osteomyelitis, native vertebral due to Cutibacterium 2016). Note: In uncomplicated acute bacterial rhino-
acnes (alternative agent): IV: 600 to 900 mg every sinusitis, initial observation and symptom manage-
8 hours for 6 weeks (IDSA [Berbari 2015]) ment without antibiotic therapy is appropriate in most
Pelvic inflammatory disease, severe: IV: 900 mg patients (AAO-HNS [Rosenfeld 2015]; Harris 2016).
every 8 hours with gentamicin; after 24 to 48 hours Septic arthritis due to Staphylococcus aureus
of sustained clinical improvement, transition to clin- (including MRSA) (alternative agent): Oral, IV:
damycin 450 mg orally 4 times daily (or oral doxycy- 600 mg 3 times daily for 3 to 4 weeks (Goldenberg
cline) to complete 14 days of therapy. Note: If tubo- 2018; IDSA [Liu 2011]). Note: A longer course of
ovarian abscess is present, oral clindamycin should parenteral therapy (4 weeks) may be required for
328
patients with concomitant bacteremia (in the or extensive disease; after completion of acute
absence of endocarditis) (Goldenberg 2019). therapy, all patients should receive long-term main-
Skin and soft tissue infections: tenance therapy (HHS [OI adult 2017];
Impetigo or ecthyma if MRSA is suspected or con- Schwartz 2013).
firmed (alternative agent): Oral: 300 to 450 mg 4 Long-term maintenance therapy: Oral: 600 mg every
times daily for 7 days (IDSA [Stevens 2014) 8 hours in combination with pyrimethamine and
Nonpurulent cellulitis or erysipelas due to beta- leucovorin (HHS [OI adult 2017]; Schwartz 2013);
hemolytic streptococci or Staphylococcus aureus in HIV-infected patients, may discontinue when
(including MRSA), empiric or pathogen-directed asymptomatic with a CD4 count >200 cells/mm3
therapy (alternative agent): and an undetectable HIV viral load for >6 months
Oral: 300 to 450 mg 4 times daily in response to ART (HHS [OI adult 2017])
IV: 600 mg to 900 mg every 8 hours Renal Impairment: Adult
Note: Transition to oral therapy once improving; Mild to severe impairment: No dosage adjustment
treat for at least 5 days but may extend to 14 days necessary
depending on severity and clinical response
End-stage renal disease (ESRD) on hemodialysis or
(IDSA [Stevens 2014]; Spelman 2018).
peritoneal dialysis: Not removed from serum (eg,
Purulent cellulitis or abscess due to Staphylococcus
poorly dialyzed); no supplemental dose or dosage
aureus (including MRSA) or beta-hemolytic strep-
adjustment necessary (Aronoff 2007).
tococci (alternative agent):
Continuous renal replacement therapy (CRRT) (eg,
Oral: 300 to 450 mg 4 times daily. Treat for 5 to 14
days depending on severity and clinical response. CVVH, CVVHD, CVVHDF): No supplemental dose
Note: Systemic antibiotics only indicated for certain or dosage adjustment necessary (Heintz 2009).
instances (eg, immunocompromised patients, Hepatic Impairment: Adult
signs of systemic infection, large or multiple Mild impairment: There are no dosage adjustments
abscess, indwelling device, high risk for adverse provided in the manufacturer's labeling.
outcome with endocarditis). If at risk for gram- Moderate to severe impairment: There are no dosage
negative bacilli, use in combination with an appro- adjustments provided in the manufacturer's labeling.
priate agent (IDSA [Stevens 2014]; Spel- In studies of patients with moderate or severe liver
man 2018). disease, half-life is prolonged; however, when admin-
Necrotizing soft tissue infections (alternative agent): istered on an every-8-hour schedule, accumulation
IV: 600 to 900 mg every 8 hours as part of an should rarely occur. In severe liver disease, use
appropriate combination regimen. Note: Antibiotic caution and monitor liver enzymes periodically during
therapy must be used in conjunction with early and therapy.
aggressive surgical exploration and debridement of Pediatric
necrotic tissue (IDSA [Stevens 2014]; Stevens General dosing, susceptible infection:
2018a). IM, IV:
Streptococcus: Manufacturer's labeling: Infants, Children, and
Group A: Adolescents 1 month to 16 years:
Bloodstream infection: IV: 900 mg every 8 hours in Weight-directed dosing: 20 to 40 mg/kg/day div-
combination with IV penicillin G; duration is indi- ided every 6 to 8 hours
vidualized, but clindamycin may be discontinued BSA-directed dosing: 350 to 450 mg/m2/day div-
within 48 hours for patients without septic shock, ided every 6 to 8 hours
organ failure, or necrotizing infection. Continue Alternate dosing (Red Book [AAP], 2012): Infants,
penicillin G to complete ≥14 days of therapy Children, and Adolescents:
(Stevens 2019b). Mild to moderate infections: 20 mg/kg/day div-
Pharyngitis (alternative agent for penicillin-allergic ided every 8 hours; maximum daily dose:
patients) (off-label use): Oral: 300 mg 3 times 1800 mg/day
daily for 10 days (IDSA [Shulman 2012])
Severe infections: 40 mg/kg/day divided every 6
Chronic carriage (off-label use): Oral: 300 mg 3
to 8 hours; maximum daily dose: 2700 mg/day
times daily for 10 days. Note: Most individuals
Oral:
with chronic carriage do not require antimicrobial
Manufacturer’s labeling: Infants, Children, and
treatment (IDSA [Shulman 2012])
Adolescents:
Group B:
Maternal prophylaxis for prevention of neonatal Hydrochloride salt (capsule): 8 to 20 mg/kg/day
disease (alternative agent) (off-label use): IV: divided every 6 to 8 hours
900 mg every 8 hours until delivery. Note: Palmitate salt (solution): 8 to 25 mg/kg/day div-
Reserve for penicillin-allergic patients at high risk ided every 6 to 8 hours; minimum dose:
for anaphylaxis (CDC [Verani 2010]). 37.5 mg 3 times daily
Toxic shock syndrome (empiric therapy): IV: Alternate dosing (Red Book [AAP]; 2012): Infants,
900 mg every 8 hours as part of an appropriate Children, and Adolescents:
combination regimen (Lappin 2009; Wong 2013). Mild to moderate infections: 10 to 25 mg/kg/day
Duration of therapy varies based on causative organ- divided every 8 hours; maximum daily dose:
ism and response to therapy; treat patients who are 1800 mg/day
bacteremic for at least 14 days (Stevens 2019b). Severe infections: 30 to 40 mg/kg/day divided
Toxoplasma gondii encephalitis and pneumonitis every 6 to 8 hours; maximum daily dose:
(alternative agent) (off-label use): 1800 mg/day
Initial treatment: Oral, IV: 600 mg every 6 hours in Babesiosis: Infants, Children, and Adolescents:
combination with pyrimethamine and leucovorin. Oral: 20 to 40 mg/kg/day divided every 8 hours
Continue therapy for at least 6 weeks; longer for 7 to 10 days plus quinine; maximum single dose:
duration may be required if incomplete response 600 mg (Red Book [AAP], 2012)
329
Bacterial endocarditis prophylaxis for dental and IDSA guidelines (Shulman, 2012): Children and
upper respiratory procedures in penicillin-aller- Adolescents: Oral:
gic patients (Red Book [AAP], 2012; Wilson, Treatment and primary prevention of rheumatic
2007): Infants, Children, and Adolescents: fever: 21 mg/kg/day in divided doses 3 times
IM, IV: 20 mg/kg 30 minutes before procedure; daily for 10 days; maximum single dose: 300 mg
maximum single dose: 600 mg Treatment of chronic carriers: 20 to 30 mg/kg/day
Oral: 20 mg/kg 1 hour before procedure; maximum in divided doses 3 times daily for 10 days;
single dose: 600 mg maximum single dose: 300 mg
Note: American Heart Association (AHA) guide- Pneumococcal disease, invasive: Infants, Chil-
lines now recommend prophylaxis only in patients dren, and Adolescents: IV: 25 to 40 mg/kg/day
divided every 6 to 8 hours (Red Book [AAP], 2012)
undergoing invasive procedures and in whom
Pneumocystis jirovecii (formerly carnii) pneumo-
underlying cardiac conditions may predispose to
nia (PCP):
a higher risk of adverse outcomes should infection
Non HIV-exposed/-positive (Red Book [AAP],
occur. As of April 2007, routine prophylaxis for GI/ 2012): Infants, Children, and Adolescents:
GU procedures is no longer recommended by Mild to moderate disease: Oral: 10 mg/kg 3 to 4
the AHA. times daily for 21 days; in combination with other
Catheter (peritoneal dialysis); exit-site or tunnel agents; maximum single dose: 450 mg
infection: Infant, Children, and Adolescents: Oral: Moderate to severe disease: IV: 15 to 25 mg/kg 3
10 mg/kg/dose 3 times daily; maximum dose: to 4 times daily for 21 days; give with pentam-
600 mg/dose (Warady [ISPD 2012]) idine or primaquine; maximum single dose:
Intra-abdominal infection, complicated: Infants, 600 mg. May switch to oral dose after clinical
Children, and Adolescents: IV: Note: Not recom- improvement.
mended for community-acquired infections due to HIV-exposed/-positive: Adolescents (DHHS [adult],
increasing Bacteroides fragilis resistance: 20 to 2013):
40 mg/kg/day divided every 6 to 8 hours in combi- Mild to moderate disease: Oral: 300 mg every 6
nation with gentamicin or tobramycin (Solo- hours or 450 mg every 8 hours with primaquine
mkin, 2010) for 21 days
Malaria, treatment: Infants, Children, and Adoles- Moderate to severe disease:
cents: Oral: 300 mg every 6 hours or 450 mg every 8
Uncomplicated: Oral: 20 mg/kg/day divided every 8 hours with primaquine for 21 days
hours for 7 days plus quinine (CDC, 2011; Red IV: 600 mg every 6 hours or 900 mg every 8
hours with primaquine for 21 days
Book [AAP], 2012)
Pneumonia:
Severe: IV: Loading dose: 10 mg/kg once followed
Community-acquired pneumonia (CAP) (IDSA/
by 15 mg/kg/day divided every 8 hours plus IV
PIDS, Bradley, 2011): Infants ≥3 months, Chil-
quinidine gluconate; switch to oral therapy (clin-
dren, and Adolescents: Note: In children ≥5 years,
damycin and quinine, see above) when able for a macrolide antibiotic should be added if atypical
total treatment duration of 7 days. Note: Quinine pneumonia cannot be ruled out.
duration is region specific; consult CDC for current Moderate to severe infection: IV: 40 mg/kg/day
recommendations (CDC, 2011). divided every 6 to 8 hours
Osteomyelitis, septic arthritis, due to MRSA: Mild infection, step-down therapy: Oral: 30 to
Infants, Children, and Adolescents: IV, Oral: 40 mg/kg/day divided every 6 to 8 hours
40 mg/kg/day divided every 6 to 8 hours for at least MRSA pneumonia: IV: 40 mg/kg/day divided every
4 to 6 weeks (osteomyelitis) or 3 to 4 weeks (septic 6 to 8 hours for 7 to 21 days (Liu, 2011)
arthritis) (Liu, 2011) Rhinosinusitis, acute bacterial: Children and Ado-
Otitis media, acute: Infants ≥6 months, Children, lescents: Oral: 30 to 40 mg/kg/day divided every 8
and Adolescents: Oral: 30 to 40 mg/kg/day divided hours with concomitant cefixime or cefpodoxime for
every 8 hours; administer with or without a third 10 to 14 days. Note: Recommended in patients
generation cephalosporin (AAP [Lieberthal, 2013]) with nontype I penicillin allergy, after failure to initial
Peritonitis (peritoneal dialysis): therapy, or in patients at risk for antibiotic resistance
Prophylaxis (Warady [ISPD 2012]): (eg, daycare attendance, age <2 years, recent
Invasive dental procedures: Oral: 20 mg/kg hospitalization, antibiotic use within the past month)
administered 30 to 60 minutes before procedure; (Chow, 2012).
maximum dose: 600 mg Skin and soft tissue infection: Infants, Children,
and Adolescents:
Gastrointestinal or genitourinary procedures: IV:
Impetigo: Oral: 10 to 20 mg/kg/day in divided doses
10 mg/kg administered 30 to 60 minutes before
3 times daily; treatment duration: 7 days; max-
procedure; maximum dose: 600 mg
imum single dose: 400 mg (Stevens, 2005)
Treatment: Intraperitoneal, continuous: Loading MRSA infection (Liu, 2011):
dose: 300 mg per liter of dialysate; maintenance Cellulitis, nonpurulent or purulent: Oral: 40 mg/kg/
dose: 150 mg per liter; Note: 125 mg/liter has day divided every 6 to 8 hours; maximum single
also been recommended as a maintenance dose dose: 450 mg; treatment duration based on clin-
(Aronoff, 2007; Warady [ISPD 2012]) ical response, usually 7 to 14 days
Pharyngitis: Complicated SSTI infection: IV, Oral: 40 mg/kg/
AHA guidelines (Gerber, 2009): Children and Ado- day divided every 6 to 8 hours for 7 to 14 days;
lescents: Oral: 20 mg/kg/day in divided doses 3 maximum single dose range: 450 to 600 mg
times daily for 10 days; maximum single dose: MSSA infection (Stevens, 2005): Duration of treat-
600 mg ment dependent upon site and severity of
330
infection; cellulitis and abscesses typically require be discontinued. Institute appropriate fluid and
5 to 10 days of therapy electrolyte management, protein supplementation,
IV: 25 to 40 mg/kg/day in divided doses 3 times antibiotic treatment of C. difficile, and surgical
daily; maximum single dose: 600 mg evaluation as clinically indicated. Use with caution
Oral: 10 to 20 mg/kg/day in divided doses 3 times in patients with a history of gastrointestinal disease,
daily; maximum single dose: 450 mg particularly colitis. Use may result in overgrowth of
Surgical prophylaxis: Children and Adolescents: nonsusceptible organisms, particularly yeast. Should
IV: 10 mg/kg 30 to 60 minutes prior to the proce- superinfection occur, appropriate measures should be
dure; may repeat in 6 hours; maximum single dose: taken as indicated by the clinical situation. Severe
900 mg (Bratzler, 2013) hypersensitivity reactions, including severe skin reac-
Toxoplasmosis (HIV-exposed/positive or hemato- tions (eg, drug reaction with eosinophilia and systemic
poietic cell transplantation recipients): symptoms [DRESS], Stevens-Johnson syndrome
Infants and Children (CDC, 2009; Red Book [AAP], [SJS], and toxic epidermal necrolysis [TEN]), some
2012; Tomblyn, 2009): fatal, and anaphylactic reactions, including anaphylactic
Treatment, HIV-exposed/-positive: IV, Oral: 5 to shock, have been reported. Permanently discontinue
7.5 mg/kg/dose 4 times daily with pyrimethamine treatment and institute appropriate therapy if these
and leucovorin; maximum single dose: 600 mg reactions occur. Some products may contain tartrazine
Secondary prevention: (FD&C yellow no. 5), which may cause allergic reac-
HIV-exposed/-positive: Oral: 7 to 10 mg/kg/dose tions in certain individuals. Allergy is frequently seen in
every 8 hours and pyrimethamine plus leuco- patients who also have an aspirin hypersensitivity. Use
vorin; maximum single dose: 600 mg (DHHS caution in atopic patients. A subgroup of older patients
[pediatric], 2013) with associated severe illness may tolerate diarrhea
Hematopoietic cell transplantation recipients: less well. Monitor carefully for changes in bowel fre-
Oral: 5 to 7.5 mg/kg/dose every 6 hours and quency. Not appropriate for use in the treatment of
pyrimethamine plus leucovorin; maximum sin- meningitis due to inadequate penetration into the CSF.
gle dose: 450 mg Do not inject IV undiluted as a bolus. Product should be
Adolescents (DHHS [adult], 2013; Red Book [AAP], diluted in compatible fluid and infused over 10 to 60
2012; Tomblyn, 2009): minutes. Potentially significant interactions may exist,
Treatment: Oral, IV: 600 mg every 6 hours with
pyrimethamine and leucovorin for at least 6
weeks; longer if clinical or radiologic disease is
extensive or response is incomplete Benzyl alcohol and derivatives: Some dosage forms
Secondary prevention: may contain benzyl alcohol; large amounts of benzyl
HIV-exposed/-positive: Oral: 600 mg every 8 alcohol (≥99 mg/kg/day) have been associated with a
hours with pyrimethamine and leucovorin potentially fatal toxicity ("gasping syndrome") in neo-
Hematopoietic cell transplantation recipients: nates; the "gasping syndrome" consists of metabolic
Oral: 300 to 450 mg every 6 to 8 hours with acidosis, respiratory distress, gasping respirations,
pyrimethamine and leucovorin CNS dysfunction (including convulsions, intracranial
Renal Impairment: Pediatric No adjustment hemorrhage), hypotension and cardiovascular collapse
required. Not dialyzable (0% to 5%). (AAP ["Inactive" 1997]; CDC 1982); some data sug-
Hepatic Impairment: Pediatric No adjustment gests that benzoate displaces bilirubin from protein
required. Use caution with severe hepatic impairment. binding sites (Ahlfors 2001); avoid or use dosage forms
Mechanism of Action Reversibly binds to 50S ribo- containing benzyl alcohol with caution in neonates. See
somal subunits preventing peptide bond formation thus manufacturer’s labeling.
inhibiting bacterial protein synthesis; bacteriostatic or Drug Interactions
bactericidal depending on drug concentration, infection Metabolism/Transport Effects Substrate of
site, and organism CYP3A4 (minor); Note: Assignment of Major/Minor
Contraindications substrate status based on clinically relevant drug
Hypersensitivity to clindamycin, lincomycin, or any com- interaction potential
ponent of the formulation. Avoid Concomitant Use
Canadian labeling: Additional contraindications (not in Avoid concomitant use of Clindamycin (Systemic) with
US labeling): Oral clindamycin: Infants <30 days any of the following: BCG (Intravesical); Cholera Vac-
of age. cine; Mecamylamine
Warnings/Precautions Dosage adjustment may be Increased Effect/Toxicity
necessary in patients with severe hepatic dysfunction. Clindamycin (Systemic) may increase the levels/
[US Boxed Warning]: Can cause severe and possi- effects of: Mecamylamine; Neuromuscular-Blocking
bly fatal colitis. Should be reserved for serious Agents
infections where less toxic antimicrobial agents Decreased Effect
are inappropriate. It should not be used in patients Clindamycin (Systemic) may decrease the levels/
with nonbacterial infections such as most upper effects of: BCG (Intravesical); BCG Vaccine (Immuni-
respiratory tract infections. Hypertoxin-producing zation); Cholera Vaccine; Lactobacillus and Estriol;
strains of C. difficile cause increased morbidity Sodium Picosulfate; Typhoid Vaccine
and mortality, as these infections can be refractory
to antimicrobial therapy and may require colec- The levels/effects of Clindamycin (Systemic) may be
tomy. C. difficile -associated diarrhea (CDAD) must decreased by: CYP3A4 Inducers (Strong); Kaolin
be considered in all patients who present with Pharmacodynamics/Kinetics
diarrhea following antibiotic use. CDAD has been Half-life Elimination Neonates: Premature: 8.7
observed >2 months postantibiotic treatment. If hours; Full-term: 3.6 hours; Infants 1 month to 1 year:
CDAD is suspected or confirmed, ongoing antibi- 3 hours; Children: ~2.5 hours; Adults: 3 hours; Elderly
otic use not directed against C. difficile may need to (oral) ~4 hours (range: 3.4 to 5.1 hours)
331
Time to Peak Serum: Oral: Within 60 minutes; IM: 1 to Generic: 300 mg/50 mL (50 mL); 600 mg/50 mL (50
3 hours mL); 900 mg/50 mL (50 mL); 300 mg/2 mL (2 mL);
Pregnancy Considerations 600 mg/4 mL (4 mL); 900 mg/6 mL (6 mL); 300 mg/
Clindamycin crosses the placenta and can be detected 50 mL in NaCl 0.9% (50 mL); 600 mg/50 mL in NaCl
in the cord blood and fetal tissue (Philipson 1973; 0.9% (50 mL); 900 mg/50 mL in NaCl 0.9% (50 mL)
Weinstein 1976). Clindamycin injection contains benzyl Solution Reconstituted, Oral:
alcohol which may also cross the placenta. Cleocin: 75 mg/5 mL (100 mL)
Clindamycin pharmacokinetics are not affected by preg- Dosage Forms: Canada
nancy (Philipson 1976; Weinstein 1976). Clindamycin is Capsule, Oral, as hydrochloride [strength expressed
recommended for use in pregnant women for the pro- as base]:
phylaxis of group B streptococcal disease in newborns Dalacin C: 150 mg, 300 mg
(alternative therapy) (ACOG 485, 2011); prophylaxis Solution, Intravenous, as phosphate [strength
and treatment of Toxoplasma gondii encephalitis (alter- expressed as base]:
native therapy), or Pneumocystis pneumonia (PCP) Dalacin C Phosphate: 150 mg/mL (2 mL, 4 mL, 6
(alternative therapy) (HHS [OI adult 2015]); bacterial mL, 60 mL) [contains benzyl alcohol, edetate
vaginosis (CDC [Workowski 2015]); anthrax (Meaney- disodium]
Delman 2014); or malaria (CDC 2013). Clindamycin is Solution Reconstituted, Oral, as palmitate hydro-
also one of the antibiotics recommended for prophylac- chloride [strength expressed as base]:
tic use prior to cesarean delivery and may be used in Dalacin C Flavoured Granules: 75 mg/5 mL (100
certain situations prior to vaginal delivery in women at mL) [contains ethylparaben]
high risk for endocarditis (ACOG 199 2018). Dental Health Professional Considerations About
Breastfeeding Considerations 1% of clindamycin users develop pseudomembranous
Clindamycin is present in breast milk. colitis. Symptoms may occur 2 to 9 days after initiation
The relative infant dose (RID) of clindamycin is 1.2% to of therapy; however, it has never occurred with the 1-
4.7% when calculated using the highest verifiable dose regimen of clindamycin used to prevent bacterial
breast milk concentration located and compared to endocarditis.
an infant therapeutic dose of 10 to 40 mg/kg/day. In
general, breastfeeding is considered acceptable when
the RID is <10% (Anderson 2016; Ito 2000). Clindamycin (Topical) (klin da MYE sin)
Using the highest verifiable milk concentration (3.1 Brand Names: US Cleocin; Cleocin-T; Clindacin ETZ;
mcg/mL), the estimated daily infant dose via breast Clindacin Pac; Clindacin-P; Clindagel; ClindaMax
milk is 0.465 mg/kg/day. This milk concentration was [DSC]; Clindesse; Evoclin
obtained following maternal administration of oral
Brand Names: Canada Clinda-T; Clindasol; Clindets;
clindamycin 150 mg three times daily for at least 1
Dalacin T; Dalacin Vaginal
week (Stéen 1982). The manufacturer reports that
Pharmacologic Category Antibiotic, Lincosamide;
clindamycin breast milk concentrations range from
Topical Skin Product, Acne
<0.5 to 3.8 mcg/mL (maternal dose, route, and dura-
Use
tion not specified).
Acne vulgaris: Treatment of acne vulgaris (topical gel,
One case of bloody stools in an infant occurred after a
topical lotion, topical solution)
mother received clindamycin while breastfeeding;
Bacterial vaginosis: Treatment of bacterial vaginosis
however, a causal relationship was not confirmed
(vaginal cream, vaginal suppository)
(Mann 1980). In general, antibiotics that are present
in breast milk may cause non-dose-related modifica- Local Anesthetic/Vasoconstrictor Precautions
tion of bowel flora.
According to the manufacturer, the decision to continue Effects on Dental Treatment No significant effects or
or discontinue breastfeeding during therapy should complications reported
take into account the risk of infant exposure, the Effects on Bleeding No information available to
benefits of breastfeeding to the infant, and benefits require special precautions
of treatment to the mother; alternate therapies may be Adverse Reactions
preferred. Additional guidelines recommend to avoid Topical: >10%: Dermatologic: Xeroderma (18% to
clindamycin in breastfeeding women if possible; mon- 23%; gel, lotion, solution), oily skin (gel, lotion: 10%
itor breastfeeding infants for GI disturbances, diar- to 18%; solution: 1%), erythema (7% to 16%; gel,
rhea, and bloody stools if maternal treatment is lotion, solution), burning sensation of skin (10% to
required (WHO 2002). 11%; gel, lotion, solution), exfoliation of skin (7% to
Dosage Forms: US 11%; lotion, solution), pruritus (7% to 11%; gel, lotion,
Capsule, Oral: solution)
Cleocin: 75 mg, 150 mg, 300 mg Vaginal:
Generic: 75 mg, 150 mg, 300 mg >10%: Genitourinary: Vaginal moniliasis (≤13%)
Kit, Injection: 1% to 10%:
CLIN Single Use: 300 mg/2 mL Dermatologic: Pruritus (≤1% nonapplication site; <1%
Solution, Injection: application site)
Cleocin Phosphate: 300 mg/2 mL (2 mL); 600 mg/4 Genitourinary: Vulvovaginal disease (3% to 9%), vul-
mL (4 mL); 900 mg/6 mL (6 mL); 9 g/60 mL (60 mL) vovaginitis (≤7%), vaginal pain (2%), trichomonal
Generic: 300 mg/2 mL (2 mL); 600 mg/4 mL (4 mL); vaginitis (≤1%)
900 mg/6 mL (6 mL); 9000 mg/60 mL (60 mL); 9 g/ Infection: Fungal infection (≤1%)
60 mL (60 mL) <1%, postmarketing, and/or case reports (all routes):
Solution, Intravenous: Abdominal cramps, abdominal pain, application site
Cleocin Phosphate: 300 mg/2 mL (2 mL); 600 mg/4 pain, bacterial infection, bloody diarrhea, colitis, con-
mL (4 mL); 900 mg/6 mL (6 mL) stipation, contact dermatitis, diarrhea (hemorrhagic or
332
CLOBAZAM
severe), dizziness, dysgeusia, dyspepsia, dysuria, 1% to 10%:

edema, endometriosis, epistaxis, erythema, eye pain, Dermatologic: Stinging of the skin (application site:
fever, flank pain, flatulence, folliculitis, folliculitis ≤7%), sunburn (local; 1%)
(gram-negative infection), gastrointestinal disease, Local: Application site burning (≤10%), application site
gastrointestinal distress, halitosis, headache, hyper- reaction (3%)
sensitivity reaction, hyperthyroidism, maculopapular <1%, postmarketing, and/or case reports: Anaphylaxis,
rash, menstrual disease, nausea, pain, pseudomem- application site irritation, application site pain, contact
branous colitis, pyelonephritis, severe colitis, skin dermatitis, hypersensitivity reaction, local discolora-
rash, upper respiratory infection, urinary tract infection, local skin exfoliation, skin rash, urticaria
tion, urticaria, uterine hemorrhage, vaginal discharge, Mechanism of Action
vertigo, vomiting, vulvovaginal pruritus Benzoyl peroxide: Releases free-radical oxygen, which
Mechanism of Action Reversibly binds to 50S ribo- oxidizes bacterial proteins in the sebaceous follicles,
somal subunits preventing peptide bond formation thus decreasing the number of anaerobic bacteria and
inhibiting bacterial protein synthesis; bacteriostatic or decreasing irritating-type free fatty acids.
bactericidal depending on drug concentration, infection Clindamycin: Reversibly binds to 50S ribosomal sub-
site, and organism units preventing peptide bond formation thus inhibiting
Pharmacodynamics/Kinetics bacterial protein synthesis; bacteriostatic or bacterici-
Half-life Elimination Vaginal cream: 1.5 to 2.6 hours dal depending on drug concentration, infection site,
following repeated dosing; Vaginal suppository: 11 and organism.
hours (range: 4 to 35 hours, limited by absorption rate) Pregnancy Risk Factor C
Time to Peak Vaginal cream: ~10 to 14 hours (range: Pregnancy Considerations Animal reproduction
4 to 24 hours); Vaginal suppository: ~5 hours (range: 1 studies have not been conducted with this combination.
to 10 hours) Refer to individual monographs.
Adverse effects were not observed in animal reproduc-
tion studies. Clindamycin crosses the placenta following
CloBAZam (KLOE ba zam)
oral and parenteral dosing (Philipson 1973; Weinstein Brand Names: US Onfi; Sympazan
1976). The amount of clindamycin available systemi- Brand Names: Canada Frisium
cally is less following topical and vaginal application Pharmacologic Category Anticonvulsant, Benzodia-
than with IV or oral administration. zepine; Benzodiazepine
Various clindamycin vaginal products are available for Use
the treatment of bacterial vaginosis. Recommendations US labeling: Lennox-Gastaut syndrome: Adjunctive
for use in pregnant woman vary by product labeling. treatment of seizures associated with Lennox-Gastaut
Current guidelines note that the same oral or vaginal syndrome in patients ≥2 years
regimens used in nonpregnant women may be used Canadian labeling: Epilepsy: Adjunctive treatment of
during pregnancy, including oral or vaginal clindamycin epilepsy
(CDC [Workowski 2015]). Local Anesthetic/Vasoconstrictor Precautions
If treatment for acne is needed during pregnancy, top-
ical clindamycin may be considered if an antibiotic is
needed. To decrease systemic exposure, pregnant
flow resumes upon discontinuation). Paradoxical reac-
women should avoid application to inflamed skin for
tions (including excitation, agitation, hallucinations, and
long periods of time, or to large body surface areas
psychosis) are known to occur with benzodiazepines.
(Kong 2013).
Clindamycin and Benzoyl Peroxide Adverse Reactions
(klin da MYE sin & BEN zoe il peer OKS ide) >10%:
Related Information Central nervous system: Drowsiness (16% to 25%),
lethargy (10% to 15%), drooling (13% to 14%),
Clindamycin (Topical) on page 332
aggressive behavior (8% to 14%), irritability (11%)
Brand Names: US Acanya; BenzaClin; Duac; Neuac;
Respiratory: Upper respiratory tract infection (13%
Onexton
to 14%)
Brand Names: Canada BenzaClin; Clindoxyl Miscellaneous: Fever (10% to 17%)
Pharmacologic Category Acne Products; Topical 1% to 10%:
Skin Product; Topical Skin Product, Acne Central nervous system: Ataxia (10%), sedation (9%),
Use Acne: Topical treatment of acne vulgaris insomnia (5% to 7%), psychomotor agitation (5%),
Local Anesthetic/Vasoconstrictor Precautions fatigue (3% to 5%), dysarthria (2% to 5%)
No information available to require special precautions Gastrointestinal: Constipation (2% to 10%), vomiting
Effects on Dental Treatment No significant effects or (7% to 9%), decreased appetite (7%), increased
complications reported appetite (2% to 5%), dysphagia (5%)
Effects on Bleeding No information available to Genitourinary: Urinary tract infection (2% to 5%)
require special precautions Respiratory: Cough (3% to 7%), pneumonia (3% to
Adverse Reactions Also see individual agents. 7%), bronchitis (2% to 5%)
>10%: Postmarketing and/or case reports: Abdominal disten-
Dermatologic: Application site scaling (≤21%), local tion, agitation, anemia, angioedema, anxiety, apathy,
dryness (≤16%) behavioral changes, blurred vision, confusion, delir-
Local: Application site erythema (<31%), local des- ium, delusions, depression, diplopia, eosinophilia,
quamation (2% to 19%), application site itch- facial edema, hallucination, hypothermia, increased
ing (≤17%) liver enzymes, leukopenia, lip edema, mood changes,
333
CLOBAZAM
muscle spasm, pulmonary aspiration, respiratory Generic Availability (US) May be product dependent
depression, skin rash, Stevens-Johnson syndrome, Pharmacologic Category Corticosteroid, Topical
suicidal ideation, suicidal tendencies, thrombocytope- Dental Use Short-term relief of oral mucosal inflamma-
nia, toxic epidermal necrolysis, urinary retention, urti- tion
caria, withdrawal syndrome Use Steroid-responsive dermatoses: Short-term relief
Mechanism of Action Clobazam is a 1,5 benzodiaze- of inflammation and pruritic manifestations of moderate
pine which binds to stereospecific benzodiazepine to severe corticosteroid-responsive dermatoses
receptors on the postsynaptic GABA neuron at several Local Anesthetic/Vasoconstrictor Precautions
sites within the central nervous system, including the No information available to require special precautions
limbic system, reticular formation. Enhancement of the Effects on Dental Treatment No significant effects or
inhibitory effect of GABA on neuronal excitability results complications reported
by increased neuronal membrane permeability to chlor- Effects on Bleeding No information available to
ide ions. This shift in chloride ions results in hyper- require special precautions
polarization (a less excitable state) and stabilization. Adverse Reactions Frequency may depend upon
Benzodiazepine receptors and effects appear to be formulation used, length of application, surface area
linked to the GABA-A receptors. Benzodiazepines do covered, and the use of occlusive dressings.
not bind to GABA-B receptors (Vinkers 2012). >10%: Endocrine & metabolic: HPA-axis suppression
Pharmacodynamics/Kinetics (13% to 56%)
Onset of Action Maximum effect: 5 to 9 days 1% to 10%:
Half-life Elimination Children: Clobazam: 16 hours Central nervous system: Localized burning (≤10%),
(Ng 2007); Adults: Clobazam: 36 to 42 hours; N- headache (≤2%), numbness of fingers (<2%), local
desmethyl (active): 71 to 82 hours discomfort (1%)
Time to Peak Oral film: 0.33 to 4 hours; Tablet: 0.5 to Dermatologic: Skin atrophy (≤4%), telangiectasia
4 hours; Oral suspension: 0.5 to 2 hours (≤3%), eczema (pruritus hiemalis: 2%), xeroderma
Pregnancy Considerations Clobazam crosses the (≤2%), erythema (<2%), folliculitis (<2%), pruritus
placenta. (<2%), skin fissure (<2%), stinging of skin (<2%),
hypopigmentation (1% to 2%)
An increased risk of fetal malformations may be asso-
Local: Application site reaction (2% to 4%), local
ciated with first trimester benzodiazepine exposure
irritation (<2%)
(data not consistent). Exposure to benzodiazepines
immediately prior to or during birth may result in hypo-
nasopharyngitis (5%), streptococcal pharyngitis (1%)
thermia, hypotonia, respiratory depression, and diffi-
culty feeding in the neonate; neonates exposed to
Dermatologic: Local acneiform eruptions, urticaria
benzodiazepines late in pregnancy may develop
Local: Application site edema
dependence and withdrawal. The incidence of prema- <1%, postmarketing, and/or case reports: Alopecia,
ture birth and low birth weights may be increased application site induration, atrophic striae, cataract,
following maternal use of benzodiazepines; hypoglyce- contact dermatitis, Cushing syndrome, dermatitis,
mia and respiratory problems in the neonate may occur desquamation, exacerbation of psoriasis, excoriation,
following exposure late in pregnancy. Neonatal with- exfoliation of skin, eye irritation, glaucoma, hypertri-
drawal symptoms may occur within days to weeks after chosis, increased intraocular pressure, indurated pla-
birth and "floppy infant syndrome" (which also includes ques of the skin, lichenoid eruption, miliaria, papule,
withdrawal symptoms) has been reported with some perioral dermatitis, retinopathy (central serous), scalp
benzodiazepines (Bergman 1992; Iqbal 2002; Wikner pustules, scalp tightness, secondary infection, skin
2007). A combination of factors influences the potential pain, skin rash, skin tenderness (scalp), tingling of
teratogenicity of anticonvulsant therapy. When treating skin (scalp)
women with epilepsy, monotherapy with the lowest Dental Usual Dosage Oral mucosal inflammation:
effective dose and avoidance medications known to Children ≥12 years and Adults: Cream: Apply twice
have a high incidence of teratogenic effects is recom- daily for up to 2 weeks (maximum dose: 50 g/week);
mended (Harden 2009; Wlodarczyk 2012). discontinue application when control is achieved; if no
Patients exposed to clobazam during pregnancy are improvement is seen, reassessment of diagnosis may
encouraged to enroll themselves into the North Amer- be necessary
ican Antiepileptic Drug (NAAED) Pregnancy Registry by Dosing
calling 1-888-233-2334. Additional information is avail- Adult & Geriatric Note: Discontinue when control
able at www.aedpregnancyregistry.org. achieved; if improvement not seen within 2 weeks,
Controlled Substance C-IV reassessment of diagnosis may be necessary.
Oral mucosal inflammation (off-label use): Topical:
Cream: Apply twice daily for up to 2 weeks (max-
Clobetasol (kloe BAY ta sol) imum dose: 50 g/week); discontinue application
when control is achieved; if no improvement is seen,
Related Information reassessment of diagnosis may be necessary.
Ulcerative, Erosive, and Painful Oral Mucosal Disorders Steroid-responsive dermatoses: Topical: Cream
on page 1544 (0.05%), emollient cream, foam, gel, lotion, ointment,
Related Sample Prescriptions solution: Apply twice daily for up to 2 weeks (max-
Ulcerative and Erosive Disorders - Sample Prescrip- imum dose: 50 g/week or 50 mL/week).
tions on page 47 Mild to moderate plaque-type psoriasis of non-
Brand Names: US Clobetasol Propionate E; Clobex; scalp areas: Topical: Foam: Apply twice daily for
Clobex Spray; Clodan; Cormax Scalp Application up to 2 weeks (maximum dose: 50 g/week).
[DSC]; Impoyz; Olux; Olux-E; Temovate; Temovate E Moderate to severe plaque-type psoriasis: Topical:
[DSC] Cream (0.025%), emollient cream, lotion: Apply twice
Brand Names: Canada Clobex; Dermovate; Olux-E daily for up to 2 weeks (cream) or up to 4 weeks if
334
CLOBETASOL
needed (emollient cream, lotion) when application Shampoo: Adolescents ≥18 years: Topical: Apply
is <10% of body surface area (maximum dose: thin film to dry scalp once daily; leave in place for
50 g/week or 50 mL/week). Treatment with lotion 15 minutes, then add water, lather, and rinse
beyond 2 weeks should be limited to localized thoroughly; maximum weekly dose: 50 g/week
lesions (<10% body surface area) that have not or 50 mL/week. Limit treatment to 4 consecutive
improved sufficiently. weeks.
Spray: Apply by spraying directly onto affected area Renal Impairment: Pediatric There are no dosage
twice daily and gently rub into skin. Limit treatment adjustments provided in manufacturer's labeling.
to 4 consecutive weeks; treatment beyond 2 weeks Hepatic Impairment: Pediatric There are no dos-
should be limited to localized lesions that have not age adjustments provided in manufacturer's labeling.
improved sufficiently. Maximum total dose: 50 g/ Mechanism of Action Topical corticosteroids have
week or 59 mL/week. Do not use more than 26 anti-inflammatory, antipruritic, and vasoconstrictive
sprays per application or 52 sprays per day. properties. May depress the formation, release, and
Scalp psoriasis, moderate to severe: Topical: activity of endogenous chemical mediators of inflam-
Foam: Apply twice daily for up to 2 weeks (maximum mation (kinins, histamine, liposomal enzymes, prosta-
dose: 50 g/week). glandins) through the induction of phospholipase A2
Shampoo: Apply thin film to dry scalp once daily inhibitory proteins (lipocortins) and sequential inhibition
(maximum dose: 50 g/week or 50 mL/week); leave of the release of arachidonic acid. Clobetasol has very
in place for 15 minutes, then add water, lather, and high range potency.
rinse thoroughly. Limit treatment to 4 consecutive Contraindications
weeks. Hypersensitivity to clobetasol, other corticosteroids, or
Renal Impairment: Adult There are no dosage any component of the formulation; primary infections
adjustments provided in the manufacturer's labeling. of the scalp (scalp solution only)
Hepatic Impairment: Adult There are no dosage Canadian labeling: Additional contraindications (not in
adjustments provided in the manufacturer's labeling. US labeling): Treatment of rosacea, acne vulgaris,
Pediatric Note: Dosage should be based on severity perioral dermatitis, or perianal and genital pruritus;
of disease and patient response; use the smallest viral (eg, herpes or varicella) lesions of the skin,
amount for the shortest period of time to avoid HPA bacterial or fungal skin infections, parasitic infections,
suppression; discontinue therapy when control is skin manifestations relating to tuberculosis or syphilis,
achieved; reassess diagnosis if no improvement is eruptions following vaccinations; ulcerous wounds;
seen within 2 weeks. Due to the high incidence of application to eyes or eyelids; children <2 years of
adrenal suppression noted in clinical studies, clobeta- age (shampoo); children <1 year of age (cream, oint-
sol lotion, shampoo, and spray are not recommended ment, scalp application). Note: Product labels may
for use in patients <18 years of age. vary (refer also to product labels).
Dermatoses (steroid-responsive): Children ≥12 Warnings/Precautions Systemic absorption of topical
years and Adolescents: Topical: corticosteroids may cause hypothalamic-pituitary-adre-
Cream, emollient cream, gel, ointment: Apply spar- nal (HPA) axis suppression particularly in younger chil-
ingly twice daily for up to 2 weeks; maximum dren. HPA axis suppression may lead to adrenal crisis.
weekly dose: 50 g/week Allergic contact dermatitis may occur; it is usually
Solution: Apply sparingly to affected area of scalp diagnosed by failure to heal rather than clinical exacer-
twice daily for up to 2 weeks; maximum weekly bation. Prolonged treatment with corticosteroids has
dose: 50 mL/week been associated with the development of Kaposi sar-
Plaque-type psoriasis of nonscalp areas; mild to coma (case reports); if noted, discontinuation of therapy
moderate: Children ≥12 years and Adolescents: should be considered. Local effects may occur, includ-
Topical: Foam: Apply sparingly to affected area ing folliculitis, acneiform eruptions, hypopigmentation,
twice daily for up to 2 weeks; maximum weekly perioral dermatitis, allergic contact dermatitis, secon-
dose: 50 g/week or 21 capfuls/week dary infection, striae, miliaria, skin atrophy and telan-
Plaque-type psoriasis; moderate to severe: giectasia; may be irreversible. Topical corticosteroids,
Emollient cream: Adolescents ≥16 years: Topical: including clobetasol, may increase the risk of posterior
Apply sparingly twice daily for up to 2 weeks; if subcapsular cataracts and glaucoma. Monitor for ocular
response is not adequate, may be used for up to 2 changes. Avoid contact with eyes. Concomitant skin
more weeks if application is <10% of body surface infections may be present or develop during therapy;
area; use with caution; maximum weekly dose: discontinue if dermatological infection persists despite
50 g/week appropriate antimicrobial therapy. Adverse systemic
Lotion: Adolescents ≥18 years: Topical: Apply twice effects including Cushing syndrome, hyperglycemia,
daily for up to 2 weeks; maximum weekly dose: glycosuria, and HPA suppression may occur when used
50 g/week or 50 mL/week) on large surface areas, denuded skin, or with an
Spray: Adolescents ≥18 years: Apply by spraying occlusive dressing. Use in children <12 years of age
directly onto affected area twice daily and gently is not recommended. Children may absorb proportion-
ally larger amounts after topical application and may be
rub into skin. Limit treatment to 4 consecutive
more prone to systemic effects. Prolonged use may
weeks; treatment beyond 2 weeks should be
affect growth velocity; growth should be routinely moni-
limited to localized lesions which have not
tored in pediatric patients. Clobex lotion, Clobex sham-
improved sufficiently. Maximum weekly dose:
poo, Clobex spray, and Clodan shampoo are not
50 g/week or 59 mL/week. Do not use more than
recommended for use in pediatric patients ≤17 years.
26 sprays per application or 52 sprays per day.
Scalp psoriasis, moderate to severe: Do not use on the face, axillae, or groin or for the
Foam: Children ≥12 years and Adolescents: Top- treatment of acne vulgaris, rosacea or perioral derma-
ical: Apply twice daily for up to 2 weeks; maximum titis. Emollient cream contains imidurea; may cause
weekly dose: 50 g/week or 21 capfuls/week) allergic sensitization or irritation upon skin contact with
335
CLOBETASOL
the skin. Foam and spray are flammable; do not use potency topical steroids should be used only when
near open flame. clearly needed and after the first trimester (Bae 2012).
Warnings: Additional Pediatric Considerations Breastfeeding Considerations
The extent of percutaneous absorption is dependent Systemic corticosteroids are present in human milk. It is
on several factors, including epidermal integrity (intact not known if topical application of clobetasol will result
vs abraded skin), formulation, age of the patient, pro- in detectable quantities in breast milk.
longed duration of use, and the use of occlusive dress- Information related to the use of clobetasol and breast-
ings. Percutaneous absorption of topical steroids is feeding is limited (Carrillo Dde 2006). According to the
increased in neonates (especially preterm neonates), manufacturer, the decision to breastfeed during ther-
infants, and young children. Infants and small children apy should consider the risk of infant exposure, the
may be more susceptible to HPA axis suppression, benefits of breastfeeding to the infant, and benefits of
intracranial hypertension, Cushing syndrome, or other treatment to the mother. Low to moderate potency
systemic toxicities due to larger skin surface area to topical corticosteroids are preferred for initial treat-
body mass ratio. Due to the high incidence of adrenal ment of psoriasis in breastfeeding females (Bae
suppression noted in clinical studies, clobetasol lotion, 2012). Do not apply topical corticosteroids to breast
shampoo, and spray are not recommended for use in until breastfeeding ceases (Leachman 2006); hyper-
patients <18 years of age. In a study of patients with tension was noted in a breastfed infant when a high
moderate to severe atopic dermatitis (involving ≥20% potency topical corticosteroid was applied to the nip-
BSA) receiving Clobex 0.05% lotion twice daily for 2 ple (Butler 2014; Leachman 2006).
weeks, 9 of the14 pediatric patients (12 to 17 years of Dosage Forms: US
age) included developed adrenal suppression, com- Cream, External:
pared to 2 of the 10 pediatric patients receiving the Clobetasol Propionate E: 0.05% (15 g, 30 g, 60 g)
cream. In a study of patients receiving Clobex 0.05% Impoyz: 0.025% (60 g)
shampoo, 5 of 12 pediatric patients (12 to 17 years of Temovate: 0.05% (30 g, 60 g)
age) developed HPA axis suppression. Generic: 0.05% (15 g, 30 g, 45 g, 60 g)
Some dosage forms may contain propylene glycol; in Foam, External:
neonates large amounts of propylene glycol delivered Olux: 0.05% (50 g, 100 g)
orally, intravenously (eg, >3,000 mg/day), or topically Olux-E: 0.05% (50 g, 100 g)
have been associated with potentially fatal toxicities Generic: 0.05% (50 g, 100 g)
which can include metabolic acidosis, seizures, renal Gel, External:
failure, and CNS depression; toxicities have also been Generic: 0.05% (15 g, 30 g, 60 g)
reported in children and adults including hyperosmolal- Kit, External:
ity, lactic acidosis, seizures and respiratory depression; Clodan: 0.05%
use caution (AAP, 1997; Shehab, 2009). Liquid, External:
Drug Interactions Clobex Spray: 0.05% (59 mL, 125 mL)
Metabolism/Transport Effects None known. Generic: 0.05% (59 mL, 125 mL)
Lotion, External:
Clobex: 0.05% (59 mL, 118 mL)
Avoid concomitant use of Clobetasol with any of the
Generic: 0.05% (59 mL, 118 mL)
following: Aldesleukin
Ointment, External:
Temovate: 0.05% (15 g, 30 g)
Clobetasol may increase the levels/effects of: Defer-
Generic: 0.05% (15 g, 30 g, 45 g, 60 g)
asirox; Ritodrine
Shampoo, External:
Decreased Effect Clobex: 0.05% (118 mL)
Clobetasol may decrease the levels/effects of: Alde- Clodan: 0.05% (118 mL)
sleukin; Corticorelin; Hyaluronidase Generic: 0.05% (118 mL)
Pregnancy Considerations Solution, External:
Information related to the use of clobetasol in preg- Generic: 0.05% (25 mL, 50 mL)
nancy is limited (Westermann 2012).
Systemic bioavailability of topical corticosteroids is var- Clodronate (KLOE droh nate)
iable (integrity of skin, use of occlusion, etc.) and may
be further influenced by trimester of pregnancy (Chi Related Information
2017). In general, the use of topical corticosteroids is Osteonecrosis of the Jaw on page 1486
not associated with a significant risk of adverse preg- Brand Names: Canada Bonefos; Clasteon
nancy outcomes. However, there may be an increased Pharmacologic Category Bisphosphonate Derivative
risk of low birth weight infants following maternal use of Use Note: Not approved in the US
potent or very potent topical products, especially in high Hypercalcemia of malignancy: Management of
doses. Use of mild to moderate potency topical cortico- hypercalcemia of malignancy
steroids is preferred in pregnant females and the use of Osteolytic bone metastases: Adjunct in the manage-
large amounts or use for prolonged periods of time ment of osteolysis due to bone metastases of malig-
should be avoided (Chi 2016; Chi 2017; Murase nant tumors
2014). Also avoid areas of high percutaneous absorp-
tion (Chi 2017). The risk of stretch marks may be
increased with use of topical corticosteroids (Mur-
Effects on Dental Treatment Osteonecrosis of the
ase 2014).
jaw (ONJ), generally associated with local infection and/
The treatment of psoriasis in pregnancy is initiated with or tooth extraction and often with delayed healing, has
conservative treatment as in nonpregnant females. been reported in patients taking bisphosphonates.
When a topical steroid is needed, low to moderate Symptoms included nonhealing extraction socket or
potency corticosteroids are preferred initially. High an exposed jawbone. Most reported cases of
336
CLODRONATE
bisphosphonate-associated osteonecrosis have been in hypocalcemia after birth (Djokanovic 2008; Stathopou-
cancer patients treated with intravenous bisphospho- los 2011).
nates. However, some have occurred in patients with Product Availability Not available in the US
postmenopausal osteoporosis taking oral bisphospho- Dental Health Professional Considerations A
nates. Dental surgery, particularly tooth extraction, may review of 2,408 published cases of bisphosphonate-
increase the risk for ONJ. Patients who develop ONJ associated osteonecrosis of the jaw bone (BP-associ-
while on bisphosphonate therapy should receive care
ated ONJ) was done by Filleul 2010. BP therapy was
by an oral surgeon. See Dental Health Professional
associated with 89% of the cases to treat malignancies
Considerations.
and 11% of the cases to treat nonmalignant conditions.
Information on the specific bisphosphonate used was
available for 1,694 of the patients. Intravenous therapy
Adverse Reactions
(primarily zoledronic acid) was received by 88% of the
>10%: Hepatic: Increased serum transaminases (post-
menopausal osteopenic women: 18%; >2 x ULN: 2%) patients and 12% received oral treatment (primarily
1% to 10%: alendronate). Of all the cases of BP-associated ONJ,
Cardiovascular: Cardiac failure (1%) 67% were preceded by tooth extraction and for 26% of
Endocrine & metabolic: Hypocalcemia (2% to 3%) patients, there was no predisposing factor identified.
Gastrointestinal: Gastrointestinal disease (≤10%; A 2010 retrospective case review reported the preva-
includes stomach pain), nausea (3%), diarrhea lence of BP-associated ONJ in patients using alendro-
(2%), anorexia (1%)
nate-type drugs was 1 out of 952 patients or ~0.1% (Lo
Neuromuscular & skeletal: Bone fracture (1%)
2010). Of the 8,572 respondents, nine cases of ONJ
Renal: Increased serum creatinine (1%)
were identified; five had developed ONJ spontaneously
Respiratory: Pneumonia (1%)
<1%, postmarketing, and/or case reports: Arthralgia and four developed ONJ after tooth extraction. When
(severe), bronchospasm (patients with aspirin-sensi- extrapolated to patient-years of bisphosphonate expo-
tive asthma), conjunctivitis, dysphagia, erythematous sure, this prevalence rate of 0.1% equates to a fre-
rash, femur fracture (atypical subtrochanteric and dia- quency of 28 cases per 100,000 person-years of oral
physeal), hypersensitivity reactions (angioedema, bisphosphonate treatment. An Australian group (Mav-
dyspnea [in patients with aspirin-sensitive asthma], rokokki 2007), identified the frequency of BP-associated
pruritus, respiratory disorder, skin rash, urticaria), ONJ in osteoporotic patients, mainly taking weekly oral
hypophosphatemia (transient), increased liver alendronate, was 1 in 8,470 to 1 in 2,260 (0.01% to
enzymes, increased parathyroid hormone, leukemia 0.04%) patients. If extractions were carried out, the
(rare), maculopapular rash, mouth irritation, myalgia calculated frequency was 1 in 1,130 to 1 in 296
(severe), myelodysplasia (rare), ropharyngeal ulcer, (0.09% to 0.34%) patients. The median time to onset
ostealgia (severe), osteonecrosis (jaw or external of ONJ in alendronate patients was 24 months.
auditory canal), proteinuria, renal failure, renal insuffi-
ciency, uveitis According to the 2011 report by the American Dental
Mechanism of Action A bisphosphonate that lowers Association (ADA), the incidence of BP-associated ONJ
serum calcium by inhibition of bone resorption via remains low and the benefits of using oral bisphosph-
actions on osteoclasts or on osteoclast precursors; onates significantly outweighs the risk of developing
may also have indirect inhibitory effects through osteo- BP-associated ONJ for treatment and prevention of
blastic cells, which control recruitment and activity of osteoporosis and cancer treatment (Hellstein 2011).
osteoclasts. The full 47-page report can be accessed at http://www.-
Pharmacodynamics/Kinetics ada.org/~/media/ADA/Member%20Center/FIles/
Onset of Action Calcium-lowering effects: IV: Within topics_ARONJ_report.ashx.
48 hours
Duration of Action Calcium-lowering effects: 5 days The ADA review of 2011 stated the incidence of oral
to 3 weeks following discontinuation BP-associated ONJ was one case for every 1,000
Half-life Elimination Terminal: Oral: ~6 hours; IV: 13 individuals exposed to oral bisphosphonates (0.1%)
hours (serum); prolonged in bone tissue (Hellstein 2011).
Time to Peak Plasma: Oral: 30 minutes The most comprehensive review to date on osteonec-
Pregnancy Considerations Use is contraindicated rosis of the jaw bone (ONJ) has been published in the
during pregnancy. Adverse events have been observed Journal of Bone and Mineral Research (Khan 2015),
in animal reproduction studies. It is not known if and written by an International Task Force of authors,
bisphosphonates cross the placenta, but fetal exposure totaling 34, from academe; industry; clinical medical
is expected (Djokanovic 2008; Stathopoulos 2011). and dental practice; oral and maxillofacial surgery; bone
Available data have not shown that exposure to
and mineral research; epidemiology; medical and den-
bisphosphonates during pregnancy significantly
tal oncology; orthopedic surgery; osteoporosis
increases the risk of adverse fetal events (Djokanovic
research; muscle and bone research; endocrinology
2008; Levy 2009; Stathopoulos 2011). However until
additional data is available, most sources recommend and diagnostic sciences. The work provides a system-
discontinuing bisphosphonate therapy in women of atic review of the literature and international consensus
reproductive potential as early as possible prior to a on the classification, incidence, pathophysiology, diag-
planned pregnancy; use in premenopausal women nosis, and management of ONJ in both oncology and
should be reserved for special circumstances when osteoporosis patient populations. This review of the
rapid bone loss is occurring (Bhalla 2010; Pereira literature from January 2003 to April 2014, with 299
2012; Stathopoulos 2011). Because hypocalcemia has references, offers recommendations for management of
been described following in utero bisphosphonate ONJ based on multidisciplinary international con-
exposure, exposed infants should be monitored for sensus.
337
CLODRONATE
Prevalence and incidence of ONJ in osteoporosis Hematologic & oncologic: Leukopenia (88%; grades
patients from the Task Force report: 3/4: 88%), anemia (83%; grades 3/4: 75%), lympho-
cytopenia (82%; grades 3/4: 82%), thrombocytope-
Prevalence – the percent of osteoporotic population
nia (81%; grades 3/4: 80%), neutropenia (10% to
affected with ONJ
64%; grades 3/4: 64%; grade 4: 7%), febrile neutro-
After reviewing all literature reports on this subject, the penia (55%; grade 3: 51%; grade 4: 3%), petechia
Task Force concluded that the prevalence of ONJ in (26%; grade 3: 6%)
patients prescribed oral BPs for the treatment of osteo- Hepatic: Increased serum ALT (81%), increased
porosis ranges from 0% to 0.04% with the majority serum AST (74%), increased bilirubin (45%)
being below 0.001%. However, the Task Force does Infection: Infection (83%; includes bacterial, fungal,
cite the study of (Lo et al) that evaluated the Kaiser and viral), sepsis (including septic shock; 17%)
Permanente database and found the prevalence of Local: Catheter infection (12%)
ONJ in those receiving BPs for more than 2 years to Neuromuscular & skeletal: Limb pain (30%), myal-
range from 0.05% to 0.21% and appeared to be related gia (14%)
to duration of exposure. As mentioned above, the Renal: Increased serum creatinine (50%)
American Dental Association has previously reported Respiratory: Epistaxis (27%), dyspnea (13%), pleural
that the prevalence of ONJ in osteoporosis patients effusion (12%)
using oral BPs to be 1 out of 1,000 or 0.1% (Hell- Miscellaneous: Fever (39%)
stein 2011). 1% to 10%:
Cardiovascular: Pericardial effusion (8%), capillary
Incidence - the rate at which ONJ occurs or the number
leak syndrome (4%)
of times it happens
Central nervous system: Drowsiness (10%), irritability
From currently available data, the incidence of ONJ in (10%), lethargy (10%), agitation (5%), mental status
the osteoporosis patient population appears to be low changes (1% to 4%)
ranging from 0.15% to less than 0.001% person-years Dermatologic: Cellulitis (8%), pruritic rash (8%)
drug exposure. In terms of the osteoporosis patient Gastrointestinal: Rectal pain (8%), upper abdominal
population taking oral BPs, the incidence ranges from pain (8%), pseudomembranous colitis (7%), stoma-
1.04 to 69 per 100,000 patient years of drug exposure. titis (7%), pancreatitis (1% to 4%), typhlitis (1%
to 4%)
Hematologic & oncologic: Tumor lysis syndrome (6%;
Clofarabine (klo FARE a been)
grade 3: 6%), oral mucosal petechiae (5%; grade
Brand Names: US Clolar 3: 4%)
Brand Names: Canada Clolar Hepatic: Jaundice (8%), hyperbilirubinemia (1% to
Pharmacologic Category Antineoplastic Agent, Anti- 4%), hepatic sinusoidal obstruction syndrome (for-
metabolite; Antineoplastic Agent, Antimetabolite merly known as hepatic veno-occlusive disease: 2%)
(Purine Analog) Hypersensitivity: Hypersensitivity (1% to 4%)
Infection: Herpes simplex infection (10%), bacteremia
Use Acute lymphoblastic leukemia, relapsed or
(9%), candidiasis (7%), herpes zoster (7%), staph-
refractory: Treatment of relapsed or refractory acute
ylococcal bacteremia (6%), staphylococcal sepsis
lymphoblastic leukemia (ALL) in patients 1 to 21 years
of age (after at least 2 prior regimens) (5%), influenza (1% to 4%), sepsis syndrome (2%)
Neuromuscular & skeletal: Back pain (10%), ostealgia
(10%), weakness (10%), arthralgia (9%)
Renal: Acute renal failure
Respiratory: Pneumonia (10%), respiratory distress
related to dental treatment: Mucosal inflammation and
(10%), tachypnea (9%), upper respiratory tract infec-
gingival bleeding.
tion (5%), pulmonary edema (1% to 4%), sinusitis
Effects on Bleeding Chemotherapy may result in (1% to 4%)
significant myelosuppression, potentially including sig-
<1%, postmarketing, and/or case reports: Enterocolitis
nificant reduction in platelet counts and altered hemo-
(occurs more frequently within 30 days of treatment
stasis. In patients who are under active treatment with
and with combination chemotherapy), exfoliative der-
these agents, medical consult is suggested.
matitis, gastrointestinal hemorrhage, hallucination
Due to the thrombocytopenic effects of clofarabine, an (Jeha 2006), hepatic failure, hepatitis, hepatomegaly
increased risk of bleeding may be seen in patients (Jeha 2006), hypokalemia (Jeha 2006), hyponatremia,
receiving concomitant NSAIDs (including aspirin). hypophosphatemia, increased right ventricular pres-
Adverse Reactions Incidences include off-label use in sure (Jeha 2006), left ventricular systolic dysfunction
the treatment of AML. (Jeha 2006), major hemorrhage (including cerebral
>10%: and pulmonary; majority of cases associated with
Cardiovascular: Tachycardia (35%), hypotension thrombocytopenia), Stevens-Johnson syndrome, toxic
(29%), flushing (19%), hypertension (13%), epidermal necrolysis
edema (12%) Mechanism of Action Clofarabine, a purine (deoxy-
Central nervous system: Headache (43%), chills adenosine) nucleoside analog, is metabolized to clofar-
(34%), fatigue (34%), anxiety (21%), pain (15%) abine 5'-triphosphate. Clofarabine 5'-triphosphate
Dermatologic: Pruritus (43%), skin rash (38%), pal- decreases cell replication and repair as well as causing
mar-plantar erythrodysesthesia (16%), eryth- cell death. To decrease cell replication and repair,
ema (11%) clofarabine 5'-triphosphate competes with deoxyadeno-
Gastrointestinal: Vomiting (78%), nausea (73%), diar- sine triphosphate for the enzymes ribonucleotide reduc-
rhea (56%), abdominal pain (35%), anorexia (30%), tase and DNA polymerase. Cell replication is decreased
gingival bleeding (17%), mucosal inflammation when clofarabine 5'-triphosphate inhibits ribonucleotide
(16%), oral candidiasis (11%) reductase from reacting with deoxyadenosine triphos-
Genitourinary: Hematuria (13%) phate to produce deoxynucleotide triphosphate which is
338
CLOMIPRAMINE
needed for DNA synthesis. Cell replication is also loss (temporary/prolonged), vitreous detachment
decreased when clofarabine 5'-triphosphate competes (posterior), weakness, weight gain, weight loss
with DNA polymerase for incorporation into the DNA Mechanism of Action Clomiphene is a racemic mix-
chain; when done during the repair process, cell repair ture consisting of zuclomiphene (~38%) and enclomi-
is affected. To cause cell death, clofarabine 5'-triphos- phene (~62%), each with distinct pharmacologic
phate alters the mitochondrial membrane by releasing properties. Clomiphene acts at the level of the hypo-
proteins, an inducing factor and cytochrome C. thalamus, occupying cell surface and intracellular estro-
Pharmacodynamics/Kinetics gen receptors (ERs) for longer durations than estrogen.
Half-life Elimination Children and Adolescents 2 to This interferes with receptor recycling, effectively
19 years: 5.2 hours; Children and Adults: 7 hours; may depleting hypothalamic ERs and inhibiting normal estro-
be prolonged in in the elderly and in patients with renal genic negative feedback. Impairment of the feedback
impairment (Bonate, 2011) signal results in increased pulsatile GnRH secretion
Pregnancy Risk Factor D from the hypothalamus and subsequent pituitary gona-
Pregnancy Considerations Adverse events were dotropin (FSH, LH) release, causing growth of the
ovarian follicle, followed by follicular rupture (ASRM
observed in animal reproduction studies. May cause
2013; Dickey 1996).
fetal harm if administered to a pregnant woman.
Women of childbearing potential should avoid becom-
Onset of Action Ovulation: 5 to 10 days following
ing pregnant during therapy. All patients should use
course of treatment
effective contraception to prevent pregnancy during
Duration of Action Effects are cumulative; ovulation
treatment.
may occur in the cycle following the last treatment
(Dickey 1996)
ClomiPHENE (KLOE mi feen) Half-life Elimination ~5 days (Goldstein 2000)
Time to Peak ~6 hours (Goldstein 2000)
Brand Names: Canada Clomid; Serophene Pregnancy Considerations
Pharmacologic Category Ovulation Stimulator; Use is contraindicated in females who are already
Selective Estrogen Receptor Modulator (SERM) pregnant.
Use Treatment of ovulatory dysfunction: Treatment of
ovulatory dysfunction in women desiring pregnancy The incidence of adverse fetal effects following mater-
nal use of clomiphene for ovulation induction is similar
to those seen in the general population.
complications reported ClomiPRAMINE (kloe MI pra meen)
require special precautions Related Information
Adverse Reactions Dentin Hypersensitivity, Acid Erosion, High Caries
>10%: Endocrine & metabolic: Ovary enlargement
mia on page 1548
(14%)
Vasoconstrictor Interactions With Antidepressants on
1% to 10%:
page 1606
Endocrine & metabolic: Hot flash (10%)
Brand Names: US Anafranil
Gastrointestinal: Abdominal distention (≤6%), abdomi- Brand Names: Canada Anafranil; Apo-Clomipramine;
CO Clomipramine; Dom-Clomipramine; Novo-Clomipr-
nal distress (≤6%), bloating (≤6%), nausea (≤2%),
amine
vomiting (≤2%)
Genitourinary: Breast disease (discomfort: 2%),
Pharmacologic Category Antidepressant, Tricyclic
(Tertiary Amine)
abnormal uterine bleeding (1%)
Ophthalmic: Visual disturbance (2%)
Use Obsessive-compulsive disorder: Treatment of
obsessive-compulsive disorder
<1%, postmarketing/case reports: Accommodation dis-
turbance, acne vulgaris, alopecia, anxiety, arthralgia,
Use with caution; epinephrine and levonordefrin have
back pain, cardiac arrhythmia, cataract, cerebrovas-
been shown to have an increased pressor response in
cular accident, chest pain, constipation, depression,
combination with TCAs. Clomipramine is one of the
dermatitis, diarrhea, dizziness, dry hair, dyspnea,
drugs confirmed to prolong the QT interval and is
ectopic pregnancy, edema, endometriosis, endome- accepted as having a risk of causing torsade de
trium disease (reduced thickness), erythema, eryth- pointes. The risk of drug-induced torsade de pointes
ema multiforme, erythema nodosum, eye pain, is extremely low when a single QT interval prolonging
fatigue, fever, hepatitis, hypersensitivity reaction, drug is prescribed. In terms of epinephrine, it is not
hypertension, hypertrichosis, hypertriglyceridemia, known what effect vasoconstrictors in the local anes-
increased appetite, increased serum transaminases, thetic regimen will have in patients with a known history
increased urine output, insomnia, irritability, leukocy- of congenital prolonged QT interval or in patients taking
tosis, macular edema, migraine, mood changes, myal- any medication that prolongs the QT interval. Until more
gia, neoplasm, nervousness, optic neuritis, ovarian information is obtained, it is suggested that the clinician
cyst, ovarian hemorrhage, ovarian hyperstimulation consult with the physician prior to the use of a vaso-
syndrome, palpitations, pancreatitis, paresthesia, constrictor in suspected patients, and that the vaso-
phlebitis, photopsia, pruritus, psychosis, pulmonary constrictor (epinephrine, mepivacaine and
embolism, retinal hemorrhage, retinal thrombosis, ret- levonordefrin [Carbocaine® 2% with Neo-Cobefrin®])
inal vascular spasm, seizure, severe abdominal pain, be used with caution.
skin rash, syncope, tachycardia, thrombophlebitis, Effects on Dental Treatment Key adverse event(s)
thyroid disease, tinnitus, urinary frequency, urticaria, related to dental treatment: Xerostomia and changes in
uterine hemorrhage, vaginal dryness, vertigo, vision salivation (normal salivary flow resumes upon
339
CLOMIPRAMINE
discontinuation). Long-term treatment with TCAs, such Genitourinary: Urinary retention (children & adoles-
as clomipramine, increases the risk of caries by reduc- cents 7%; adults 2%), urinary tract infection (adults
ing salivation and salivary buffer capacity. 6%), urinary frequency (adults 5%), lactation (non-
Effects on Bleeding No information available to puerperal; adults 4%), breast hypertrophy (adults
require special precautions 2%), cystitis (adults 2%), leukorrhea (adults 2%),
Adverse Reactions Data shown for children reflects vaginitis (adults 2%), mastalgia (adults 1%)
both children and adolescents studied in clinical trials. Hematologic & oncologic: Purpura (adults 3%)
>10%: Hepatic: Increased serum ALT (>3 x ULN: 3%),
Central nervous system: Dizziness (adults 54%; chil- increased serum AST (>3 x ULN: 1%)
dren & adolescents 41%), drowsiness (46% to 54%), Hypersensitivity: Hypersensitivity reaction (children &
headache (adults 52%), fatigue (35% to 39%), adolescents 7%)
insomnia (adults 25%; children & adolescents Neuromuscular & skeletal: Weakness (1% to 2%)
11%), nervousness (adults 18%; children & adoles- Ophthalmic: Abnormal lacrimation (adults 3%), aniso-
cents 4%), myoclonus (adults 13%; children & ado- coria (children & adolescents 2%), blepharospasm
lescents 2%) (children & adolescents 2%), mydriasis (adults 2%),
Dermatologic: Diaphoresis (adults 29%; children & ocular allergy (children & adolescents 2%), conjunc-
adolescents 9%) tivitis (adults 1%)
Endocrine & metabolic: Change in libido (adults 21%), Otic: Tinnitus (4% to 6%)
weight gain (adults 18%; children & adolescents 2%) Respiratory: Bronchospasm (children & adolescents
Gastrointestinal: Xerostomia (adults 84%, children & 7%; adults 2%), sinusitis (adults 6%), dyspnea (chil-
adolescents 63%), constipation (adults 47%; children dren & adolescents 2%), epistaxis (adults 2%), lar-
& adolescents 22%), nausea (adults 33%), dyspep- yngitis (children & adolescents 2%)
sia (13% to 22%), anorexia (12% to 22%), diarrhea Miscellaneous: Fever (adults 4%)
(7% to 13%), abdominal pain (adults 11%), increased <1%, postmarketing, and/or case reports: Abnormal
appetite (adults 11%) electroencephalogram, accommodation disturbance,
agranulocytosis, albuminuria, alopecia, altered sense
Genitourinary: Ejaculation failure (adults 42%, children
of smell, anemia, aneurysm, angle-closure glaucoma,
& adolescents 6%), impotence (adults 20%), diffi-
anticholinergic syndrome, apathy, aphasia, apraxia,
culty in micturition (adults 14%; children & adoles-
ataxia, atrial flutter, blepharitis, bloody stools, bone
cents 4%)
marrow depression, bradycardia, brain disease,
Neuromuscular & skeletal: Tremor (adults 54%; chil-
breast fibroadenosis, bronchitis, bundle branch block,
dren & adolescents 33%), myalgia (adults 13%)
cardiac arrhythmia, cardiac failure, catatonic-like
Ophthalmic: Visual disturbance (adults 18%; children
state, cellulitis, cerebral hemorrhage, cervical dyspla-
& adolescents 7%)
sia, cheilitis, chloasma, cholinergic syndrome, chor-
Respiratory: Pharyngitis (adults 14%), rhinitis
eoathetosis, chromatopsia, chronic enteritis, colitis,
(adults 12%)
coma, conjunctival hemorrhage, cyanosis, deafness,
1% to 10%:
dehydration, delirium, delusions, dental caries, dermal
Cardiovascular: Flushing (7% to 8%), chest pain (chil- ulcer, diabetes mellitus, diplopia, DRESS syndrome,
dren & adolescents 7%), orthostatic hypotension duodenitis, dyskinesia, dystonia, eczema, edema,
(children, adolescents, and adults 4% to 6%), palpi- edema (oral), endometrial hyperplasia, endometriosis,
tations (4%), tachycardia (children, adolescents, and enlargement of salivary glands, epididymitis, erythem-
adults 2% to 4%), ECG abnormality (2%), syncope atous rash, exophthalmos, exostosis, extrapyramidal
(children & adolescents 2%) reaction, extrasystoles, gastric dilation, gastric ulcer,
Central nervous system: Anxiety (adults 9%; children gastroesophageal reflux disease, glycosuria, goiter,
& adolescents 2%), paresthesia (adults 9%), mem- gout, gynecomastia, hallucination, heart block, hema-
ory impairment (7% to 9%), sleep disorder (4% to turia, hemiparesis, hemoptysis, hepatic injury
9%), twitching (adults 7%), depression (adults 5%), (severe), hepatitis, hostility, hyperacusis, hypercholes-
lack of concentration (adults 5%), pain (3% to 4%), terolemia, hyperesthesia, hyperglycemia, hyperkine-
hypertonia (2% to 4%), abnormal dreams (adults sia, hyperreflexia, hyperthermia, hyperthyroidism,
3%), agitation (adults 3%), migraine (adults 3%), hyperuricemia, hyperventilation, hypnogenic halluci-
psychosomatic disorder (adults 3%), speech disturb- nations, hypoesthesia, hypokalemia, hypokinesia,
ance (adults 3%), yawning (adults 3%), confusion hypothyroidism, hypoventilation, intestinal obstruction,
(2% to 3%), aggressive behavior (children & adoles- irritable bowel syndrome, ischemic heart disease,
cents 2%), chills (adults 2%), depersonalization keratitis, laryngismus, leukemoid reaction, leukopenia,
(2%), emotional lability (adults 2%), irritability (chil- local inflammation (uterine), lupus erythematous-like
dren & adolescents 2%), paresis (children & adoles- rash, lymphadenopathy, maculopapular rash, manic
cents 2%), myasthenia (1% to 2%), panic attack (1% reaction, muscle spasm, mutism, myocardial infarc-
to 2%), abnormality in thinking (≥1%), vertigo (≥1%) tion, myopathy, myositis, nephrolithiasis, neuralgia,
Dermatologic: Skin rash (4% to 8%), pruritus (adults neuropathy, nocturnal amblyopia, oculogyric crisis,
6%), body odor (children & adolescents 2%), derma- oculomotor nerve paralysis, ovarian cyst, pancytope-
titis (adults 2%), xeroderma (adults 2%), urticaria nia, paralytic ileus, paranoia, peptic ulcer, periarteritis
(adults 1%) nodosa, peripheral ischemia, pharyngeal edema, pho-
Endocrine & metabolic: Weight loss (children & ado- bia, photophobia, pneumonia, premature ejaculation,
lescents 7%), hot flash (2% to 5%), menstrual dis- pseudolymphoma, psoriasis, psychosis, pyelonephri-
ease (adults 4%), amenorrhea (adults 1%) tis, pyuria, rectal hemorrhage, renal cyst, schizophre-
Gastrointestinal: Dysgeusia (4% to 8%), vomiting niform disorder, scleritis, seizure, sensory disturbance,
(7%), flatulence (adults 6%), aphthous stomatitis serotonin syndrome, skin hypertrophy, skin photosen-
(children & adolescents 2%), dysphagia (adults sitivity, somnambulism, strabismus, stupor, suicidal
2%), gastrointestinal disease (adults 2%), halitosis ideation, thrombocytopenia, thrombophlebitis, tongue
(children & adolescents 2%), esophagitis (adults 1%) ulcer, torticollis, urinary incontinence, uterine
340
CLONAZEPAM
hemorrhage, vaginal hemorrhage, vasospasm, ven- Use

tricular tachycardia, visual field defect, voice disorder, Panic disorder: Treatment of panic disorder, with or
withdrawal syndrome without agoraphobia.
Mechanism of Action Clomipramine appears to affect Seizure disorders: Mono- or adjunctive therapy in the
serotonin uptake while its active metabolite, desmethyl- treatment of the Lennox-Gastaut syndrome (petit mal
clomipramine, affects norepinephrine uptake variant), akinetic, and myoclonic seizures; absence
Pharmacodynamics/Kinetics seizures (petit mal) unresponsive to succinimides.
Onset of Action Onset of action: 1 to 2 weeks; Local Anesthetic/Vasoconstrictor Precautions
maximum effect: 8 to 12 weeks No information available to require special precautions
Duration of Action 1 to 2 days Effects on Dental Treatment Key adverse event(s)
Half-life Elimination Adults (following a 150 mg related to dental treatment: Xerostomia and changes in
dose): Clomipramine 19 to 37 hours (mean: 32 hours); salivation (normal salivary flow resumes upon discon-
DMI: 54 to 77 hours (mean: 69 hours) tinuation), gum soreness, and coated tongue.
Time to Peak 2 to 6 hours Effects on Bleeding No information available to
Pregnancy Risk Factor C require special precautions
Pregnancy Considerations Adverse events were Adverse Reactions Reactions reported in patients
observed in some animal reproduction studies. Clomipr- with seizure disorder, unless otherwise noted. Fre-
amine and its metabolite desmethylclomipramine cross quency not always defined.
the placenta and can be detected in cord blood and >10%: Central nervous system: Drowsiness (seizure
neonatal serum at birth (Loughhead 2006; ter Horst disorder: ~50%; panic disorder: 26% to 50%), ataxia
2012). Data from five newborns found the half-life for (seizure disorder: ~30%; panic disorder: 1% to 9%),
behavioral problems (seizure disorder: ~25%), dizzi-
clomipramine in the neonate to be 42 ± 16 hours
ness (panic disorder: 5% to 12%)
following in utero exposure. Serum concentrations were
1% to 10%:
not found to correlate to withdrawal symptoms (ter
Central nervous system: Fatigue (panic disorder: 6%
Horst 2012). Withdrawal symptoms (including jitteri-
to 9%), depression (panic disorder: 6% to 8%),
ness, tremor, and seizures) have been observed in
memory impairment (panic disorder: 4% to 5%),
neonates whose mothers took clomipramine up to
nervousness (panic disorder: 3% to 4%), dysarthria
delivery.
(panic disorder: ≤4%), reduced intellectual ability
The ACOG recommends that therapy for depression (panic disorder: ≤4%), emotional lability (panic dis-
during pregnancy be individualized; treatment should order: 2%), confusion (panic disorder: ≤2%), delayed
incorporate the clinical expertise of the mental health ejaculation (panic disorder ≤2%)
clinician, obstetrician, primary health care provider, and Endocrine & metabolic: Decreased libido (panic dis-
pediatrician (ACOG 2008). According to the American order: ≤3%)
Psychiatric Association (APA), the risks of medication Gastrointestinal: Constipation (panic disorder: 3% to
treatment should be weighed against other treatment 5%), decreased appetite (panic disorder: 3%),
options and untreated depression. For women who abdominal pain (panic disorder: 2%)
discontinue antidepressant medications during preg- Genitourinary: Dysmenorrhea (panic disorder: 3% to
nancy and who may be at high risk for postpartum 6%), vaginitis (panic disorder: 2% to 4%), impotence
depression, the medications can be restarted following (panic disorder: ≤3%), urinary tract infection (panic
delivery (APA 2010). Treatment algorithms have been disorder: ≤2%), urinary frequency (panic disorder:
developed by the ACOG and the APA for the manage- 1% to 2%)
ment of depression in women prior to conception and Hypersensitivity: Hypersensitivity (panic disorder: 2%
during pregnancy (Yonkers 2009). to 4%)
Neuromuscular & skeletal: Myalgia (panic disorder:
Data collection to monitor pregnancy and infant out- 2% to 4%)
comes following exposure to clomipramine is ongoing. Ophthalmic: Blurred vision (panic disorder: 2% to 3%)
Pregnant women exposed to antidepressants during Respiratory: Upper respiratory tract infection (panic
pregnancy are encouraged to enroll in the National disorder: 6% to 10%), sinusitis (panic disorder: 4%
Pregnancy Registry for Antidepressants (NPRAD). to 8%), influenza (panic disorder: 4% to 5%), cough
Women 18 to 45 years of age or their health care (panic disorder: ≤4%), rhinitis (panic disorder: 2% to
providers may contact the registry by calling 4%), pharyngitis (panic disorder: 2% to 3%), bron-
844-405-6185. Enrollment should be done as early in chitis (panic disorder: 2%)
pregnancy as possible. Frequency not defined:
Dental Health Professional Considerations See Cardiovascular: Edema (ankle or facial), palpitations
Local Anesthetic/Vasoconstrictor Precautions Central nervous system: Amnesia, aphonia, chorei-
form movements, coma, glassy-eyed appearance,
hallucination, headache, hemiparesis, hypotonia,
ClonazePAM (kloe NA ze pam) hysteria, insomnia, myasthenia, psychosis, slurred
Related Information speech, vertigo
Dermatologic: Alopecia, skin rash
Endocrine & metabolic: Dehydration, hirsutism,
increased libido, weight gain, weight loss
mia on page 1548
Gastrointestinal: Anorexia, coated tongue, diarrhea,
Brand Names: US KlonoPIN encopresis, gastritis, gingival pain, increased appe-
Brand Names: Canada Clonapam; Rivotril tite, nausea, xerostomia
Generic Availability (US) Yes Genitourinary: Dysuria, nocturia, urinary incontinence,
Pharmacologic Category Anticonvulsant, Benzodia- urinary retention
zepine; Benzodiazepine Hematologic & oncologic: Anemia, eosinophilia, leu-
Dental Use Burning mouth syndrome kopenia, lymphadenopathy, thrombocytopenia
341
CLONAZEPAM
Hepatic: Hepatomegaly, increased serum alkaline studied (Bottai 1995; Chouinard 1983; Clark 1997;
phosphatase (transient), increased serum transami- Edwards 1991; WFSBP [Grunze 2009]).
nases (transient) Burning mouth syndrome (off-label use):
Neuromuscular & skeletal: Dysdiadochokinesia, Oral: Initial: 0.25 at bedtime for 1 week; increase
tremor dose by ≤0.25 mg every week; maximum dose:
Ophthalmic: Abnormal eye movements, diplopia, nys- 3 mg daily in 3 divided doses. Note: Use should
tagmus be limited (Buchanan 2008; Grushka 1998).
Respiratory: Chest congestion, dyspnea, respiratory Topical: May administer topically with 1 mg 3 times
depression, rhinorrhea, upper respiratory complaint daily (after each meal). Note: Patient should be
(hypersecretion) instructed to suck on the tablet, retain saliva in
Miscellaneous: Fever, paradoxical reactions (including mouth near the pain sites without swallowing for 3
aggressive behavior, agitation, anxiety excitability, minutes, and then expectorate saliva (Gremeau-
hostility, irritability, nervousness, nightmares, sleep Richard 2004).
disturbance, vivid dreams), physical health deterio- Essential tremor (off-label use): Oral: Initial: 0.5 mg
ration at bedtime; increase dose by 0.5 mg every 3 to 4
<1%, postmarketing, and/or case reports (any indica- days; maximum dose: 6 mg daily (Biary 1987;
tion): Abdominal distress, abnormal behavior Thompson 1984; Zesiewicz 2005; Zesiewicz 2011).
(increased oppositional behavior), accidental injury, REM sleep behavior disorder (off-label use): 0.25
acne flare, ageusia, aggressive behavior, alcohol to 2 mg 30 minutes prior to bedtime (maximum: 4 mg
intoxication, anxiety, apathy, arthralgia, back pain, 30 minutes prior to bedtime). Note: Use with caution
bladder dysfunction, bone fracture, burn, burning sen- in patients with dementia, gait disorders, or obstruc-
sation of skin, candidiasis, cellulitis, chest pain, con- tive sleep apnea (Aurora 2010).
tact dermatitis, cystitis, depersonalization, dermal Restless leg syndrome (off-label use): Oral: Initial:
hemorrhage, dermatological reaction, disinhibition 1 mg 30 minutes prior to bedtime; increase dose by
(organic), dyspepsia, ejaculatory disorder, epistaxis, 0.5 to 1 mg at weekly intervals. Doses up to 2 mg
exacerbation of asthma, excitement, excoriation, eye once daily have been used in clinical trials (Monta-
irritation, falling, flatulence, flushing, foot pain, fre- gna 1984; Peled 1987; Saletu 2001). Additional data
quent bowel movements, fungal infection, gastric dis- may be necessary to further define the role of
tress, gout, heartburn, heavy headedness, clonazepam in the treatment of this condition.
hemorrhoids, herpes simplex infection, hoarseness, Tardive dyskinesia (off-label use): Oral: Initial:
hordeolum, hyperactivity, hypertonia, hypoesthesia, 1 mg/day; adjust dosage based on response and
hunger, illusion, increased dream activity, increased tolerability by 1 mg/day every 3 to 4 days up to a
thirst, infectious mononucleosis, irregular menses, maximum dose of 4.5 mg/day (Thaker 1990).
irritability, jaw pain, knee effusion, knee pain, lack of Tic disorders (off-label use): Oral: Initial: 0.5 mg at
concentration, leg pain, leg thrombophlebitis, local bedtime; adjust dose by 0.5 mg every 2 weeks
inflammation, lower back pain, malaise, mastalgia, based on response and tolerability. Dosing range in
migraine, motion sickness, orthostatic hypotension, clinical studies was 1 to 12 mg/day (Merikangas
otalgia, otitis, pain, paresis, paresthesia, pedal edema, 1985; Troung 1988).
pelvic pain, periorbital edema, pleurisy, pneumonia, Geriatric Refer to adult dosing. Initiate with low doses
polyuria, pruritus, pustular rash, shivering, shoulder and observe closely.
pain, sialorrhea, sleep disorder, slowed reaction time, Renal Impairment: Adult There are no dosage
sneezing, sprain, strain, streptococcal infection, suici- adjustments provided in the manufacturer’s labeling;
dal ideation, suicidal tendencies, tendonitis, tongue use with caution. Clonazepam metabolites may accu-
edema, toothache, twitching, twitching of eye, urinary mulate in patients with renal impairment.
tract hemorrhage, urine discoloration, viral infection, Hepatic Impairment: Adult There are no dosage
visual disturbance, visual field defect, withdrawal syn- adjustments provided in the manufacturer’s labeling;
drome, xeroderma, xerophthalmia, yawning use with caution. Clonazepam undergoes hepatic
Dental Usual Dosage Burning mouth syndrome (off- metabolism. Contraindicated in patients with signifi-
label use): Adults: Oral: 0.25-3 mg/day in 2 divided cant hepatic impairment.
doses, in morning and evening Pediatric Note: If necessary to discontinue clonaze-
Dosing pam therapy, drug should be withdrawn gradually.
Adult Neuroirritability, agitation (palliative care): Lim-
Panic disorder: Oral: 0.25 mg twice daily; increase in ited data available: Infants, Children, and Adoles-
increments of 0.125 to 0.25 mg twice daily every 3 cents: Oral:
days; target dose: 1 mg daily (maximum: 4 mg/day). Patient weight:
Discontinuation of treatment: To discontinue, treat- <30 kg: Initial: 0.01 to 0.03 mg/kg/day in divided
ment should be withdrawn gradually. Decrease doses up to 3 to 4 times daily; increase dose to
dose by 0.125 mg twice daily every 3 days until desired effect up to a maximum daily dose:
medication is completely withdrawn. 0.2 mg/kg/day in 3 divided doses (Kliegman
Seizure disorders: Oral: 2017; Wustoff 2007)
Initial daily dose not to exceed 1.5 mg given in 3 ≥30 kg: Initial: ≤0.25 mg/dose 3 times daily; may
divided doses; may increase by 0.5 to 1 mg every increase by 0.5 to 1 mg/day every 3 days up to
third day until seizures are controlled or adverse maintenance dose range: 0.05 to 0.2 mg/kg/day
effects seen (maximum: 20 mg/day). up to maximum daily dose: 20 mg/day (Klieg-
Usual maintenance dose: 2 to 8 mg daily in 1 to 2 man 2017)
divided doses (Brodie 1997); do not exceed Seizure disorders:
20 mg/day. Infants and Children <10 years or ≤30 kg: Oral:
Bipolar disorder, mixed or manic episodes (off- Initial: 0.01 to 0.03 mg/kg/day in 2 to 3 divided
label use): Oral: 2 to 8 mg daily, in 2 to 4 divided doses; maximum initial daily dose: 0.05 mg/kg/
doses; total daily doses as high as 16 mg have been day; increase by ≤0.25 to 0.5 mg every third day
342
CLONAZEPAM
until seizures are controlled or adverse effects disorder or psychiatric/personality disorders (Mancuso
observed 2004). Clonazepam may cause respiratory depression
Maintenance dose: 0.1 to 0.2 mg/kg/day in 3 and may produce an increase in salivation; use with
divided doses; maximum daily dose: caution in patients with compromised respiratory func-
0.2 mg/kg/day tion (eg, chronic obstructive pulmonary disease, sleep
Children ≥10 years or >30 kg and Adolescents: apnea) and in patients who have difficulty handling
Oral: secretions. May be used in patients with open angle
Initial: 0.01 to 0.05 mg/kg/day in 2 or 3 divided glaucoma who are receiving appropriate therapy; con-
doses; maximum initial dose: 0.5 mg/dose 3 traindicated in acute narrow angle glaucoma. Use with
times daily; may increase dose by 25% or by caution in patients with a history of drug abuse or acute
0.5 to 1 mg every 3 to 7 days until seizures are alcoholism; potential for drug dependency exists. Toler-
controlled or adverse effects observed (Klieg- ance, psychological and physical dependence may
man 2017) occur with prolonged use. Use with caution in patients
Maintenance dose range: 0.05 to 0.2 mg/kg/day in with hepatic impairment; accumulation likely to occur.
2 to 3 divided doses; maximum daily dose: Contraindicated in patients with significant hepatic
20 mg/day (Kliegman 2017) impairment. Use with caution in patients with renal
Panic disorder: Adolescents ≥18 years: Oral: Initial: impairment; clonazepam metabolites are renally elimi-
0.25 mg twice daily; increase in increments of nated. Use with caution in debilitated patients. Elderly
0.125 to 0.25 mg twice daily every 3 days; target patients may be at an increased risk of death with use;
dose: 1 mg/day in divided doses; some patients risk has been found highest within the first 4 months of
may require higher doses up to a maximum daily use in elderly dementia patients (Jennum 2015; Saar-
dose: 4 mg/day. To discontinue, treatment should elainen 2018). Use with extreme caution in patients who
be withdrawn gradually; decrease dose by are at risk of falls; benzodiazepines have been asso-
0.125 mg twice daily every 3 days until medication ciated with falls and traumatic injury (Nelson 1999). Use
is completely withdrawn. with caution in patients with porphyria; may have a
Renal Impairment: Pediatric There are no dosage porphyrogenic effect. Hazardous sleep-related activities
adjustments provided in the manufacturer’s labeling; such as sleep-driving, cooking and eating food, and
use with caution. Clonazepam metabolites may accu- making phone calls while asleep have been noted with
mulate in patients with renal impairment. benzodiazepines (Dolder 2008).
Does not have analgesic, antidepressant, or antipsy-
chotic properties. Worsening of seizures may occur
ing; use with caution. Clonazepam undergoes hepatic
when added to patients with multiple seizure types.
metabolism. Contraindicated in patients with signifi-
Loss of anticonvulsant activity may occur (typically
cant hepatic impairment.
within 3 months of initiation); dose adjustment may be
Mechanism of Action The exact mechanism is
necessary. Periodically reevaluate the long-term useful-
unknown, but believed to be related to its ability to
ness of clonazepam for the individual patient. Clonaze-
enhance the activity of GABA; suppresses the spike-
pam is a long half-life benzodiazepine. Duration of
and-wave discharge in absence seizures by depressing
action after a single dose is determined by redistribution
nerve transmission in the motor cortex.
rather than metabolism. Tolerance develops to the
Contraindications anticonvulsant effects. It does not develop to the anx-
Hypersensitivity to clonazepam, other benzodiaze- iolytic effects (Vinkers 2012). Chronic use of this agent
pines, or any component of the formulation; significant may increase the perioperative benzodiazepine dose
liver disease; acute narrow-angle glaucoma needed to achieve desired effect. Rebound or with-
Canadian labeling: Additional contraindications (not in drawal symptoms may occur following abrupt discontin-
US labeling): Severe respiratory insufficiency; sleep
uation or large decreases in dose. Use caution when
apnea syndrome; myasthenia gravis
reducing dose or withdrawing therapy; decrease slowly
Warnings/Precautions Pooled analysis of trials and monitor for withdrawal symptoms. Flumazenil may
involving various antiepileptics (regardless of indication) cause withdrawal in patients receiving long-term ben-
showed an increased risk of suicidal thoughts/behavior zodiazepine therapy (Brogden 1988). Potentially signifi-
(incidence rate: 0.43% treated patients compared to cant drug-drug interactions may exist, requiring dose or
0.24% of patients receiving placebo); risk observed as frequency adjustment, additional monitoring, and/or
early as 1 week after initiation and continued through selection of alternative therapy. [US Boxed Warning]:
duration of trials (most trials ≤24 weeks). Monitor all Concomitant use of benzodiazepines and opioids
patients for notable changes in behavior that might may result in profound sedation, respiratory
indicate suicidal thoughts or depression; notify health depression, coma, and death. Reserve concomitant
care provider immediately if symptoms occur. Use prescribing of these drugs for use in patients for
caution in patients with depression, particularly if suici- whom alternative treatment options are inadequate.
dal risk may be present. Limit dosages to the minimum required. Follow
Benzodiazepines have been associated with anterog- patients for signs and symptoms of respiratory
rade amnesia (Nelson 1999). May cause CNS depres- depression and sedation.
sion, which may impair physical or mental abilities; Drug Interactions
patients must be cautioned about performing tasks Metabolism/Transport Effects Substrate of
which require mental alertness (eg, operating machi- CYP3A4 (major); Note: Assignment of Major/Minor
nery or driving); increased risk may occur with the use substrate status based on clinically relevant drug
of multiple anticonvulsants. Paradoxical reactions, interaction potential
including hyperactive or aggressive behavior, have Avoid Concomitant Use
been reported with benzodiazepines; risk may be Avoid concomitant use of ClonazePAM with any of the
increased in adolescent/pediatric patients, geriatric following: Azelastine (Nasal); Bromperidol; Conivap-
patients, or patients with a history of alcohol use tan; Fusidic Acid (Systemic); Idelalisib; OLANZapine;
343
CLONAZEPAM
Orphenadrine; Oxomemazine; Paraldehyde; Sodium i n f o r m a t i o n i s a v a i l a b l e a t w w w.aed-

Oxybate; Thalidomide pregnancyregistry.org.
Increased Effect/Toxicity Breastfeeding Considerations Clonazepam is
ClonazePAM may increase the levels/effects of: Alco-
present in breast milk.
hol (Ethyl); Azelastine (Nasal); Blonanserin; Brexano-
lone; Buprenorphine; CloZAPine; CNS Depressants; The relative infant dose (RID) of clonazepam is 2.8%
Flunitrazepam; HYDROcodone; Methadone; Methotri- when calculated using the highest breast milk concen-
meprazine; MetyroSINE; Mirtazapine; Opioid Ago- tration from a case report and compared to a weight-
nists; Orphenadrine; OxyCODONE; Paraldehyde;
adjusted maternal dose of 4 mg/day.
Piribedil; Pramipexole; ROPINIRole; Rotigotine;
Selective Serotonin Reuptake Inhibitors; Sodium Oxy- In general, breastfeeding is considered acceptable
bate; Suvorexant; Thalidomide; Zolpidem when an RID of a medication is <10% (Anderson
The levels/effects of ClonazePAM may be increased 2016; Ito 2000). However, some sources note breast-
by: Alizapride; Aprepitant; Brimonidine (Topical); Bro- feeding should only be considered if the RID is <5% for
mopride; Bromperidol; Cannabidiol; Cannabis; Chlor- psychotropic agents (Larsen 2015).
methiazole; Chlorphenesin Carbamate; Clofazimine;
Cobicistat; Conivaptan; Cosyntropin; CYP3A4 Inhib- The RID of clonazepam was calculated using a milk
itors (Moderate); CYP3A4 Inhibitors (Strong); Dime- concentration of 0.0107 mcg/mL, providing an esti-
thindene (Topical); Doxylamine; Dronabinol; mated daily infant dose via breast milk of 1.6 mcg/kg/
Droperidol; Duvelisib; Esketamine; Fosaprepitant;
day. This milk concentration was obtained following
Fosnetupitant; Fusidic Acid (Systemic); HydrOXYzine;
Idelalisib; Kava Kava; Larotrectinib; Lofexidine; Mag- maternal administration of clonazepam 2 mg twice daily
nesium Sulfate; Melatonin; Methotrimeprazine; MiFE- during pregnancy and after delivery; milk samples were
PRIStone; Minocycline; Nabilone; Netupitant; obtained on days 2 to 4 postpartum (Söderman 1988).
OLANZapine; Oxomemazine; Palbociclib; Perampa- Slightly higher milk concentrations (0.013 mcg/mL)
nel; Rufinamide; Simeprevir; Stiripentol; Tapentadol; were noted in a second report. The mother was taking
Teduglutide; Tetrahydrocannabinol; Tetrahydrocanna- clonazepam throughout pregnancy (dose not specified);
binol and Cannabidiol; Trimeprazine; Vigabatrin
milk sampling began 72 hours after delivery (Fisher
Decreased Effect
The levels/effects of ClonazePAM may be decreased 1985). Clonazepam was detected in the serum of the
by: Bosentan; CYP3A4 Inducers (Moderate); CYP3A4 breastfeeding infants (Fisher 1985; Söderman 1988)
Inducers (Strong); Dabrafenib; Deferasirox; Enzaluta- and concentrations may have been influenced not only
mide; Fosphenytoin; Ivosidenib; Lorlatinib; Mitotane; by breast milk but also by in utero exposure.
Phenytoin; Pitolisant; Sarilumab; Siltuximab; St John's
Wort; Theophylline Derivatives; Tocilizumab; Yohim- Apnea, CNS depression, hypotonia, and somnolence
bine have been reported in infants exposed to clonazepam
Pharmacodynamics/Kinetics via breast milk (Fisher 1985; Kelly 2012; Soussan
Onset of Action ~20 to 40 minutes (Hanson 1972) 2014). In a review of females taking various doses of
Duration of Action Infants and young children: 6 to 8 clonazepam (range: 0.5 to 2 mg/day) during pregnancy
hours (Hanson 1972); Adults: ≤12 hours (Hanson and postpartum (n=10) or only postpartum (n=1), clo-
1972)
nazepam was measurable in the serum of two infants;
Half-life Elimination Children: 22 to 33 hours (Wal-
son 1996); Adults: 17 to 60 hours (Walson 1996) however, adverse events were not reported (Birn-
Time to Peak Serum: 1 to 4 hours baum 1999).
Pregnancy Considerations Clonazepam crosses the Clonazepam has a long half-life and may accumulate in
placenta. Teratogenic effects have been observed with
the breastfed infant, especially preterm infants or those
some benzodiazepines; however, additional studies are
needed. The incidence of premature birth and low birth exposed to chronic maternal doses (Davanzo 2013). A
weights may be increased following maternal use of single maternal dose may be compatible with breast-
benzodiazepines; hypoglycemia and respiratory prob- feeding (WHO 2002). If chronic use of a benzodiaze-
lems in the neonate may occur following exposure late pine is needed in breastfeeding females, use of shorter
in pregnancy. Neonatal withdrawal symptoms may acting agents is preferred (Davanzo 2013; Veiby 2015;
occur within days to weeks after birth and "floppy infant WHO 2002). Infants of females using medications for
syndrome" (which also includes withdrawal symptoms)
seizure disorders should be monitored for drowsiness,
has been reported with some benzodiazepines, includ-
ing clonazepam (Bergman 1992; Iqbal 2002; Wikner decreased feeding, and poor weight gain (Veiby 2015).
2007). A combination of factors influences the potential According to the manufacturer, the decision to breast-
teratogenicity of anticonvulsant therapy. When treating feed during therapy should consider the risk of infant
pregnant females with epilepsy, monotherapy with the exposure, the benefits of breastfeeding to the infant,
lowest effective dose and avoidance medications and benefits of treatment to the mother.
known to have a high incidence of teratogenic effects
Controlled Substance C-IV
is recommended (Harden 2009; Wlodarczyk 2012).
When treating pregnant females with panic disorder, Dosage Forms: US
psychosocial interventions should be considered prior Tablet, Oral:
to pharmacotherapy (APA 2009). KlonoPIN: 0.5 mg, 1 mg, 2 mg
Patients exposed to clonazepam during pregnancy are Generic: 0.5 mg, 1 mg, 2 mg
encouraged to enroll themselves into the AED Preg- Tablet Disintegrating, Oral:
nancy Registry by calling 1-888-233-2334. Additional Generic: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg
344
CLONIDINE
(transdermal 1%), withdrawal syndrome (1%),

CloNIDine (KLON i deen) aggressive behavior, agitation, anxiety, behavioral
changes, delirium, delusions, hallucination (visual
Related Information and auditory), malaise, numbness (localized; trans-
Cardiovascular Diseases on page 1442 dermal), paresthesia, parotid pain (oral), restless-
Dentin Hypersensitivity, Acid Erosion, High Caries ness, vivid dream
Index, Management of Alveolar Osteitis, and Xerosto- Dermatologic: Localized vesiculation (transdermal
mia on page 1548 7%), allergic contact sensitivity (transdermal 5%),
Brand Names: US Catapres; Catapres-TTS-1; Cata- hyperpigmentation (transdermal 5%), burning sensa-
pres-TTS-2; Catapres-TTS-3; Duraclon; Kapvay tion of skin (transdermal 3%), excoriation (transder-
Brand Names: Canada Catapres; Dixarit mal 3%), macular eruption (1%), papule (transdermal
Pharmacologic Category Alpha2-Adrenergic Agonist; 1%), alopecia, hypopigmentation (localized; trans-
Antihypertensive dermal), pallor, skin rash, urticaria
Use Endocrine & metabolic: Gynecomastia (1%), weight
Attention-deficit/hyperactivity disorder (extended- gain (<1%), decreased libido, hyperglycemia (tran-
release tablet): Treatment of attention-deficit/hyper- sient; oral), increased thirst
activity disorder (ADHD) (monotherapy or as adjunc- Gastrointestinal: Constipation (1% to 10%), viral gas-
tive therapy) trointestinal infection (5%), anorexia (1%), abdominal
Hypertension (immediate-release tablet and trans- pain (oral), diarrhea, gastrointestinal pseudo-
dermal patch): Management of hypertension. Note: obstruction (oral), nausea, parotitis (oral), sore
Not recommended for the initial treatment of hyper- throat, vomiting
tension (ACC/AHA [Whelton 2017]). Clonidine should Genitourinary: Urinary incontinence (4%), sexual dis-
be avoided for the treatment of hypertension in order (3%), erectile dysfunction (2% to 3%), nocturia
patients with heart failure with reduced ejection frac- (1%), pollakiuria, urinary retention
tion (HFrEF) of ischemic origin (AHA/ACC/ASH [Rose- Hematologic & oncologic: Thrombocytopenia (oral)
ndorff 2015]). Hepatic: Abnormal hepatic function tests (mild transi-
Pain management (epidural): Continuous epidural ent abnormalities; <1%), hepatitis
administration as adjunctive therapy with opioids for Hypersensitivity: Angioedema
treatment of severe cancer pain in patients tolerant to Neuromuscular & skeletal: Weakness (10%), tremor
or unresponsive to opioids alone; epidural clonidine is (1% to 4%), arthralgia (1%), myalgia (1%), leg
generally more effective for neuropathic pain and less cramps (<1%), increased creatine phosphokinase
effective (or possibly ineffective) for somatic or vis- (transient; oral), limb pain
ceral pain. Ophthalmic: Accommodation disturbance, blurred
Local Anesthetic/Vasoconstrictor Precautions vision, burning sensation of eyes, decreased lacri-
No information available to require special precautions mation, dry eye syndrome, increased lacrimation
Effects on Dental Treatment Key adverse event(s) Otic: Otitis media (≤3%), otalgia
related to dental treatment: Significant xerostomia (nor- Respiratory: Asthma, dry nose, epistaxis, flu-like
mal salivary flow resumes upon discontinuation) and symptoms, nasal congestion, nasopharyngitis, respi-
abnormal taste; Patients may experience orthostatic ratory tract infection, rhinorrhea
hypotension as they stand up after treatment; especially Miscellaneous: Crying (1% to 3%), fever
if lying in dental chair for extended periods of time. Use Epidural: Note: The following adverse events occurred
caution with sudden changes in position during and more often than placebo in cancer patients with
after dental treatment. intractable pain being treated with concurrent epidural
Effects on Bleeding No information available to morphine.
require special precautions >10%:
Adverse Reactions Frequency not always defined. Cardiovascular: Hypotension (45%), orthostatic hypo-
Oral, Transdermal: Incidence of adverse events may tension (32%)
be less with transdermal compared to oral due to the Central nervous system: Confusion (13%), dizzi-
lower peak/trough ratio. ness (13%)
>10%: Gastrointestinal: Xerostomia (13%)
Central nervous system: Drowsiness (2% to 38%), 1% to 10%:
headache (1% to 29%), fatigue (4% to 16%), dizzi- Cardiovascular: Chest pain (5%)
ness (2% to 16%) Central nervous system: Hallucination (5%)
Dermatologic: Transient skin rash (localized; charac- Dermatologic: Diaphoresis (5%)
terized by pruritus and erythema; transdermal 15% Gastrointestinal: Nausea and vomiting (8%)
to 50%), contact dermatitis (transdermal 8% to 34%) Otic: Tinnitus (5%)
Gastrointestinal: Xerostomia (≤40%), upper abdomi- Mechanism of Action Stimulates alpha2-adrenocep-
nal pain (15%) tors in the brain stem, thus activating an inhibitory
1% to 10%: neuron, resulting in reduced sympathetic outflow from
Cardiovascular: Bradycardia (≤4%), edema (3%), the CNS, producing a decrease in peripheral resist-
localized blanching (transdermal 1%), palpitations ance, renal vascular resistance, heart rate, and blood
(1%), tachycardia (≤3%), atrioventricular block, car- pressure; epidural clonidine may produce pain relief at
diac arrhythmia, cardiac failure, cerebrovascular spinal presynaptic and postjunctional alpha2-adreno-
accident, chest pain, ECG abnormality, flushing, ceptors by preventing pain signal transmission; pain
orthostatic hypotension, prolonged Q-T Interval on relief occurs only for the body regions innervated by
ECG, Raynaud's phenomenon, syncope the spinal segments where analgesic concentrations of
Central nervous system: Sedation (3% to 10%), irrita- clonidine exist. For the treatment of ADHD, the mech-
bility (5% to 9%), nightmares (4% to 9%), insomnia anism of action is unknown; it has been proposed that
(≤6%), emotional disturbance (4%), lethargy (3%), postsynaptic alpha2-agonist stimulation regulates sub-
nervousness (1% to 3%), depression (1%), throbbing cortical activity in the prefrontal cortex, the area of the
345
CLONIDINE
brain responsible for emotions, attentions, and behav- Use

iors and causes reduced hyperactivity, impulsiveness, Acute coronary syndrome:
and distractibility. Epidurally administered clonidine pro- Acute ST-segment elevation myocardial infarc-
duces dose-dependent analgesia not antagonized by tion: To reduce the rate of myocardial infarction
opiate antagonists. The analgesia is limited to the body and stroke in conjunction with aspirin in patients with
regions innervated by the spinal segments where anal- acute ST-elevation MI (STEMI) who are to be man-
gesic concentrations of clonidine are present. Clonidine aged medically.
is thought to produce analgesia at presynaptic and Unstable angina/non-ST-segment elevation myo-
postjunctional alpha-2-adrenoceptors in the spinal cord cardial infarction: To decrease the rate of MI and
by preventing pain signal transmission to the brain. stroke in conjunction with aspirin in patients with non-
Pharmacodynamics/Kinetics ST-segment elevation acute coronary syndrome
Onset of Action (unstable angina/non-ST-elevation myocardial
Antihypertensive effect: Oral: Immediate release: 0.5 infarction [UA/NSTEMI]), including patients who are
to 1 hour (maximum reduction in blood pressure: 2 to to be managed medically and those who are to be
4 hours); Transdermal: Initial application: 2 to 3 days; managed with coronary revascularization.
Transdermal: Steady state reached in ~3 days Recent myocardial infarction, recent stroke, or
Attention-deficit/hyperactivity disorder: Oral: Extended established peripheral arterial disease: To reduce
release (Kapvay): Onset of action: 1 to 2 weeks (AAP the rate of MI and stroke in patients with a history of
[Wolraich] 2011) recent MI, recent stroke, or established peripheral
Half-life Elimination arterial disease.
Children: 6.13 ± 1.33 hours (Lonnqvist 1993) Local Anesthetic/Vasoconstrictor Precautions
Adults: Normal renal function: 12 to 16 hours; Renal No information available to require special precautions
impairment: ≤41 hours Effects on Dental Treatment Aspirin in combination
Epidural administration: CSF half-life elimination: 1.3 with clopidogrel (Plavix®), prasugrel (Effient®), or tica-
± 0.5 hours; plasma half-life elimination: 22 ± 15 grelor (Brilinta™) is the primary prevention strategy
hours against stent thrombosis after placement of drug-eluting
Transdermal: Half-life elimination (after patch metal stents in coronary patients. Premature discontin-
uation of combination antiplatelet therapy (ie, dual anti-
removal): ~20 hours (due to skin depot effect;
platelet therapy) strongly increases the risk of a
increase in plasma clonidine concentrations may
catastrophic event of stent thrombosis leading to myo-
occur after patch removal [MacGregor 1985])
cardial infarction and/or death, so says a science
Time to Peak Plasma: Oral: Immediate release: 1 to 3 advisory issued in January 2007 from the American
hours; Extended release (Kapvay): 7 to 8 hours Heart Association in collaboration with the American
Pregnancy Considerations Clonidine crosses the Dental Association and other professional healthcare
placenta; concentrations in the umbilical cord plasma organizations. The advisory stresses a 12-month ther-
are similar to those in the maternal serum and concen- apy of dual antiplatelet therapy after placement of a
trations in the amniotic fluid may be 4 times those in the drug-eluting stent in order to prevent thrombosis at the
maternal serum. stent site. Any elective surgery should be postponed for
The pharmacokinetics of clonidine may be altered dur- 1 year after stent implantation, and if surgery must be
ing pregnancy due to an increase in nonrenal clearance performed, consideration should be given to continuing
(Buchanan 2009; Claessens 2010). Untreated chronic the antiplatelet therapy during the perioperative period
maternal hypertension is associated with adverse in high-risk patients with drug-eluting stents.
events in the fetus, infant, and mother. If treatment for This advisory was issued from a science panel made up
chronic or acute hypertension during pregnancy is of representatives from the American Heart Associa-
needed, other agents are preferred (ACOG 2013); use tion (AHA), the American College of Cardiology, the
Society for Cardiovascular Angiography and Interven-
may be considered as an alternative agent for severe
tions, the American College of Surgeons, the Ameri-
hypertension (Magee 2014).
can Dental Association (ADA), and the American
[US Boxed Warning]: Epidural clonidine is not rec- College of Physicians (Grines, 2007).
ommended for obstetrical or postpartum pain due Effects on Bleeding Clopidogrel irreversibly inhibits
to risk of hemodynamic instability. However, in a platelet aggregation which persists for the life of the
rare obstetrical, or postpartum patient, potential platelet (7-10 days) and until new platelets are
benefits may outweigh the possible risks. Clonidine released. Clopidogrel should not be discontinued in
has been evaluated for use as an adjunctive agent for patients with cardiac stents that have not completed
epidural labor analgesia (Kumari 2018; Landau 2002; their full course of dual antiplatelet therapy (eg, aspirin
Roelants 2015; Zhang 2015) including patients who are and clopidogrel [prasugrel or ticagrelor]); patient-spe-
opioid dependent (Hoyt 2018). cific situations need to be discussed with cardiologist. If
normal platelet function is desired, clopidogrel should
be discontinued for at least 5 days. A medical consult is
Clopidogrel (kloh PID oh grel) recommended to determine the benefit:risk of continu-
ing or discontinuing clopidogrel therapy for invasive
Related Information
dental procedures.
Adverse Reactions As with all drugs that may affect
tistry on page 1454
hemostasis, bleeding is associated with clopidogrel.
Cardiovascular Diseases on page 1442 Hemorrhage may occur at virtually any site. Risk is
Brand Names: US Plavix dependent on multiple variables, including the concur-
Brand Names: Canada Plavix rent use of multiple agents that alter hemostasis and
Generic Availability (US) Yes patient susceptibility.
Pharmacologic Category Antiplatelet Agent; Antipla- 1% to 10%:
telet Agent, Thienopyridine Gastrointestinal: Gastrointestinal hemorrhage (2%)
346
CLOPIDOGREL
Hematologic & oncologic: Minor hemorrhage (4% to Higher versus standard maintenance dosing: May
5%), major hemorrhage (1% to 4%) consider a maintenance dose of 150 mg once
Frequency not defined: daily for 6 days, then 75 mg once daily thereafter
Hematologic & oncologic: Hematoma in patients not at high risk for bleeding (CUR-
Respiratory: Epistaxis RENT-OASIS 7 Investigators 2010); however, in
<1%, postmarketing, and/or case reports: Abnormal another study, in patients with high on-treatment
hepatic function tests, acute generalized exanthema- platelet reactivity, the use of 150 mg once daily for
tous pustulosis, acute hepatic failure, ageusia, agra- 6 months did not demonstrate a difference in 6-
nulocytosis, anaphylactoid reaction, angioedema, month incidence of death from cardiovascular
aplastic anemia, arthralgia, arthritis, bronchospasm, causes, nonfatal MI, or stent thrombosis com-
bullous rash, colitis (including ulcerative or lympho- pared to standard dose therapy (Price 2011).
cytic), confusion, diarrhea, DRESS syndrome, drug- Duration of clopidogrel (in combination with aspirin)
induced hypersensitivity, duodenal ulcer, eczema, after stent placement for ACS: Premature inter-
eosinophilic pneumonitis, erythema multiforme, eryth- ruption of therapy may result in stent throm-
ematous rash, exfoliative dermatitis, fever, gastric bosis with subsequent fatal and nonfatal MI.
ulcer, hallucination, headache, hemophilia A According to the ACC/AHA Duration of Dual Anti-
(acquired), hepatitis (noninfectious), hypersensitivity platelet Therapy (DAPT) guidelines, at least 12
reaction, hypotension, increased serum creatinine, months of a P2Y12 inhibitor (eg, clopidogrel) is
interstitial pneumonitis, intracranial hemorrhage, recommended for those with ACS receiving either
lichen planus, maculopapular rash, myalgia, pancrea- stent type (bare metal [BMS] or drug eluting stent
titis, pancytopenia, pruritus, serum sickness, Stevens- [DES]). The DAPT score may be useful in deter-
Johnson syndrome, stomatitis, taste disorder, throm- mining whether to prolong or extend DAPT in
botic thrombocytopenic purpura, toxic epidermal nec- patients with stent placement (Yeh 2016). In
rolysis, urticaria, vasculitis patients with DES placement with a high risk of
Dosing bleeding or significant overt bleeding on DAPT, it
Adult & Geriatric may be reasonable to discontinue clopidogrel
Acute coronary syndrome (ACS): Oral: after 6 months of therapy (ACC/AHA [Lev-
Unstable angina, non-ST-segment elevation myocar- ine 2016]).
dial infarction (UA/NSTEMI) (also referred to as CYP2C19 poor metabolizers (ie, CYP2C19*2 or *3
NSTE-ACS): Initial: 300 mg or 600 mg loading carriers): Although routine genetic testing is not
dose, followed by 75 mg once daily for up to 12 recommended in patients treated with clopidogrel
months in combination with aspirin, followed by undergoing PCI, testing may be considered to
aspirin indefinitely (ACC/AHA [Amsterdam 2014]). identify poor metabolizers who would be at risk for
Note: If patient is to undergo PCI, see Percuta- poor outcomes while receiving clopidogrel; if iden-
neous coronary intervention (PCI) for acute coro- tified, these patients may be considered for an
nary syndrome dosing. alternative P2Y12 inhibitor (Levine 2011). An appro-
ST-segment elevation myocardial infarction (STEMI) priate regimen for this patient population has not
receiving fibrinolytic therapy (in combination with been established in clinical outcome trials. Although
aspirin and appropriate anticoagulant) (ACCF/ a 600 mg loading dose, followed by 150 mg once
AHA [O'Gara 2013]): Note: If patient is to undergo daily produced greater active metabolite exposure
primary PCI, see Percutaneous coronary interven- and antiplatelet response compared to the 300 mg/
tion (PCI) for acute coronary syndrome dosing. 75 mg regimen, it does not appear that this dosing
Age ≤75 years: Loading dose of 300 mg followed strategy improves outcomes for this patient popu-
by 75 mg once daily for at least 14 days up to 1 lation (Price 2011; Simon 2011).
year (in the absence of bleeding). Carotid artery stenosis, symptomatic (including
Age >75 years: 75 mg once daily (no loading dose) recent carotid endarterectomy) (off-label use):
for at least 14 days up to 1 year (in the absence of Oral: 75 mg once daily (ACCP [Guyatt 2012])
bleeding). Coronary artery bypass graft surgery (secondary
Percutaneous coronary intervention (PCI) for acute prevention) (off-label use) (AHA [Kulik 2015]):
coronary syndrome (eg, NSTE-ACS or STEMI) (off- Following off-pump CABG: 75 mg once daily (in
label use): 600 mg (loading dose) given as early as combination with aspirin) for 1 year
possible before or at the time of PCI, followed by Aspirin-allergic or -intolerant patients: 75 mg once
75 mg once daily (in combination with aspirin) for at daily; continue indefinitely
least 12 months (bare metal or drug-eluting stent) Coronary artery disease (CAD), established (off-
(ACC/AHA [Amsterdam 2014]); ACC/AHA [Levine label use): Oral: 75 mg once daily. Note: Estab-
2016]; ACCF/AHA/SCAI [Levine 2011]; ACCF/AHA lished CAD defined as patients 1-year post ACS,
[O'Gara 2013]). with prior revascularization, coronary stenosis
PCI after fibrinolytic therapy (ACCF/AHA [O'Gara >50% by angiogram, and/or evidence for cardiac
2013]): ischemia on diagnostic testing (includes patients
Fibrinolytic administered with a loading dose of after the first year post-ACS and/or with prior CABG
clopidogrel: Continue 75 mg once daily and do surgery) (ACCP [Guyatt 2012]).
not administer an additional loading dose. Percutaneous coronary intervention (PCI), non-
Fibrinolytic administered within previous 24 hours acute coronary syndrome (ie, stable ischemic
without a loading dose of clopidogrel: Adminis- heart disease) (off-label use): 600 mg (loading
ter 300 mg loading dose before or at the time dose) given as early as possible before or at the
of PCI. time of PCI, followed by 75 mg once daily (in combi-
Fibrinolytic administered more than 24 hours ago nation with aspirin) for at least 1 month (bare metal
without a loading dose of clopidogrel: Administer stent) or for at least 6 months (drug-eluting stent)
600 mg loading dose before or at the time (ACC/AHA [Levine 2016]; ACCF/AHA/SCAI [Lev-
of PCI. ine 2011]).
347
CLOPIDOGREL
Duration of clopidogrel (in combination with aspirin) Renal Impairment: Adult

after stent placement for stable ischemic heart No dosage adjustment necessary (Basra 2011). Note:
disease (SIHD): Premature interruption of ther- GFR stage 5 (ie, ESRD or an eGFR <15 mL/minute)
apy may result in stent thrombosis with subse- is associated with higher residual platelet reactivity
quent fatal and nonfatal MI. According to the with maintenance dosing (Muller 2012).
ACC/AHA Duration of Dual Antiplatelet Therapy Hemodialysis: Not dialyzable (NCS/SCCM [Fron-
(DAPT) guidelines, those receiving a newer gen- tera 2016])
eration DES, at least 6 months of clopidogrel Hepatic Impairment: Adult No dosage adjustment
therapy is recommended. Those receiving a BMS necessary.
should be given clopidogrel for a minimum of 1 Pediatric
month. The DAPT score may be useful in determin- Antiplatelet effect: Limited data available:
ing whether to prolong or extend DAPT in patients Infants and Children ≤24 months: In the PICOLO
with stent placement (Yeh 2016). In patients with trial, a dose of 0.2 mg/kg/dose once daily was
DES placement with a high risk of bleeding or found to achieve a mean inhibition of platelet
significant overt bleeding on DAPT, it may be rea- aggregation similar to adults receiving the recom-
sonable to discontinue clopidogrel after 3 months of mended dose; Note: This study included pediatric
therapy (ACC/AHA [Levine 2016]). patients with a systemic-to-pulmonary artery shunt,
Peripheral artery percutaneous transluminal intracardiac or intravascular stent, Kawasaki dis-
angioplasty (with or without stenting) or periph- ease, or arterial graft; 79% of patients received
eral artery bypass graft surgery, postprocedure concomitant aspirin (Li 2008).
(off-label use): Oral: 75 mg once daily. Note: For Children >2 years and Adolescents: Initial dose:
below-knee bypass graft surgery with prosthetic 1 mg/kg once daily; titrate to response; in general,
grafts, combine with aspirin 75 to 100 mg/day do not exceed adult dose (Finkelstein 2005;
(ACCP [Guyatt 2012]). Soman 2006).
Recent MI, recent stroke, or established peripheral CYP2C19 poor metabolizers (ie, CYP2C19*2 or *3
arterial disease (PAD): Oral: 75 mg once daily. carriers): Specific pediatric recommendations are
Guideline recommendations regarding concomitant lacking; based on experience in adult patients, rou-
therapy and durations of therapy (off-label): tine genetic testing is not recommended in patients
Minor ischemic stroke or TIA, secondary preven- treated with clopidogrel undergoing PCI, testing may
tion: The combination of clopidogrel and aspirin be considered to identify poor metabolizers who
might be considered within 24 hours of a minor would be at risk for poor outcomes while receiving
ischemic stroke or TIA and continued for 21 days clopidogrel; if identified, these patients may be con-
(AHA/ASA [Kernan 2014]). sidered for an alternative P2Y12 inhibitor (Lev-
Intracranial atherosclerosis (70% to 99% stenosis ine 2011).
of a major intracranial artery), secondary preven- Renal Impairment: Pediatric No dosage adjustment
tion: The combination of clopidogrel and aspirin is required; use with caution; experience in pediatric
for 90 days is recommended in patients with patients is limited; in adults, GFR stage 5 (ie, ESRD or
recent stroke/TIA (within 30 days) due to severe an eGFR <15 mL/minute) is associated with higher
stenosis [70% to 99%]) (AHA/ASA [Ker- residual platelet reactivity with maintenance dosing
nan 2014]). (Muller 2012).
PAD: Clopidogrel is recommended as an alternative Hepatic Impairment: Pediatric There are no spe-
to aspirin or in conjunction with aspirin for those cific recommendations in pediatric patients; in adults,
who are not at an increased risk of bleeding but no dosage adjustment is necessary.
are of high cardiovascular risk. These recommen- Mechanism of Action Clopidogrel requires in vivo
dations also pertain to those with intermittent biotransformation to an active thiol metabolite. The
claudication or critical limb ischemia, prior lower active metabolite irreversibly blocks the P2Y12 compo-
extremity revascularization, or prior amputation for nent of ADP receptors on the platelet surface, which
lower extremity ischemia (ACCF/AHA prevents activation of the GPIIb/IIIa receptor complex,
[Rooke 2011]). thereby reducing platelet aggregation. Platelets blocked
Secondary prevention of cardiovascular disease by clopidogrel are affected for the remainder of their
(patients with diabetes and an aspirin allergy) lifespan (~7 to 10 days).
(off-label use): Oral: 75 mg once daily (ADA 2019) Contraindications
Transcatheter aortic valve replacement (TAVR) Hypersensitivity (eg, anaphylaxis) to clopidogrel or any
(thromboprophylaxis) (off-label use): Oral: component of the formulation; active pathological
Pre-procedure: bleeding (eg, peptic ulcer, intracranial hemorrhage).
Clopidogrel naive: 300 mg on the day of procedure. Canadian labeling: Additional contraindications (not in
Clopidogrel experienced: Continue clopidogrel US labeling): Significant liver impairment or cholestatic
75 mg once daily prior to procedure (Kalich 2018). jaundice; concomitant use of repaglinide.
Post-procedure: Warnings/Precautions [US Boxed Warning]: Effec-
Not on anticoagulation post-procedure: 75 mg once tiveness of clopidogrel results from its antiplatelet
daily for 3 to 6 months depending on valve type activity, which is dependent on its conversion to an
and patient-specific risks of bleeding or thrombo- active metabolite by the CYP-450 system, princi-
sis plus life-long aspirin (Otto 2017). pally CYP2C19. In patients who are homozygous
On anticoagulation post-procedure: Practice varies for nonfunctional alleles of the CYP2C19 genes
and local protocols should be established. It may (termed "CYP2C19 poor metabolizers"), clopidogrel
be reasonable to use anticoagulation (warfarin or at recommended doses forms less of the active
a non-warfarin oral anticoagulant) plus life-long metabolite and has a reduced effect on platelet
aspirin or clopidogrel 75 mg once daily for 3 to 6 activity. Tests are available to identify patients
months followed by life-long aspirin (eg, not dual who are CYP2C19 poor metabolizers. Consider
antiplatelet therapy) (Kalich 2018). use of another platelet P2Y12 inhibitor in patients
348
CLOPIDOGREL
identified as CYP2C19 poor metabolizers. Genetic clopidogrel (eg, toxic epidermal necrolysis, exfoliative
testing may be considered prior to initiating clopidogrel dermatitis, Stevens-Johnson syndrome, TTP)
in patients at moderate or high risk for poor outcomes (Lokhandwala 2011). Use with caution in patients with
(eg, PCI in patients with extensive and/or very complex moderate to severe renal impairment (experience is
disease). The optimal dose for CYP2C19 poor metab- limited).
olizers has yet to be determined. After initiation of
Clopidogrel increases the risk of bleeding. Use is con-
clopidogrel, functional testing (eg, VerifyNow P2Y12
traindicated in patients with active pathological bleeding
assay) may also be done to determine clopidogrel
(eg, peptic ulcer, intracranial hemorrhage). Additional
responsiveness (Holmes 2010). An individualized and
risk factors for bleeding include age ≥75 years, propen-
multidisciplinary approach should be utilized to deter-
sity to bleed (eg, recent trauma or surgery, recent or
mine therapy discontinuation and management in
recurrent GI bleeding, active peptic ulcer disease,
patients with acute lower GI bleed (LGIB) who are on
severe hepatic impairment), body weight <60 kg, CABG
antiplatelet medications; risk of ongoing bleeding
or other surgical procedure, concomitant use of medi-
should be weighed with risk of thromboembolic events.
cations that increase risk of bleeding (eg, warfarin,
In patients receiving dual antiplatelet therapy (aspirin
NSAIDs). Use with caution in patients with platelet
plus P2Y12 receptor blocker [eg, clopidogrel, prasugrel,
disorders, bleeding disorders and/or at increased risk
ticagrelor, ticlopidine]) or thienopyridine monotherapy,
for bleeding. Bleeding should be suspected if patient
the thienopyridine should generally be resumed as
becomes hypotensive after undergoing recent coronary
soon as possible and at least within 7 days taking into
angiography, PCI, CABG, or other surgical procedure
account control of bleeding and cardiovascular risk
even if overt signs of bleeding do not exist. It may be
(aspirin should not be discontinued); however, dual
possible to restore hemostasis by administering exog-
antiplatelet therapy should not be discontinued in the
enous platelets; however, platelet transfusions within 4
90 days post-acute coronary syndrome or 30 days post-
hours of the loading dose or 2 hours of the maintenance
coronary stenting (Strate 2016).
dose may be less effective. Cases of TTP (usually
In patients with coronary stents, premature interruption occurring within the first 2 weeks of therapy), resulting
of therapy may result in stent thrombosis with subse- in some fatalities, have been reported; urgent plasma-
quent fatal and nonfatal MI. Duration of therapy, in pheresis is required. In patients with recent lacunar
general, is determined by the type of stent placed (bare stroke (within 180 days), the use of clopidogrel in
metal or drug eluting) and whether an ACS event was addition to aspirin did not significantly reduce the inci-
ongoing at the time of placement (ACC/AHA [Levine dence of the primary outcome of stroke recurrence (any
2016]; AHA/ACC/SCAI/ACS/ADA [Grines 2007]). In ischemic stroke or intracranial hemorrhage) compared
patients undergoing elective surgery, consider discon- to aspirin alone; the use of clopidogrel in addition to
tinuing 5 days before surgery (except in patients with aspirin did however increase the risk of major hemor-
cardiac stents that have not completed their full course rhage and the rate of all-cause mortality (SPS3 Inves-
of dual antiplatelet therapy; patient-specific situations tigators 2012). Potentially significant interactions may
need to be discussed with cardiologist; AHA/ACC/SCAI/ exist, requiring dose or frequency adjustment, addi-
ACS/ADA Science Advisory provides recommenda- tional monitoring, and/or selection of alternative
tions) (Grines 2007). Elective noncardiac surgery therapy.
should not be performed in patients in whom dual Drug Interactions
antiplatelet therapy (DAPT) will need to be discontinued Metabolism/Transport Effects Substrate of
perioperatively within 30 days following bare metal stent CYP2C19 (major), CYP3A4 (minor); Note: Assign-
(BMS) placement or within 12 months after drug-eluting ment of Major/Minor substrate status based on clin-
stent (DES) placement. In patients undergoing urgent ically relevant drug interaction potential; Inhibits
non-cardiac surgery during the first 4 to 6 weeks after BCRP/ABCG2, CYP2B6 (weak), CYP2C8 (moderate)
BMS or DES placement, continue DAPT. In patients Avoid Concomitant Use
with stents undergoing surgery that requires discontin- Avoid concomitant use of Clopidogrel with any of the
uation of the P2Y12 inhibitor (eg, clopidogrel), continue following: Amodiaquine; PAZOPanib; Topotecan; Uro-
aspirin and re-start the P2Y12 inhibitor as soon as kinase
possible after surgery (ACC/AHA [Fleisher 2014]). In Increased Effect/Toxicity
patients undergoing elective CABG, discontinue clopi- Clopidogrel may increase the levels/effects of: Agents
dogrel at least 5 days before procedure; when urgent with Antiplatelet Properties; Amodiaquine; Anticoagu-
CABG is necessary, the ACC/AHA CABG guidelines lants; Apixaban; BuPROPion; Cephalothin; Cladribine;
recommend discontinuation for at least 24 hours prior to Collagenase (Systemic); CYP2C8 Substrates (High
surgery (ACC/AHA [Hillis 2011]). The ACC/AHA STEMI risk with Inhibitors); Dabigatran Etexilate; Dasabuvir;
guidelines recommend discontinuation for at least 24 Deoxycholic Acid; Desloratadine; Edoxaban; Ibritumo-
hours prior to on-pump CABG if possible; off-pump mab Tiuxetan; Obinutuzumab; Ombitasvir, Paritapre-
CABG may be performed within 24 hours of clopidogrel v i r, R i t o n a v i r, a n d D a s a b u v i r ; PA C L i t a x e l
administration if the benefits of prompt revascularization (Conventional); PACLitaxel (Protein Bound); PAZOPa-
outweigh the risks of bleeding (ACC/AHA nib; Pioglitazone; Repaglinide; Rivaroxaban; Rosu-
[O'Gara 2013]). vastatin; Salicylates; Selexipag; Talazoparib;
Thrombolytic Agents; Topotecan; Urokinase; Warfarin
Because of structural similarities, cross-reactivity has
been reported among the thienopyridines (clopidogrel, The levels/effects of Clopidogrel may be increased by:
prasugrel, and ticlopidine); use with caution or avoid in CYP2C19 Inducers (Strong); Dasatinib; Fat Emulsion
patients with hypersensitivity or hematologic reactions (Fish Oil Based); FluvoxaMINE; Glucosamine; Herbs
to previous thienopyridine use. Use of clopidogrel is (Anticoagulant/Antiplatelet Properties); Ibrutinib; Ino-
contraindicated in patients with hypersensitivity to clo- tersen; Limaprost; Multivitamins/Fluoride (with ADE);
pidogrel. Although desensitization may be considered Multivitamins/Minerals (with ADEK, Folate, Iron); Mul-
for mild-to-moderate hypersensitivity, do not desensitize tivitamins/Minerals (with AE, No Iron); Omega-3 Fatty
patients with prior life-threatening allergic reactions to Acids; Pentosan Polysulfate Sodium; Pentoxifylline;
349
CLOPIDOGREL
Prostacyclin Analogues; Tipranavir; Vitamin E (Sys- breastfeeding to the infant, and benefits of treatment
temic) to the mother.
Decreased Effect Dosage Forms: US
The levels/effects of Clopidogrel may be decreased Tablet, Oral:
by: Amiodarone; Calcium Channel Blockers; Cangre- Plavix: 75 mg
lor; CYP2C19 Inhibitors (Moderate); CYP2C19 Inhib- Generic: 75 mg, 300 mg
itors (Strong); Erythromycin (Systemic); Dental Health Professional Considerations There
Esomeprazole; Etravirine; FentaNYL; FluvoxaMINE; is no scientific evidence to warrant the discontinuance
Grapefruit Juice; Lansoprazole; Morphine (Systemic); of clopidogrel prior to dental surgery. Patients taking
Omeprazole; Pantoprazole; Sodium Zirconium Cyclo- one clopidogrel tablet daily as an antithrombotic and
silicate who require dental surgery should be given special
Food Interactions Consumption of three 200 mL consideration in consultation with physician.
glasses of grapefruit juice a day may substantially
reduce clopidogrel antiplatelet effects. Management:
Avoid or minimize the consumption of grapefruit or
Clorazepate (klor AZ e pate)
grapefruit juice (Holmberg 2013). Related Information

Dietary Considerations Avoid or minimize the con- Dentin Hypersensitivity, Acid Erosion, High Caries
sumption of grapefruit juice (Holmberg 2013). Index, Management of Alveolar Osteitis, and Xerosto-
Pharmacodynamics/Kinetics mia on page 1548
Onset of Action Brand Names: US Tranxene-T
Onset of action: Inhibition of platelet aggregation Brand Names: Canada Clorazepate
(IPA): Dose-dependent:
Pharmacologic Category Anticonvulsant, Benzodia-
300 to 600 mg loading dose: Detected within 2 hours
zepine; Benzodiazepine
50 to 100 mg/day: Detected by the second day of
Use
treatment
Alcohol withdrawal: Symptomatic relief of acute alco-
Peak effect: Time to maximal IPA: Dose-dependent:
hol withdrawal.
Note: Degree of IPA based on adenosine diphos-
Anxiety disorders: Management of anxiety disorders
phate (ADP) concentration used during light aggreg-
and short-term relief of the symptoms of anxiety.
ometry:
Partial seizures: Adjunct therapy in the management
300 to 600 mg loading dose:
of partial seizures.
ADP 5 micromole/L: 20% to 30% IPA at 6 hours
post administration (Montelescot 2006) Local Anesthetic/Vasoconstrictor Precautions
ADP 20 micromole/L: 30% to 37% IPA at 6 hours No information available to require special precautions
post administration (Montelescot 2006) Effects on Dental Treatment Key adverse event(s)
50 to 100 mg/day: ADP 5 micromole/L: 50% to 60% related to dental treatment: Xerostomia (normal salivary
IPA at 5 to 7 days (Herbert 1993) flow resumes upon discontinuation); drowsiness;
Duration of Action Platelet aggregation and bleeding Patients may experience orthostatic hypotension as
time gradually return to baseline after ~5 days after they stand up after treatment; especially if lying in
discontinuation. dental chair for extended periods of time. Use caution
with sudden changes in position during and after dental
Half-life Elimination Parent drug: ~6 hours; Thiol
treatment. It is suggested that opioid analgesics not be
derivative (active metabolite) ~30 minutes; carboxylic
given for pain control to patients taking clorazepate due
acid derivative (inactive; main circulating metabolite):
to enhanced sedation.
~8 hours; Note: A clopidogrel radiolabeled study has
shown that covalent binding to platelets accounts for Effects on Bleeding No information available to
2% of radiolabel and has a half-life of 11 days. require special precautions
Time to Peak Serum: ~0.75 hours Adverse Reactions Frequency not defined.
Cardiovascular: Hypotension
Central nervous system: Anxiety, ataxia, confusion,
Information related to use during pregnancy is limited
depression, dizziness, drowsiness, dysarthria, fatigue,
(Bauer 2012; De Santis 2011; Myers 2011). Based on
headache, insomnia, irritability, memory impairment,
available data, an increased risk of major birth defects,
nervousness, slurred speech
miscarriage, or adverse fetal outcomes has not been
associated with maternal use of clopidogrel. According
Endocrine & metabolic: Decreased libido
to the manufacturer, use should not be withheld if
Gastrointestinal: Constipation, decreased appetite,
needed for emergent treatment of stroke or myocardial
diarrhea, increased appetite, nausea, vomiting, xero-
infarction during pregnancy. Discontinue use 5 to 7
stomia
days prior to labor, delivery, or neuraxial blockade if
Hepatic: Increased serum transaminases, jaundice
possible due to increased risk of maternal bleeding and
Neuromuscular & skeletal: Tremor
hemorrhage.
Ophthalmic: Blurred vision, diplopia
Available guidelines recommend using clopidogrel only Mechanism of Action Binds to stereospecific benzo-
when strictly needed and for the shortest duration diazepine receptors on the postsynaptic GABA neuron
possible until additional fetal safety data are available at several sites within the central nervous system,
(ESC [Regitz-Zagrosek 2018]). including the limbic system and reticular formation.
Breastfeeding Considerations Enhancement of the inhibitory effect of GABA on neuro-
It is not known if clopidogrel is present in breast milk. nal excitability results by increased neuronal membrane
Adverse events have not been reported in breastfed permeability to chloride ions. This shift in chloride ions
infants (limited data). According to the manufacturer, results in hyperpolarization (a less excitable state) and
the decision to breastfeed during therapy should con- stabilization. Benzodiazepine receptors and effects
sider the risk of infant exposure, the benefits of appear to be linked to the GABA-A receptors.
350
CLOTRIMAZOLE (ORAL)
Benzodiazepines do not bind to GABA-B receptors Dental Usual Dosage Oropharyngeal candidiasis:
(Nelson 1999). Children >3 years and Adults: Oral:
Pharmacodynamics/Kinetics Prophylaxis: 10 mg troche dissolved 3 times/day for the
Half-life Elimination Nordiazepam: 20 to 160 hours; duration of chemotherapy or until steroids are reduced
Oxazepam: 6 to 24 hours (Riss, 2008) to maintenance levels
Time to Peak Serum: ~0.5 to 2 hour (Carrigan, 1977; Treatment: 10 mg troche dissolved slowly 5 times/day
Riss, 2008) for 14 consecutive days
Pregnancy Considerations Nordiazepam, the active Dosing
metabolite of clorazepate, crosses the placenta and is Adult & Geriatric
measurable in cord blood and amniotic fluid. Terato- Oropharyngeal candidiasis (prophylaxis): Oral:
genic effects have been observed with some benzodia- 10 mg dissolved slowly 3 times daily for the duration
zepines (including clorazepate); however, additional of chemotherapy or until steroids are reduced to
studies are needed. The incidence of premature birth maintenance levels.
and low birth weights may be increased following Oropharyngeal candidiasis (treatment): Oral:
maternal use of benzodiazepines; hypoglycemia and 10 mg dissolved slowly 5 times daily for 14 consec-
respiratory problems in the neonate may occur follow- utive days. Note: When used for initial treatment in
ing exposure late in pregnancy. Neonatal withdrawal patients with HIV-1, duration of therapy is 7 to 14
symptoms may occur within days to weeks after birth
days (DHHS [adult] 2014; DHHS [pediatric] 2013).
and "floppy infant syndrome" (which also includes with-
drawal symptoms) has been reported with some ben-
Renal Impairment: Adult There are no dosage
zodiazepines (Bergman 1992; Iqbal 2002; Patel 1980; adjustments provided in the manufacturer’s labeling.
Rey 1979; Wikner 2007). A combination of factors Hepatic Impairment: Adult There are no dosage
influences the potential teratogenicity of anticonvulsant adjustments provided in the manufacturer’s labeling.
therapy. When treating women with epilepsy, monother- Pediatric Candidiasis, oropharyngeal; treatment:
apy with the lowest effective dose and avoidance of Children ≥3 years and Adolescents: Oral: 10 mg
medications known to have a high incidence of terato- troche dissolved slowly 5 times daily for 14 consec-
genic effects is recommended (Harden 2009; Wlodarc- utive days. Note: When used for initial treatment in
zyk 2012). patients with HIV, duration of therapy is 7 to 14 days
(HHS [OI adult 2016]; HHS [OI pediatric 2016]).
Patients exposed to clorazepate during pregnancy are
encouraged to enroll themselves into the AED Preg-
nancy Registry by calling 1-888-233-2334. Additional
information is available at www.- Hepatic Impairment: Pediatric There are no dos-
aedpregnancyregistry.org. age adjustments provided in the manufacturer's label-
Controlled Substance C-IV ing.
Mechanism of Action Binds to phospholipids in the
fungal cell membrane altering cell wall permeability
Clotrimazole (Oral) (kloe TRIM a zole) resulting in loss of essential intracellular elements
Contraindications
Related Information
Hypersensitivity to clotrimazole or any component of
Fungal Infections on page 1538
the formulation
Related Sample Prescriptions
Documentation of allergenic cross-reactivity for antifun-
Fungal Infections - Sample Prescriptions on page 39 gals is limited. However, because of similarities in
Generic Availability (US) Yes chemical structure and/or pharmacologic actions, the
Pharmacologic Category Antifungal Agent, Imida- possibility of cross-sensitivity can not be ruled out with
zole Derivative; Antifungal Agent, Oral Nonabsorbed certainty.
Dental Use Treatment of susceptible fungal infections, Warnings/Precautions Clotrimazole should not be
including oropharyngeal candidiasis; limited data sug- used for treatment of systemic fungal infection. Abnor-
gest that clotrimazole troches may be effective for
mal LFTs have been reported, including abnormal
prophylaxis against oropharyngeal candidiasis in neu-
aspartate aminotransferase (AST). Elevations are usu-
tropenic patients
ally minimal. Monitor LFTs periodically, especially in
Use
patients with preexisting hepatic impairment. Clotrima-
Oropharyngeal candidiasis (treatment): Local treat-
zole must be slowly dissolved in the mouth for max-
ment of oropharyngeal candidiasis.
imum efficacy. Potentially significant drug-drug
Oropharyngeal candidiasis (prophylaxis): To reduce
interactions may exist, requiring dose or frequency
the incidence of oropharyngeal candidiasis in immu-
nocompromised patients undergoing chemotherapy, adjustment, additional monitoring, and/or selection of
radiotherapy, or steroid therapy utilized in the treat- alternative therapy.
ment of leukemia, solid tumors, or renal transplan- Drug Interactions
tation. Metabolism/Transport Effects Inhibits CYP3A4
Local Anesthetic/Vasoconstrictor Precautions (weak)
No information available to require special precautions Avoid Concomitant Use
Effects on Dental Treatment No significant effects or Avoid concomitant use of Clotrimazole (Oral) with any
complications reported of the following: Pimozide
Effects on Bleeding No information available to Increased Effect/Toxicity
require special precautions Clotrimazole (Oral) may increase the levels/effects of:
Adverse Reactions ARIPiprazole; Dofetilide; Flibanserin; Lomitapide; Ner-
>10%: Hepatic: Abnormal liver function tests atinib; NiMODipine; Pimozide; Tacrolimus (Systemic)
Frequency not defined: Decreased Effect There are no known significant
Dermatologic: Pruritus interactions involving a decrease in effect.
Gastrointestinal: Nausea, vomiting Pregnancy Risk Factor C
351
CLOTRIMAZOLE (ORAL)
Pregnancy Considerations Adverse events have Tinea versicolor: Topical: Cream, solution: Apply to
been observed in animal reproduction studies. affected area twice daily; if no improvement occurs
Breastfeeding Considerations It is not known if after 4 weeks of therapy, re-evaluate diagnosis.
clotrimazole is excreted in breast milk following oral Vulvovaginal candidiasis: Intravaginal:
(troche) administration (data not located); however, Cream (1%): Insert 1 applicatorful of 1% vaginal
systemic absorption is low (Sawyer 1975). cream daily (at bedtime) for 7 consecutive days.
Dosage Forms: US Note: Guidelines recommend a duration of 7 to 14
Lozenge, Mouth/Throat: days (CDC [Workowski 2015]). May also apply
Generic: 10 mg (70 ea, 140 ea) externally twice daily for 7 days as needed for
Troche, Mouth/Throat: itching and irritation.
Generic: 10 mg Canesten 6 day intravaginal cream (1%) [Canadian
product]: Insert 1 applicatorful of 1% vaginal cream
daily (preferably at bedtime) for 6 consecutive days.
Clotrimazole (Topical) (kloe TRIM a zole)
Cream (2%): Insert 1 applicatorful of 2% vaginal
Brand Names: US 3 Day Vaginal [OTC]; Alevazol cream daily (preferably at bedtime) for 3 consec-
[OTC]; Clotrimazole 3 Day [OTC]; Clotrimazole GRx utive days. May also apply externally twice daily for
[OTC]; Desenex [OTC]; Gyne-Lotrimin 3 [OTC]; Gyne- 7 days as needed for itching and irritation.
Lotrimin [OTC]; Lotrimin AF For Her [OTC]; Lotrimin AF Cream (10%) [Canadian product]: Insert 1 applica-
[OTC] [DSC]; Pro-Ex Antifungal [OTC]; Shopko Athletes torful of 10% vaginal cream as a single dose
Foot [OTC] (preferably at bedtime)
Brand Names: Canada Canesten Topical; Canesten Tablet [Canadian product]:
Vaginal; Clotrimaderm; Trivagizole-3 500 mg tablet: Insert 1 vaginal tablet as a single
Generic Availability (US) Yes dose (preferably at bedtime)
Pharmacologic Category Antifungal Agent, Imida- 200 mg tablet: Insert 1 vaginal tablet once daily for
zole Derivative; Antifungal Agent, Oral Nonabsorbed/ 3 consecutive days (preferably at bedtime)
Partially Absorbed; Antifungal Agent, Topical; Antifungal Note: When tablets are used in conjunction with an
Agent, Vaginal external cream, apply cream over the irritated
area 1 to 2 times/day as needed for up to 7
Use
consecutive days
Topical cream and solution: Topical treatment of
candidiasis due to Candida albicans and tinea versi- Renal Impairment: Adult There are no dosage
color caused by Malassezia furfur adjustments provided in the manufacturer's labeling;
OTC labeling: Topical treatment of tinea pedis, tinea however, dosage adjustment unlikely due to low sys-
cruris, and tinea corporis temic absorption.
Topical ointment: OTC labeling: Topical treatment of Hepatic Impairment: Adult There are no dosage
tinea cruris, C. albicans, tinea corporis, and tinea adjustments provided in the manufacturer's labeling;
pedis however, dosage adjustment unlikely due to low sys-
Vaginal cream: Treatment of vaginal yeast infections temic absorption.
and relief of associated external vulvar itching and Pediatric
irritation Cutaneous candidiasis: Topical ointment: Children
Vaginal tablet [Canadian product]: Treatment of vag- ≥2 years and Adolescents: Topical: Apply twice daily
inal candidiasis (morning and night) for 2 weeks.
Local Anesthetic/Vasoconstrictor Precautions Tinea corporis, tinea cruris, and tinea pedis: Top-
No information available to require special precautions ical cream, ointment, or solution: Children ≥2 years
Effects on Dental Treatment No significant effects or and Adolescents: Topical: Apply twice daily (morning
complications reported and night). Duration: 2 weeks for tinea cruris; 4
Effects on Bleeding No information available to weeks for tinea corporis and tinea pedis
require special precautions Vulvovaginal candidiasis: Children ≥12 years and
Adverse Reactions Vaginal: Adolescents: Intravaginal:
1% to 10%: Genitourinary: Vulvovaginal burning Cream (1%): Insert 1 applicatorful of 1% vaginal
<1% (Limited to important or life-threatening): Burning cream daily (preferably at bedtime) for 7 consec-
sensation of the penis (of sexual partner), polyuria, utive days; some patients may require 14 days
pruritus vulvae, vaginal discharge, vulvar pain, vulvar (CDC [Workowski 2015]). May also apply externally
swelling twice daily for 7 days as needed for itching and
Dental Usual Dosage Cutaneous candidiasis: Chil- irritation.
dren >3 years and Adults: Topical (cream, solution): Cream (2%): Insert 1 applicatorful of 2% vaginal
Apply twice daily; if no improvement occurs after 4 cream daily (preferably at bedtime) for 3 consec-
weeks of therapy, re-evaluate diagnosis. utive days. May also apply externally twice daily for
Dosing 7 days as needed for itching and irritation.
Adult & Geriatric Renal Impairment: Pediatric There are no dosage
Cutaneous candidiasis: Topical: adjustments provided in the manufacturer's labeling;
Cream, solution: Apply to affected area twice daily; if however, dosage adjustment unlikely needed due to
no improvement occurs after 4 weeks of therapy, low systemic absorption.
re-evaluate diagnosis. Hepatic Impairment: Pediatric There are no dos-
Ointment (OTC labeling): Apply to affected area age adjustments provided in the manufacturer's label-
twice daily for 2 weeks. ing; however, dosage adjustment unlikely needed due
Tinea corporis, tinea cruris, tinea pedis (OTC to low systemic absorption.
labeling): Topical: Cream, ointment, solution: Apply Mechanism of Action Binds to phospholipids in the
to affected area twice daily for 2 weeks (tinea cruris) fungal cell membrane altering cell wall permeability
or 4 weeks (tinea corporis, tinea pedis). resulting in loss of essential intracellular elements
352
CLOXACILLIN
Contraindications Breastfeeding Considerations It is not known if

Hypersensitivity to clotrimazole or any component of clotrimazole is present in breast milk. The manufacturer
the formulation. recommends that caution be exercised when adminis-
OTC labeling: When used for self-medication, do not tering clotrimazole to breastfeeding women.
use vaginal cream if you have never had a vaginal Dosage Forms: US
yeast infection diagnosed by a doctor. Cream, External:
Documentation of allergenic cross-reactivity for imida- Clotrimazole GRx [OTC]: 1% (14 g)
zole antifungals is limited. However, because of sim- Desenex [OTC]: 1% (30 g)
ilarities in chemical structure and/or pharmacologic Lotrimin AF For Her [OTC]: 1% (24 g)
actions, the possibility of cross-sensitivity cannot be Pro-Ex Antifungal [OTC]: 1% (42 g)
ruled out with certainty. Shopko Athletes Foot [OTC]: 1% (28.4 g)
Warnings/Precautions Topical formulations are for Generic: 1% (15 g, 28.4 g, 30 g, 45 g)
external use only; avoid contact with the eyes. Not Cream, Vaginal:
effective for treatment of scalp or nails. When used for 3 Day Vaginal [OTC]: 2% (21 g)
self-medication, discontinue use and contact a health- Clotrimazole 3 Day [OTC]: 2% (22.2 g)
care provider if there is no improvement in 2 weeks Gyne-Lotrimin [OTC]: 1% (45 g)
(jock itch) or 4 weeks (athlete's foot, ringworm). If Gyne-Lotrimin 3 [OTC]: 2% (21 g)
irritation/sensitivity develops, discontinue therapy and Generic: 1% (45 g)
institute appropriate alternative therapy. When vaginal Ointment, External:
formulations are used for self-medication (OTC), con- Alevazol [OTC]: 1% (56.7 g)
sult a health care provider before use if experiencing Solution, External:
vaginal itching and discomfort for the first time, frequent Generic: 1% (10 mL, 29.57 mL, 30 mL)
vaginal yeast infections (eg, monthly, 3 in 6 months), or
exposure to HIV. A mild increase in vaginal itching,
Cream, Vaginal:
burning, or irritation may occur with use; a health care
Canesten 6 DAY Internal Cream: 1%
provider should be consulted before switching to
another agent if patient does not experience complete
relief. Discontinue use and contact a health care pro-
vider if symptoms do not improve in 3 days or last more Tablet, Vaginal:
than 7 days, or if symptoms of a more serious condition Canesten ComforTAB 1: 500 mg
occur (eg, abdominal pain, back/shoulder pain, fever, Canesten ComforTAB 3: 200 mg
chills, nausea, vomiting, foul-smelling vaginal dis-
charge). For vaginal use only; do not use tampons, Cloxacillin (kloks a SIL in)
douches, spermicides, or other vaginal products or
have vaginal intercourse during treatment. Brand Names: Canada Apo-Cloxi; Cloxacillin for
injection; Novo-Cloxin
Pharmacologic Category Antibiotic, Penicillin
may contain benzyl alcohol; large amounts of benzyl
alcohol (≥99 mg/kg/day) have been associated with a
Use Note: Not approved in the US
potentially fatal toxicity ("gasping syndrome") in neo- Bacterial infections: Treatment of bacterial infections
nates; the "gasping syndrome" consists of metabolic including endocarditis, pneumonia, bone and joint
acidosis, respiratory distress, gasping respirations, infections, skin and soft-tissue infections, and sepsis
CNS dysfunction (including convulsions, intracranial that are caused by susceptible strains of penicillinase-
hemorrhage), hypotension and cardiovascular collapse producing staphylococci.
(AAP ["Inactive" 1997]; CDC 1982); some data sug- Limitations of use: Exhibits good activity against Staph-
gests that benzoate displaces bilirubin from protein ylococcus aureus; has activity against many strepto-
binding sites (Ahlfors 2001); avoid or use dosage forms cocci, but is less active than penicillin and is generally
containing benzyl alcohol with caution in neonates. See not used in clinical practice to treat streptococcal
manufacturer's labeling. infections. Not effective against methicillin-resistant
Drug Interactions staphylococci.
Metabolism/Transport Effects None known. Local Anesthetic/Vasoconstrictor Precautions
Avoid Concomitant Use No information available to require special precautions
Avoid concomitant use of Clotrimazole (Topical) with Effects on Dental Treatment Key adverse event(s)
any of the following: Progesterone related to dental treatment: Prolonged use of penicillins
Increased Effect/Toxicity may lead to development of oral candidiasis.
Clotrimazole (Topical) may increase the levels/effects Effects on Bleeding No information available to
of: Sirolimus; Tacrolimus (Systemic) require special precautions
Decreased Effect Adverse Reactions Frequency not defined. Adverse
Clotrimazole (Topical) may decrease the levels/effects effects may be reported as class effects rather than
of: Progesterone specific to cloxacillin.
Pharmacodynamics/Kinetics Cardiovascular: Hypotension, thrombophlebitis
Time to Peak Serum: Vaginal cream: ~24 hours Central nervous system: Confusion, lethargy, myoclo-
Pregnancy Risk Factor B nus, seizure (high doses and/or renal failure),
Pregnancy Considerations Following topical and twitching
vaginal administration, small amounts of imidazoles Dermatologic: Pruritus, skin rash, urticaria
are absorbed systemically (Duhm 1974). Vaginal topical Gastrointestinal: Abdominal pain, diarrhea, epigastric
azole products (7-day therapies only) are the preferred distress, flatulence, hairy tongue, loose stools, mela-
treatment of vulvovaginal candidiasis in pregnant noglossia, nausea, oral candidiasis, pseudomembra-
women. This product may weaken latex condoms and nous colitis, stomatitis, vomiting
diaphragms (CDC [Workowski 2015]). Genitourinary: Hematuria, proteinuria
353
CLOXACILLIN
Hematologic & oncologic: Agranulocytosis, anemia, Adverse Reactions

bone marrow depression, eosinophilia, granulocytope- >10%:
nia, hemolytic anemia, immune thrombocytopenia, Cardiovascular: Tachycardia (17% to 25%), hypoten-
leukopenia, neutropenia, thrombocytopenia sion (9% to 13%), hypertension (4% to 12%)
Hepatic: Increased serum alkaline phosphatase, Central nervous system: Drowsiness (≤39% to 46%),
increased serum ALT, increased serum AST, hepato- sedation (≤39%), dizziness (14% to 27%), insomnia
toxicity (2% to 20%), vertigo (≤19%)
Hypersensitivity: Anaphylaxis, angioedema, hypersen- Gastrointestinal: Sialorrhea (13% to 48%), weight gain
sitivity reaction (immediate and delayed) (4% to 31%), constipation (14% to 25%), nausea
Immunologic: Serum sickness-like reaction (5% to 17%), vomiting (3% to 17%), dyspepsia (14%)
Neuromuscular & skeletal: Laryngospasm Miscellaneous: Fever (5% to 13%)
Renal: Interstitial nephritis, renal insufficiency, renal 1% to 10%:
tubular disease Cardiovascular: Syncope (6%)
Respiratory: Bronchospasm, laryngeal edema, sneez- Central nervous system: Headache (7% to 10%),
ing, wheezing agitation (4%), restlessness (4%), akinesia (≤4%),
Miscellaneous: Fever disturbed sleep (≤4%), nightmares (≤4%), akathisia
Mechanism of Action Inhibits bacterial cell wall syn- (3%), confusion (3%), seizure (3%; dose related),
thesis by binding to one or more of the penicillin-binding fatigue (2%)
proteins (PBPs) which in turn inhibit the final trans- Dermatologic: Diaphoresis (6%), skin rash (2%)
peptidation step of peptidoglycan synthesis in bacterial Gastrointestinal: Xerostomia (5% to 6%), abdominal
cell walls, thus inhibiting cell wall biosynthesis. Bacteria distress (≤4%), heartburn (≤4%), diarrhea (2%)
eventually lyse due to ongoing activity of cell wall Genitourinary: Urine abnormality (2%)
autolytic enzymes (autolysins and murein hydrolases) Hematologic & oncologic: Leukopenia (≤3%), neutro-
while cell wall assembly is arrested. penia (≤3%), eosinophilia (1%)
Pharmacodynamics/Kinetics Neuromuscular & skeletal: Tremor (6%), hypokinesia
Half-life Elimination 0.5 to 1.5 hours; prolonged with (≤4%), muscle rigidity (3%)
renal impairment and in neonates Ophthalmic: Visual disturbance (5%)
Time to Peak Oral: Serum: ~1 hour <1%, postmarketing, and/or case reports: Abnormal
Pregnancy Considerations Cloxacillin crosses the electrocephalogram, agranulocytosis, angioedema,
placenta and distributes into fetal tissue aspiration, bradycardia, cardiac arrhythmia (atrial or
Product Availability Not available in the US ventricular), cardiac failure, cardiomyopathy (usually
dilated), cataplexy, cerebrovascular accident, choles-
tasis, colitis, deep vein thrombosis, delirium, diabetes
CloZAPine (KLOE za peen) mellitus, DRESS syndrome, dyschromia, dysphagia,
enlargement of salivary glands, erythema multiforme,
Brand Names: US Clozaril; FazaClo; Versacloz
esophageal dysmotility, fecal impaction, gastroenter-
Brand Names: Canada AA-Clozapine; Clozaril; Gen- itis, granulocytopenia, hepatic cirrhosis, hepatic fibro-
Clozapine sis, hepatic insufficiency, hepatic necrosis, hepatitis,
Pharmacologic Category Second Generation (Atyp- hepatotoxicity, hyperglycemia, hyperosmolar coma,
ical) Antipsychotic hypersensitivity reaction, hyperuricemia, hyponatre-
Use mia, increased creatine phosphokinase, increased
Schizophrenia, treatment resistant: Treatment of erythrocyte sedimentation rate, increased hematocrit,
severely ill patients with schizophrenia who fail to increased hemoglobin, increased serum cholesterol,
respond adequately to antipsychotic treatment. increased serum triglycerides, interstitial nephritis
Suicidal behavior in schizophrenia or schizoaffec- (acute), intestinal obstruction, jaundice, ketoacidosis,
tive disorder: To reduce the risk of suicidal behavior leukocytosis, liver injury, liver steatosis, lower respira-
in patients with schizophrenia or schizoaffective dis- tory tract infection, mitral valve insufficiency, myasthe-
order who are judged to be at chronic risk for reexper- nia syndrome, myocardial infarction, myocarditis,
iencing suicidal behavior, based on history and recent myoclonus, neuroleptic malignant syndrome, noctur-
clinical state. nal enuresis, obsessive compulsive disorder, obstruc-
Local Anesthetic/Vasoconstrictor Precautions tive sleep apnea syndrome (Shirani 2011), orthostatic
Most pharmacology textbooks state that in presence hypotension, palpitations, pancreatitis (acute), para-
of phenothiazines, systemic doses of epinephrine paralytic ileus, paresthesia, periorbital edema, pheochro-
doxically decrease the blood pressure. This is the so mocytoma (pseudo), pleural effusion, pneumonia,
called "epinephrine reversal" phenomenon. This has priapism, prolonged QT interval on ECG, psychosis
never been observed when epinephrine is given by (exacerbated), pulmonary embolism, renal failure, ret-
infiltration as part of the local anesthesia procedure. rograde ejaculation, rhabdomyolysis, sialadenitis, sep-
Effects on Dental Treatment Key adverse event(s) sis, skin photosensitivity, status epilepticus, Stevens-
related to dental treatment: Sialorrhea and xerostomia Johnson syndrome, syncope, systemic lupus erythe-
(normal salivary flow resumes upon discontinuation); matosus, tardive dyskinesia, thrombocytopenia,
Patients may experience orthostatic hypotension as thrombocytosis, torsades de pointes, vasculitis, weight
they stand up after treatment; especially if lying in loss
dental chair for extended periods of time. Use caution Mechanism of Action The therapeutic efficacy of
with sudden changes in position during and after dental clozapine (dibenzodiazepine antipsychotic) is proposed
treatment. Do not use atropine-like drugs for xerostomia to be mediated through antagonism of the dopamine
in patients taking clozapine due to significant potentia- type 2 (D2) and serotonin type 2A (5-HT2A) receptors. In
tion. addition, it acts as an antagonist at alpha-adrenergic,
Effects on Bleeding No information available to histamine H1, cholinergic, and other dopaminergic and
require special precautions serotonergic receptors.
354
COBICISTAT
Onset of Action Within 1 week for sedation, improve- Cobicistat (koe BIK i stat)
ment in sleep; 6 to 12 weeks for antipsychotic effects;
Adequate trial: 6 to 12 weeks at a therapeutic dose Brand Names: US Tybost
and blood level; Maximum effect: 6 to 12 months; Pharmacologic Category Cytochrome P-450 Inhibi-
improvement may continue 6 to 12 months after tor
clozapine initiation (Meltzer 2003). Use
Duration of Action Variable HIV-1 infection: Treatment of HIV-1 infection to
increase systemic exposure of atazanavir or darunavir
Half-life Elimination Steady state: 12 hours (range: 4
(once-daily dosing regimen) in combination with other
to 66 hours)
antiretroviral agents
Time to Peak Suspension: 2.2 hours (range: 1 to 3.5 Limitations of use: Cobicistat is not interchangeable
hours); Tablets: 2.5 hours (range: 1 to 6 hours); with ritonavir to increase systemic exposure of daru-
Dispersible tablets: 2.3 hours (range: 1 to 6 hours) navir 600 mg twice daily, fosamprenavir, saquinavir, or
Pregnancy Risk Factor B tipranavir due to lack of exposure data. The use of
Pregnancy Considerations cobicistat is not recommended with darunavir 600 mg
Adverse events were not observed in animal reproduc- twice daily, fosamprenavir, saquinavir, or tipranavir.
tion studies. Clozapine crosses the placenta and can be Local Anesthetic/Vasoconstrictor Precautions
detected in the fetal blood and amniotic fluid (Barnas No information available to require special precautions
1994). Antipsychotic use during the third trimester of Effects on Dental Treatment No significant effects or
pregnancy has a risk for abnormal muscle movements complications reported
(extrapyramidal symptoms [EPS]) and/or withdrawal Effects on Bleeding No information available to
symptoms in newborns following delivery. Symptoms require special precautions
in the newborn may include agitation, feeding disorder, Adverse Reactions All adverse reactions are from
hypertonia, hypotonia, respiratory distress, somno- trials using cobicistat coadministered with atazanavir,
lence, and tremor; these effects may be self-limiting or emtricitabine + tenofovir unless otherwise noted.
require hospitalization. Frequency not always defined.
Central nervous system: Headache (2%), abnormal
Clozapine may theoretically cause agranulocytosis in
dreams (<2%), depression (<2%), fatigue (<2%),
the fetus and should not routinely be used in pregnancy
insomnia (<2%)
(NICE 2007). The American College of Obstetricians
and Gynecologists recommends that therapy during Endocrine & metabolic: Increased gamma-glutamyl
pregnancy be individualized; treatment with psychiatric transferase (>5 x ULN: 4%), glycosuria (3%), Fanco-
medications during pregnancy should incorporate the ni's syndrome (<2%), increased HDL cholesterol,
clinical expertise of the mental health clinician, obste- increased LDL cholesterol, increased serum choles-
trician, primary healthcare provider, and pediatrician. terol, increased serum triglycerides
Safety data related to atypical antipsychotics during Gastrointestinal: Increased serum amylase (>2 x ULN:
pregnancy is limited and routine use is not recom- 4% to 7%), diarrhea (2%), nausea (2%), upper
mended. However, if a woman is inadvertently exposed abdominal pain (<2%), vomiting (<2%)
to an atypical antipsychotic while pregnant, continuing Genitourinary: Hematuria (6%), proximal tubular nephr-
therapy may be preferable to switching to a typical opathy (2%)
antipsychotic that the fetus has not yet been exposed Hepatic: Hyperbilirubinemia (>2.5 x ULN: 73%),
to; consider risk:benefit (ACOG 2008). An increased increased serum ALT (>5 x ULN: 6%), jaundice
risk of exacerbation of psychosis should be considered (6%), increased serum AST (>5 x ULN: 4%)
when discontinuing or changing treatment during preg- Neuromuscular & skeletal: Increased creatine phospho-
nancy and postpartum. kinase (8%), rhabdomyolysis (<2%)
Ophthalmic: Scleral icterus (4%)
Healthcare providers are encouraged to enroll women
Renal: Nephrolithiasis (<2%), renal disease (<2%),
18 to 45 years of age exposed to clozapine during decreased creatinine clearance (no effect on renal
pregnancy in the Atypical Antipsychotics Pregnancy glomerular function in patients with normal renal func-
R e g i s t r y ( 1 - 8 6 6 - 9 6 1 - 2 3 8 8 o r h t t p : / / w w w. - tion), increased serum creatinine, renal insufficiency
womensmentalhealth.org/pregnancyregistry). Mechanism of Action Cobicistat is a mechanism-
Women with amenorrhea associated with use of other based inhibitor of cytochrome P450 3A (CYP3A). Inhib-
antipsychotic agents may return to normal menstruation ition of CYP3A-mediated metabolism by cobicistat and
when switching to clozapine therapy. Reliable contra- increases the systemic exposure of CYP3A substrates
ceptive measures should be employed by women of atazanavir and darunavir.
childbearing potential switching to clozapine therapy. Pharmacodynamics/Kinetics
Prescribing and Access Restrictions Canada: Half-life Elimination Terminal: ~3 to 4 hours
Currently, there are multiple manufacturers that distrib- Time to Peak ~3.5 hours
ute clozapine and each manufacturer has its own Pregnancy Considerations
registry and distribution system. Patients must be regis- Cobicistat has low placental transfer.
tered in a database that includes their location, pre- Data collected by the antiretroviral pregnancy registry
scribing physician, testing laboratory, and dispensing are insufficient to evaluate human teratogenic risk.
pharmacist before using clozapine. Patients may not Maternal antiretroviral therapy (ART) may increase the
be switched from one brand of clozapine to another risk of preterm delivery, although available information
without completion of a new registry-specific patient is conflicting possibly due to variability of maternal
registration form by signed by the prescribing physician. factors (disease severity; gestational age at initiation
Information specific to each monitoring program is of therapy). An increased risk of stillbirth, low birth
available from the individual manufacturers. weight, and small for gestational age infants has been
355
COBICISTAT
observed in some but not all studies. Because there is >10%:

clear benefit to appropriate treatment, maternal ART Cardiovascular: Decreased left ventricular ejection
should not be withheld due to concerns for adverse fraction (grades 2/3: 26%), hypertension (15%)
neonatal outcomes. Long-term follow-up is recom- Dermatologic: Skin photosensitivity (46% to 47%,
mended for all infants exposed to antiretroviral medi- grades 3/4: 4%; includes solar dermatitis and sun-
cations; children who develop significant organ system burn), acneiform eruption (16%, grades 3/4: 2%)
abnormalities of unknown etiology (particularly of the Endocrine & metabolic: Hypophosphatemia (68%),
CNS or heart) should be evaluated for potential mito- increased gamma-glutamyl transferase (65%;
chondrial dysfunction. grades 3/4: 21%), hypoalbuminemia (42%), hypona-
tremia (38%), hyperkalemia (26%), hypokalemia
The Health and Human Services (HHS) Perinatal HIV (25%), hypocalcemia (24%)
Guidelines do not recommend cobicistat for use in HIV- Gastrointestinal: Diarrhea (60%), nausea (41%), vom-
infected pregnant females who are antiretroviral-naive, iting (24%), stomatitis (14%; includes aphthous sto-
who have had ART therapy in the past but are restart- matitis, mucositis, and oral mucosa ulcer)
ing, who require a new ART regimen (due to poor Hematologic & oncologic: Lymphocytopenia (73%,
tolerance or poor virologic response of current regi- grades 3/4: 10%), anemia (69%; grades 3/4: 3%),
men), and who are not yet pregnant but are trying to thrombocytopenia (18%), hemorrhage (13%, grades
conceive. Cobicistat exposure is decreased in preg- 3/4: 1%; includes bruise, ecchymoses, epistaxis,
nancy. Use of cobicistat boosted atazanavir, darunavir, gingival hemorrhage, hematemesis, hematochezia,
or elvitegravir in pregnancy is not recommended; hemoptysis, hemorrhoidal bleeding, hypermenor-
patients who become pregnant during therapy should rhea, melena, menometrorrhagia, nail bed bleeding,
consider changing to a more effective, recommended pulmonary hemorrhage, purpura, rectal hemorrhage,
regimen. If cobicistat is continued in a pregnant patient rupture of ovarian cyst, subarachnoid hemorrhage,
who is virally suppressed, monitor the viral load more subgaleal hematoma, traumatic hematoma, uterine
frequently (eg, monthly during the second and third hemorrhage, and vaginal hemorrhage)
trimesters). Hepatic: Increased serum AST (73%, grades 3/4: 7%
to 8%), increased serum alkaline phosphatase (71%,
In general, ART is recommended for all pregnant grades 3/4: 7%), increased serum ALT (68%, grades
females with HIV to keep the viral load below the limit 3/4: 11%)
of detection and reduce the risk of perinatal trans- Neuromuscular & skeletal: Increased creatine phos-
mission. Monitoring during pregnancy is more frequent phokinase (79%, grades 3/4: 12% to 14%)
than in non-pregnant adults. ART should be continued Ophthalmic: Visual impairment (15%, grades 3/4:
postpartum for all females living with HIV and can be <1%; includes blurred vision, decreased visual
modified after delivery. acuity), chorioretinopathy (13%, grades 3/4: <1%),
retinal detachment (12%, grades 3/4: 2%; includes
Health care providers are encouraged to enroll preg-
detachment of macular retinal pigment epithelium
nant females exposed to antiretroviral medications as
and retinal pigment epithelium detachment)
early in pregnancy as possible in the Antiretroviral Renal: Increased serum creatinine (100%; grades
Pregnancy Registry (1-800-258-4263 or http://www.- 3/4: 3%)
APRegistry.com). Health care providers caring for Miscellaneous: Fever (28%)
HIV-infected females and their infants may contact the 1% to 10%:
National Perinatal HIV Hotline (888-448-8765) for clin- Central nervous system: Chills (10%)
ical consultation (HHS [perinatal] 2018). Dermatologic: Skin rash (grades 3/4: 16%; grade 4:
2%; rash resulting in hospitalization: 3%)
Cobimetinib (koe bi ME ti nib) Gastrointestinal: Gastrointestinal hemorrhage (4%)
Genitourinary: Genitourinary tract hemorrhage (2%),
Brand Names: US Cotellic hematuria (2%)
Brand Names: Canada Cotellic Hematologic & oncologic: Keratoacanthoma (≤6%),
Pharmacologic Category Antineoplastic Agent, MEK squamous cell carcinoma of skin (≤6%), basal cell
Inhibitor carcinoma (5%)
Use Melanoma, unresectable or metastatic: Treat- Hepatic: Abnormal bilirubin levels (grades 3/4: 2%)
ment of unresectable or metastatic melanoma in <1%, postmarketing, and/or case reports: Cerebral
patients with a BRAF V600E or V600K mutation (in hemorrhage, malignant melanoma (second primary),
combination with vemurafenib) malignant neoplasm (noncutaneous)
Local Anesthetic/Vasoconstrictor Precautions Mechanism of Action Cobimetinib is a potent and
selective inhibitor of the mitogen-activated extracellular
Hypertension can occur with the use of this drug.
kinase (MEK) pathway (Larkin 2014); it reversibly inhib-
Monitor for hypertension prior to using local anesthetic
its MEK1 and MEK2, which are upstream regulators of
with vasoconstrictor; medical consult if necessary.
the extracellular signal-related kinase (ERK) pathway.
Effects on Dental Treatment Key adverse event(s) The ERK pathway promotes cellular proliferation. MEK1
related to dental treatment: Stomatitis (14%; includes and MEK2 are part of the BRAF pathway, which is
aphthous stomatitis, mucositis, and oral mucosa ulcer) activated by BRAF V600E and K mutations. Vemurafe-
has been observed nib targets a different kinase in the RAS/RAF/MEK/ERK
Effects on Bleeding Hemorrhage may occur with pathway; when cobimetinib and vemurafenib are used
cobimetinib; Grade 3 to 4 bleeding has occurred. In in combination, increased apoptosis and reduced tumor
patients who are under active treatment with these growth occurs.
agents, medical consult is suggested. Pharmacodynamics/Kinetics
Adverse Reactions Half-life Elimination Mean: 44 hours (range: 23 to 70
Percentages reported as part of combination chemo- hours)
therapy regimens. Time to Peak Median: 2.4 hours (range: 1 to 24 hours)
356
CODEINE
Pregnancy Considerations Adverse events were the uptake of norepinephrine by adrenergic nerve ter-
observed in animal reproduction studies. Based on minals producing vasoconstriction
the mechanism of action, cobimetinib would be Pharmacodynamics/Kinetics
expected to cause fetal harm. Women of reproductive Onset of Action ~1 minute; Peak effect: ~5 minutes
potential should use effective contraception during ther- Duration of Action Dose dependent: ≥30 minutes;
apy and for 2 weeks after the final dose. The study cocaine metabolites may appear in urine of neonates
protocol recommended the use of two forms of effective up to 5 days after birth due to maternal cocaine use
contraception during therapy and for at least 6 months shortly before birth
following discontinuation for women of reproductive Half-life Elimination 1 to 1.7 hours
potential and for males with partners of reproductive Pregnancy Considerations Cocaine rapidly crosses
potential (Larkin 2013 [Protocol GO28141]). the placenta in concentrations equal to those in the
Prescribing and Access Restrictions Available mother. Adverse events occur in the fetus (eg, congen-
through specialty pharmacies. Further information may ital malformations, growth restriction), infant (neonatal
be obtained from the manufacturer, Genentech, at abstinence syndrome), and mother (eg, preterm labor,
1-888-249-4918, or at http://www.cotellic.com. placental abruption) following maternal abuse (Fajemir-
okun-Odudeyi 2004).
Controlled Substance C-II
Cocaine (Topical) (koe KANE)
Related Information cocaine user, regardless of how the cocaine was
Management of the Chemically Dependent Patient on administered, presents a potential life-threatening sit-
uation in the dental operatory. A patient under the
page 1511
influence of cocaine could be compared to a car going
Brand Names: US Goprelto
100 mph. Blood pressure is elevated, heart rate is likely
Pharmacologic Category Local Anesthetic increased, and the use of a local anesthetic with epi-
Use nephrine may result in a medical emergency. Such
Anesthesia: patients can be identified by their jitteriness, irritability,
Generic topical solution: Topical anesthesia (and vas- talkativeness, tremors, and short, abrupt speech pat-
oconstriction) for mucous membranes of the oral, terns. These same signs and symptoms may also be
laryngeal, or nasal cavities seen in a normal dental patient with preoperative dental
Goprelto: Topical anesthesia for mucous membranes anxiety; therefore, the dentist must be particularly alert
when performing diagnostic procedures and sur- in order to identify the potential cocaine abuser. If
geries on or through nasal cavities cocaine use is suspected, the patient should never be
Local Anesthetic/Vasoconstrictor Precautions given a local anesthetic with vasoconstrictor, for fear of
Although plain local anesthetic is not contraindicated, exacerbating the cocaine-induced sympathetic
vasoconstrictor is absolutely contraindicated in any response. Life-threatening episodes of cardiac arrhyth-
patient under the influence of or within 2 hours of mias and hypertensive crises have been reported when
cocaine use local anesthetic with vasoconstrictor was administered
Effects on Dental Treatment Key adverse event(s) to a patient under the influence of cocaine. No local
related to dental treatment: Loss of taste perception. anesthetic, used by any dentist, can interfere with, nor
See Dental Health Professional Considerations. test positive by cocaine in any urine testing screen.
Effects on Bleeding No information available to Therefore, the dentist does not need to be concerned
require special precautions with any false drug-use accusations associated with
Adverse Reactions Use of the topical solution may dental anesthesia.
produce systemic reactions from excessive and rapid
absorption. Codeine (KOE deen)
1% to 10%:
Central nervous system: Headache (3%) Related Information
Respiratory: Epistaxis (1%) Oral Pain on page 1520
Frequency not defined: Brand Names: Canada Codeine Contin
Cardiovascular: Decreased heart rate (low doses), Pharmacologic Category Analgesic, Opioid; Antitus-
myocardial infarction (Lenders 2013; Makaryus sive
2006), tachycardia, vasoconstriction, ventricular Use
arrhythmia (Lenders 2013) Pain management: Management of mild- to moder-
Central nervous system: Central nervous system ately-severe pain
depression (may follow CNS excitation), central Limitations of use: Reserve codeine for use in patients
nervous system stimulation, excitation, nervousness, for whom alternative treatment options (eg, nonopioid
restlessness, tonic-clonic seizures analgesics, opioid combination products) are ineffec-
Gastrointestinal: Vomiting tive, not tolerated, or would be otherwise inadequate.
Neuromuscular & skeletal: Tremor Local Anesthetic/Vasoconstrictor Precautions
Ophthalmic: Corneal changes (epithelium sloughing), No information available to require special precautions
corneal ulcer, mydriasis Effects on Dental Treatment No significant effects or
Miscellaneous: Fever complications reported (see Dental Health Professional
<1%, postmarketing, and/or case reports: Increased Considerations)
blood pressure Effects on Bleeding No information available to
Mechanism of Action Ester local anesthetic blocks require special precautions
both the initiation and conduction of nerve impulses by Adverse Reactions Frequency not defined.
decreasing the neuronal membrane's permeability to Cardiovascular: Bradycardia, cardiac arrest, circulatory
sodium ions, which results in inhibition of depolarization depression, flushing, hypertension, hypotension, pal-
with resultant blockade of conduction; interferes with pitations, shock, syncope, tachycardia
357
CODEINE
Central nervous system: Abnormal dreams, agitation, pregnant women or those who may become pregnant
anxiety, apprehension, ataxia, chills, depression, dis- (CDC [Dowell 2016]; Chou 2009; Kahan 2011).
orientation, dizziness, drowsiness, dysphoria, eupho- Product Availability Codeine 30 mg per 5 mL oral
ria, fatigue, hallucination, headache, increased solution has been discontinued in the US for more than
intracranial pressure, insomnia, nervousness, pares- 1 year.
thesia, sedation, shakiness, taste disorder, vertigo Controlled Substance C-II
Dermatologic: Diaphoresis, pruritus, skin rash, urticaria Dental Health Professional Considerations It is
Gastrointestinal: Abdominal cramps, abdominal pain, recommended that codeine not be used as the sole
anorexia, biliary tract spasm, constipation, diarrhea, entity for analgesia because of moderate efficacy along
nausea, pancreatitis, vomiting, xerostomia with relatively high incidence of nausea, sedation, and
Genitourinary: Urinary hesitancy, urinary retention constipation. In addition, codeine has some opioid
Hypersensitivity: Hypersensitivity reaction addiction liability. Codeine in combination with acetami-
Neuromuscular & skeletal: Laryngospasm, muscle nophen or aspirin is recommended. Maximum effective
rigidity, tremor, weakness analgesic dose of codeine is 60 mg (1 grain). Beyond
Ophthalmic: Blurred vision, diplopia, miosis, nystag- 60 mg increases respiratory depression only.
mus, visual disturbance
Respiratory: Bronchospasm, dyspnea, respiratory
arrest, respiratory depression Codeine and Chlorpheniramine
(KOE deen & klor fen IR a meen)
<1%, postmarketing, and/or case reports: Hypogonad-
ism (Brennan 2013; Debono 2011) Brand Names: US Codar AR [DSC]; Lexuss 210
Mechanism of Action Binds to opioid receptors in the [DSC]; Tuzistra XR; Z-Tuss AC [OTC]
CNS, causing inhibition of ascending pain pathways, Pharmacologic Category Analgesic, Opioid; Antitus-
altering the perception of and response to pain; causes sive; Histamine H1 Antagonist; Histamine H1 Antago-
cough suppression by direct central action in the nist, First Generation
medulla; produces generalized CNS depression Use Cough and upper respiratory symptoms: Tem-
Pharmacodynamics/Kinetics porary relief of cough and upper respiratory symptoms
Onset of Action associated with allergies or a common cold in adults
Oral: Immediate release: 0.5 to 1 hour; Injection ≥18 years of age.
[Canadian product]: 10 to 30 minutes Local Anesthetic/Vasoconstrictor Precautions
Peak effect: Oral: Immediate release: 1 to 1.5 hours; No information available to require special precautions
Injection [Canadian product]: 30 to 60 minutes Effects on Dental Treatment Key adverse event(s)
Duration of Action Oral: Immediate release: 4 to 6 related to dental treatment: Xerostomia (normal salivary
hours; Injection [Canadian product]: 4 to 6 hours flow resumes upon discontinuation).
Half-life Elimination ~3 hours Effects on Bleeding No information available to
Time to Peak Plasma: Immediate release: 1 hour; require special precautions
Controlled release [Canadian product]: 3.3 hours Adverse Reactions Frequency not defined; reactions
Pregnancy Risk Factor C reported with combination product and/or individual
Pregnancy Considerations agents. Also see individual agents.
[US Boxed Warning]: Prolonged maternal use can Cardiovascular: Chest pain, chest tightness, decreased
cause neonatal opioid withdrawal syndrome in the heart rate, facial flushing, hypertension, hypotension,
newborn which may be life-threatening if not rec- orthostatic hypotension, palpitations, peripheral
ognized and treated according to protocols devel- edema, prolonged QT interval on ECG, shock, syn-
oped by neonatology experts. If prolonged opioid cope, tachycardia
therapy is required in a pregnant woman, ensure Central nervous system: Agitation, anxiety, ataxia,
treatment is available and warn patient of risk to the coma, confusion, decreased mental acuity, depres-
neonate. sion, dizziness, drowsiness, drug abuse, drug depend-
ence, dysphoria, euphoria, excitability, falling, false
Adverse events were observed in some animal repro-
sense of well-being, fatigue, fear, hallucination, head-
duction studies. Opioids cross the placenta. Maternal
ache, increased intracranial pressure, insomnia, irrita-
use of opioids may be associated with birth defects,
bility, lethargy, malaise, migraine, nervousness, opioid
poor fetal growth, stillbirth, and preterm delivery (CDC
withdrawal syndrome, relaxation, restlessness,
[Dowell 2016]). If chronic opioid exposure occurs in
sedated state, seizure, vertigo
pregnancy, adverse events in the newborn (including
Dermatologic: Dermatitis, diaphoresis, erythema of
withdrawal) may occur (Chou 2009). Symptoms of neo-
skin, facial swelling, hyperhidrosis, pruritus, skin rash,
natal abstinence syndrome (NAS) following opioid
urticaria
exposure may be autonomic (eg, fever, temperature
Endocrine & metabolic: Altered serum glucose (change
instability), gastrointestinal (eg, diarrhea, vomiting, poor
in glucose utilization), glycosuria, gynecomastia, hot
feeding/weight gain), or neurologic (eg, high-pitched
flash, hypoglycemia, increased libido, pheochromocy-
crying, hyperactivity, increased muscle tone, increased
toma crisis
wakefulness/abnormal sleep pattern, irritability, sneez-
Gastrointestinal: Abdominal distention, abdominal pain,
ing, seizure, tremor, yawning) (Dow 2012; Hudak 2012).
acute pancreatitis, anorexia, biliary tract spasm, con-
Mothers who are physically dependent on opioids may
stipation, decreased appetite, decreased gastrointes-
give birth to Infants who are also physically dependent.
tinal motility, diarrhea, dyspepsia, dysphagia,
Opioids may cause respiratory depression and psycho-
epigastric distress, gastroesophageal reflux disease,
physiologic effects in the neonate; newborns of mothers
hiccups, increased appetite, increased serum amy-
receiving opioids during labor should be monitored.
lase, intestinal obstruction, nausea, paralytic ileus,
Agents other than codeine are commonly used to treat spasm of sphincter of Oddi, vomiting, xerostomia
maternal pain during labor and immediately postpartum Genitourinary: Dysuria, early menses, hypogonadism,
(ACOG 177 2017) as well as chronic noncancer pain in infertility, irritable bladder, lactation insufficiency,
358
COLESEVELAM
ureteral spasm, urinary frequency, urinary hesitancy, 1% to 10%:

urinary retention, urinary tract infection Central nervous system: Fatigue (1% to 4%), head-
Hematologic & oncologic: Agranulocytosis, aplastic ache (1% to 2%)
anemia, thrombocytopenia Endocrine & metabolic: Gout (4%)
Hypersensitivity: Anaphylaxis Gastrointestinal: Abdominal cramps, abdominal pain
Neuromuscular & skeletal: Arthralgia, asthenia, back Respiratory: Pharyngolaryngeal pain (2% to 3%)
pain, dyskinesia, facial dyskinesia, laryngospasm <1%, postmarketing, and/or case reports: Alopecia,
(allergic), muscle spasm, tremor, vesicle sphincter aplastic anemia, azoospermia, bone marrow depres-
spasm sion, dermatitis, disseminated intravascular coagula-
Ophthalmic: Blurred vision, diplopia, hypermetropia, tion, dysgeusia (Syed 2016), granulocytopenia,
increased lacrimation, miosis, mydriasis, photophobia, hepatotoxicity, hypersensitivity reaction, increased
visual disturbance creatine phosphokinase in blood specimen, increased
Otic: Labyrinthitis, tinnitus serum alanine aminotransferase, increased serum
Respiratory: Allergic bronchospastic disease, atelecta- aspartate aminotransferase, lactose intolerance, leu-
kopenia, maculopapular rash, myalgia, myasthenia,
sis, bronchitis, cough, dry nose, dry throat, dyspnea,
myopathy, myotonia, neuropathy, oligospermia, pan-
laryngismus, nasal congestion, nasopharyngitis, res-
cytopenia, peripheral neuritis, nonthrombocytopenic
piratory depression, respiratory distress, sinusitis,
purpura, rhabdomyolysis, skin rash, thrombocytope-
thickening of bronchial secretions, upper respiratory
nia, toxic neuromuscular disease
tract infection, wheezing
Mechanism of Action Disrupts cytoskeletal functions
Miscellaneous: Impaired physical performance
by inhibiting β-tubulin polymerization into microtubules,
Mechanism of Action preventing activation, degranulation, and migration of
Codeine: Binds to opioid receptors in the CNS, causing neutrophils associated with mediating some gout symp-
inhibition of ascending pain pathways, altering the toms. In familial Mediterranean fever, may interfere with
perception of and response to pain; causes cough intracellular assembly of the inflammasome complex
suppression by direct central action in the medulla; present in neutrophils and monocytes that mediate
produces generalized CNS depression. activation of interleukin-1β.
Chlorpheniramine: H1 receptor antagonist that also Pharmacodynamics/Kinetics
possesses anticholinergic and sedative activity. It pre- Onset of Action Oral: Pain relief: ~18 to 24 hours
vents released histamine from dilating capillaries and Half-life Elimination 27 to 31 hours (multiple oral
causing edema of the respiratory mucosa. doses; young, healthy volunteers)
Pregnancy Considerations Time to Peak Serum: Oral: 0.5 to 3 hours
[US Boxed Warning]: Prolonged use of opioids Pregnancy Risk Factor C
during pregnancy can cause neonatal withdrawal Pregnancy Considerations Adverse events were
syndrome, which may be life-threatening if not observed in animal reproduction studies. Colchicine
recognized and treated according to protocols crosses the human placenta. Use during pregnancy in
developed by neonatology experts. If opioid use is the treatment of familial Mediterranean fever has not
required for a prolonged period in a pregnant shown an increase in miscarriage, stillbirth, or terato-
woman, advise the patient of the risk of neonatal genic effects (limited data).
opioid withdrawal syndrome and ensure that appro- Product Availability Gloperba (0.6 mg/5 mL oral sol-
priate treatment will be available. ution): FDA approved January 2019; availability antici-
pated mid-2019. Information pertaining to this product
Animal reproduction studies have not been conducted within the monograph is pending revision. Consult the
with this combination. See individual agents. prescribing information for additional information.
Controlled Substance Extended Release Suspen-
sion: C-III; Liquid products: C-V
Colchicine and Probenecid
(KOL chi seen & proe BEN e sid)
Colchicine (KOL chi seen)
Related Information
Brand Names: US Colcrys; Mitigare Colchicine on page 359
Pharmacologic Category Antigout Agent Probenecid on page 1122
Use Pharmacologic Category Anti-inflammatory Agent;
Familial Mediterranean fever (tablet [eg, Colcrys] Antigout Agent; Uricosuric Agent
only): Treatment of familial Mediterranean fever in Use Treatment of chronic gouty arthritis when compli-
adults and children 4 years and older. cated by frequent, recurrent acute attacks of gout
Gout flares: Prophylaxis and treatment of acute gout Local Anesthetic/Vasoconstrictor Precautions
flares when taken at the first sign of a flare. Note: No information available to require special precautions
Mitigare is only approved for prophylaxis of gout Effects on Dental Treatment No significant effects or
flares. complications reported
Effects on Dental Treatment No significant effects or Adverse Reactions See individual agents.
complications reported Pregnancy Considerations See individual agents.
require special precautions Colesevelam (koh le SEV a lam)
Adverse Reactions Frequency not always defined.
>10%: Gastrointestinal: Gastrointestinal disease (26% Related Information
to 77%), diarrhea (23% to 77%), vomiting (17%), Cardiovascular Diseases on page 1442
nausea (4% to 17%) Brand Names: US Welchol
359
COLESEVELAM
Brand Names: Canada Lodalis Hyperlipidemia (primary) (Fredrickson type IIa),

Generic Availability (US) Yes diabetes mellitus (type 2): Oral: 3.75 g/day in 1 or
Pharmacologic Category Antilipemic Agent, Bile Acid 2 divided doses
Sequestrant Note: Use may be considered in patients with fasting
Use triglyceride level ≤300 mg/dL who do not meet
Diabetes mellitus, type 2: Improve glycemic control in cholesterol treatment goals with dietary modifica-
adults with type 2 diabetes mellitus in conjunction with tion and other lipid lowering therapies (eg, max-
diet and exercise imally tolerated statin and ezetimibe) (AHA/ACC
Guideline recommendations: Colesevelam is not gen- [Grundy 2018]).
erally used in patients with type 2 diabetes but may Renal Impairment: Adult No dosage adjustments
be tried in specific situations (ADA 2019). necessary; not absorbed from the gastrointestinal
Hyperlipidemia (primary): tract.
Management of elevated LDL-C in adults with primary Hepatic Impairment: Adult No dosage adjustments
hyperlipidemia (Fredrickson type IIa) when used necessary; not absorbed from the gastrointestinal
alone or in combination with a statin in conjunction tract.
with diet and exercise. Pediatric Note: Due to large tablet size, the manufac-
Management of heterozygous familial hypercholester- turer recommends packets of oral suspension for
olemia (heFH) in adolescent patients (males and some pediatric patients:
postmenarcheal females 10 to 17 years of age) used Heterozygous familial hypercholesterolemia:
alone or in combination with a 3-hydroxy-3-methyl- Children ≥10 years and Adolescents: Oral:
glutaryl coenzyme A (HMG-CoA) reductase inhibitor Once-daily dosing: 3.75 g (oral suspension or 6
(ie, statin) when after an adequate trial of dietary tablets) once daily (Stein, 2010)
therapy patient continues to have low-density lip- Twice-daily dosing: 1.875 g (3 tablets) twice daily
oprotein-cholesterol (LDL-C) ≥190 mg/dL or LDL-C (Stein, 2010)
≥160 mg/dL and with a positive family history of Primary hyperlipidemia: Limited data available
premature cardiovascular disease (CVD) or with (NHLBI, 2011): Children ≥10 years and Adoles-
two or more CVD risk factors. cents: Oral:
Local Anesthetic/Vasoconstrictor Precautions Once-daily dosing: 3.75 g (oral suspension or 6
No information available to require special precautions tablets) once daily
Effects on Dental Treatment No significant effects or Twice-daily dosing: 1.875 g (3 tablets) twice daily
complications reported Renal Impairment: Pediatric There are no dosage
Effects on Bleeding No information available to adjustments provided in the manufacturer's labeling;
require special precautions however, dosage adjustment unlikely necessary due
Adverse Reactions Actual frequency may be depend- to low systemic absorption.
ent upon indication. Unless otherwise noted, frequency Hepatic Impairment: Pediatric No dosage adjust-
of adverse effects is reported for adult patients. ment necessary.
>10%: Gastrointestinal: Constipation (3% to 11%) Mechanism of Action Cholesterol is the major pre-
1% to 10%: cursor of bile acid. Colesevelam binds with bile acids in
Cardiovascular: Cardiovascular toxicity (2%, including the intestine to form an insoluble complex that is elim-
myocardial infarction, aortic stenosis, bradycardia), inated in feces. This increased excretion of bile acids
hypertension (2% to 3%)
results in an increased oxidation of cholesterol to bile
Central nervous system: Headache (children and
acid and a lowering of the serum cholesterol.
adults 4% to 8%), fatigue (children 4%)
Endocrine & metabolic: Hypertriglyceridemia (4% to
Contraindications
5%; >500 mg/dL: <1%; >1,000 mg/dL: <1%), hyper- History of bowel obstruction; serum TG concentrations
glycemia (3%), hypoglycemia (3%) of more than 500 mg/dL; history of hypertriglyceride-
Gastrointestinal: Dyspepsia (3% to 8%), diarrhea mia-induced pancreatitis.
(4%), nausea (children and adults 3% to 4%), gastro- Canadian labeling: Additional contraindications (not in
esophageal reflux disease (2%), periodontal abscess US labeling): Hypersensitivity to colesevelam or any
(2%), vomiting (children 2%) component of the formulation; biliary obstruction
Hematologic & oncologic: C-reactive protein Warnings/Precautions Bile acid sequestrants can
increased (3%) increase serum triglyceride concentrations; severely
Infection: Influenza (children and adolescents 4%) elevated triglycerides can cause acute pancreatitis.
Neuromuscular & skeletal: Weakness (4%), back pain The manufacturer contraindicates use if triglycerides
(2%), increased creatine phosphokinase (children exceed 500 mg/dL and in patients with a history of
and adults 2%), myalgia (2%) hypertriglyceridemia-induced pancreatitis. The Ameri-
Respiratory: Nasopharyngitis (children 5% to 6%), can College of Cardiology/American Heart Association
upper respiratory tract infection (children and adults recommends avoiding use in patients with baseline
3% to 5%), flu-like symptoms (children 4%), phar- fasting triglyceride levels ≥300 mg/dL (ACC/AHA
yngitis (3%), rhinitis (children 2%) [Grundy 2018]). Use with caution in patients using
<1%, postmarketing, and/or case reports: Abdominal insulin, thiazolidinediones, or sulfonylureas (may cause
distension, dysphagia, esophageal obstruction, fecal increased triglyceride concentrations) or in patients
impaction, flatulence, worsening of hemorrhoids, susceptible to fat-soluble vitamin deficiencies. Use is
increased serum transaminases, infection, intestinal not recommended in patients with gastroparesis, other
obstruction, pancreatitis, unstable angina pectoris severe GI motility disorders, or a history of major GI
Dosing tract surgery or patients at risk for bowel obstruction.
Adult & Geriatric Use tablets with caution in patients with dysphagia or
Diarrhea associated with bile acid malabsorption swallowing disorders; use the oral suspension form of
(off-label use): Oral: 3.75 g/day in 1 or 2 divided colesevelam due to large tablet size and risk for esoph-
doses (Beigel 2014; Wilcox 2014) ageal obstruction.
360
COLISTIMETHATE
Minimal effects are seen on HDL-C and triglyceride Colesevelam may interfere with maternal vitamin
levels. Secondary causes of hypercholesterolemia absorption; therefore, regular supplementation may
should be excluded before initiation. Colesevelam has not be adequate.
not been studied in Fredrickson Type I, III, IV, or V Colesevelam may reduce the efficacy of oral contra-
dyslipidemias. Colesevelam is not indicated for the ception; administer oral contraceptives at least 4 hours
management of type 1 diabetes, particularly in the prior to colesevelam.
acute management (eg, DKA). It is also not indicated Breastfeeding Considerations
in type 2 diabetes mellitus as monotherapy and must be Due to lack of systemic absorption, colesevelam is not
used as an adjunct to diet, exercise, and glycemic expected to be present in breast milk.
control with insulin or oral antidiabetic agents. The When treatment for hypercholesterolemia in breast-
use of colesevelam in pediatric patients with type 2 feeding women is needed, therapy with bile acid
diabetes has not been evaluated. Combination with sequestrants may be considered, and therapy with
dipeptidyl peptidase 4 inhibitors or thiazolidinediones colesevelam is preferred (Jacobson 2015;
has not been studied extensively. There is no evidence NICE 2008).
of macrovascular disease risk reduction with colese- Product Availability Welchol 3.75 g chewable bars:
velam. FDA approved April 2019; availability anticipated in July
Use with caution in patients susceptible to fat-soluble 2019. Consult the prescribing information for additional
information.
vitamin deficiencies. Absorption of fat soluble vitamins
A, D, E, and K may be decreased; patients should take Dosage Forms Considerations Welchol contains
phenylalanine 27 mg per 3.75 gram packet
vitamins ≥4 hours before colesevelam. Potentially sig-
nificant drug-drug interactions may exist, requiring dose Dosage Forms: US
Packet, Oral:
or frequency adjustment, additional monitoring, and/or
Welchol: 3.75 g (30 ea)
selection of alternative therapy. Some products may
Generic: 3.75 g (30 ea)
contain phenylalanine. Not for use in patients with
Tablet, Oral:
diabetic ketoacidosis (DKA) or patients with type 1
Welchol: 625 mg
diabetes mellitus. Generic: 625 mg
Drug Interactions
Metabolism/Transport Effects None known. Tablet, oral:
Avoid Concomitant Use Lodalis: 625 mg
Avoid concomitant use of Colesevelam with any of the
following: Mycophenolate
Increased Effect/Toxicity There are no known sig- Colistimethate (koe lis ti METH ate)
nificant interactions involving an increase in effect. Brand Names: US Coly-Mycin M
Decreased Effect Brand Names: Canada Coly-Mycin M
Colesevelam may decrease the levels/effects of: Pharmacologic Category Antibiotic, Miscellaneous
Amiodarone; Chenodiol; Cholic Acid; Corticosteroids
Use Treatment of acute or chronic infections due to
(Oral); CycloSPORINE (Systemic); Deferasirox; Estro- sensitive strains of certain gram-negative bacilli (partic-
gen Derivatives (Contraceptive); Ethinyl Estradiol; ularly Pseudomonas aeruginosa) which are resistant to
Ezetimibe; Glimepiride; GlipiZIDE; GlyBURIDE; Leflu- other antibacterials or in patients allergic to other anti-
nomide; Lomitapide; Loop Diuretics; Methotrexate; bacterials
Multivitamins/Fluoride (with ADE); Multivitamins/Min- Local Anesthetic/Vasoconstrictor Precautions
erals (with ADEK, Folate, Iron); Multivitamins/Minerals No information available to require special precautions
(with AE, No Iron); Mycophenolate; Niacin; Nonster- Effects on Dental Treatment No significant effects or
oidal Anti-Inflammatory Agents; Norethindrone; Obe- complications reported
ticholic Acid; Olmesartan; Phenytoin; Pravastatin; Effects on Bleeding No information available to
Progestins (Contraceptive); Propranolol; Raloxifene; require special precautions
Teriflunomide; Tetracyclines; Thiazide and Thiazide- Adverse Reactions
Like Diuretics; Thyroid Products; Ursodiol; Vancomy- >10%:
cin; Vitamin D Analogs; Vitamin K Antagonists Genitourinary: Nephrotoxicity (18% to 26% [Dalfino
Dietary Considerations Some products may contain 2012; Oliveira 2009])
phenylalanine. Renal: Acute renal failure (33% to 60% [Akajagbor
Pharmacodynamics/Kinetics 2013; Deryke 2010])
Onset of Action 1% to 10%:
Lipid lowering: Therapeutic: ~2 weeks Central nervous system: Neurotoxicity (7%; higher
Reduction of hemoglobin A1C (Type II diabetes): 4-6 incidence with high-dose IV use in cystic fibrosis
weeks initial onset; 12-18 weeks maximal effect [Bosso 1991; Koch-Weser 1970])
Pregnancy Considerations Frequency not defined:
Colesevelam is not absorbed systemically following oral Central nervous system: Dizziness, oral paresthesia,
administration and maternal use is not expected to paresthesia, peripheral paresthesia, seizures,
result in fetal exposure to the drug. slurred speech, vertigo
Dermatologic: Pruritus, skin rash, urticaria
Lipid concentrations increase during pregnancy as Gastrointestinal: Clostridioides (formerly Clostridium)
required for normal fetal development. When increases difficile-associated diarrhea, gastric distress
are greater than expected, supervised dietary interven- Genitourinary: Decreased urine output
tion should be initiated. Bile acid sequestrants are Hypersensitivity: Anaphylaxis
recommended when treatment is needed, and therapy Renal: Decreased creatinine clearance, increased
with colesevelam is preferred (Avis 2009; Jacob- blood urea nitrogen, increased serum creatinine
son 2015). Respiratory: Apnea, respiratory distress
361
COLISTIMETHATE
Miscellaneous: Fever Adverse Reactions

Mechanism of Action Colistimethate (or the sodium Dupuytren's contracture:
salt [colistimethate sodium]) is the inactive prodrug that >10%:
is hydrolyzed to colistin, which acts as a cationic Cardiovascular: Peripheral edema (primarily as swel-
detergent and damages the bacterial cytoplasmic mem- ling of injected hand: 73% to 77%)
brane causing leaking of intracellular substances and Dermatologic: Pruritus (4% to 15%), hemorrhagic
cell death blister (12%)
Pharmacodynamics/Kinetics Hematologic & oncologic: Bruise (59% to 70%), lym-
Half-life Elimination IM, IV: Colistimethate: 2 to 3 phadenopathy (13%)
hours Immunologic: Antibody development (≥86%; neutraliz-
Critically ill: Infants (including premature infants), Chil- ing antibodies: AUX-I: 10%; AUX-II: 21%)
Local: Bleeding at injection site (6% to 38%), injection
dren, Adolescents, and Adults: IV: Colistimethate:
site reaction (35%; includes erythema, inflammation,
2.3 hours; Colistin: 14.4 hours (Plachouras 2009)
irritation), swelling at injection site (5% to 24%),
Cystic fibrosis: IV: Colistin: ~3.5 hours (Li 2003) tenderness at injection site (24%), pain at injection
ESRD patients receiving CAPD: IV: Colistin: 13.2 site (14%)
hours (Koomanachai 2014) Neuromuscular & skeletal: Limb pain (35% to 51%)
Time to Peak Miscellaneous: Laceration (9% to 22%)
Healthy volunteers: IV: Colistin: 2 hours (range: 1 to 4 1% to 10%:
hours) (Couet 2011) Central nervous system: Lymph node pain (8%), axil-
Critically ill: IV: Colistin: ~7 hours (Plachouras 2009) lary pain (6% to 7%)
Pregnancy Risk Factor C Dermatologic: Erythema (6%), ecchymoses (5%)
Pregnancy Considerations Adverse events have Local: Hematoma at injection site (8%)
been observed in animal reproduction studies. Colisti- <1%, postmarketing, and/or case reports: Anaphylaxis,
methate crosses the placenta in humans. antibody development (IgE; increased with successive
injections), causalgia, ligament disorder, pulley rup-
ture, rupture of tendon, sensory disturbance, vaso-
Collagen (Absorbable) (KOL la jen, ab SORB able) depressor syncope
Peyronie disease:
Related Information >10%:
Antiplatelet and Anticoagulation Considerations in Den- Genitourinary: Penile hematoma (66%; severe: 4% to
tistry on page 1454 6%), penile swelling (55%), penile pain (45%), penile
Brand Names: US CollaCote; CollaPatch; CollaPlug; ecchymoses (15%), penile popping sensation (13%)
HeliCote; HeliPlug; HeliTape Immunologic: Antibody development (55% to >99%;
Pharmacologic Category Hemostatic Agent neutralizing antibodies: AUX-I: 60%; AUX-II: 52%; no
Use Hemostatic correlation to clinical response or adverse reaction)
Local Anesthetic/Vasoconstrictor Precautions 1% to 10%:
No information available to require special precautions Central nervous system: Procedural pain (2%), supra-
pubic pain (1%)
Dermatologic: Hemorrhagic blister (5%), genital pruri-
tus (3%), skin discoloration (2%), localized vesicu-
Effects on Bleeding No information available to lation (injection site, 1%)
require special precautions Genitourinary: Blisters on penis (3%), painful erection
Adverse Reactions Frequency not defined. Reactions (3%), erectile dysfunction (2%), dyspareunia (1%)
listed are based on reports for other agents in this same Local: Itching at injection site (1% to 4%), localized
pharmacologic class and may not be specifically edema (1%)
reported for collagen (adsorbable/dental). Miscellaneous: Nodule (1%)
Hypersensitivity: Hypersensitivity reaction <1%, postmarketing, and/or case reports: Penile frac-
Miscellaneous: Foreign body reaction ture, sudden penile detumescence
<1%, postmarketing, and/or case reports: Seroma (sub- Mechanism of Action Collagenase clostridium histo-
galeal) lyticum contains two forms of microbial collagenase
Mechanism of Action The highly porous sponge (Collagenase AUX-I and Collagenase AUX-II) isolated
structure absorbs blood and wound exudate. The colla- and purified from the fermentation of Clostridium histo-
gen component causes aggregation of platelets which lyticum bacteria; collagenase lyses collagen, leading to
bind to collagen fibrils. The aggregated platelets degra- enzymatic disruption of contracted Dupuytren cord or
Peyronie plaque (both comprised primarily of collagen).
nulate, releasing coagulation factors that promote the
formation of fibrin.
been observed in animal reproduction studies. Pharma-
Collagenase (Systemic) (KOL la je nase) cokinetic studies in humans did not show quantifiable
systemic levels following intralesional injection into a
Brand Names: US Xiaflex Dupuytren cord; however, low levels were quantifiable
Brand Names: Canada Xiaflex in the plasma following administration into the penile
Pharmacologic Category Enzyme plaque. IgE-anti-drug antibodies commonly develop in
Use treated patients; effects to the fetus are unknown.
Dupuytren contracture: Treatment of adults with
Dupuytren contracture with a palpable cord Collagenase (Topical) (KOL la je nase)
Peyronie disease: Treatment of adult men with Peyr-
onie disease with a palpable plaque and curvature Brand Names: US Santyl
deformity of at least 30 degrees at the start of therapy Brand Names: Canada Santyl
362
CORTICORELIN
Pharmacologic Category Enzyme, Topical Debride- and undergo the release phenomenon. This triggers
ment aggregation of the platelets into thrombi in the inter-
Use Dermal ulcers: Debriding chronic dermal ulcers stices of the fibrous mass, initiating the formation of a
and severely burned areas. physiologic platelet plug.
No information available to require special precautions Onset of Action Hemostasis: 2 to 5 minutes
complications reported Copper IUD (KOP er eye uh dee)
require special precautions Brand Names: US Paragard Intrauterine Copper
Adverse Reactions Frequency not defined. Pharmacologic Category Contraceptive
Local: Application site burning, application site irritation, Use Contraception: For prevention of pregnancy, intra-
application site pain uterine device (IUD) may be in place for up to 10 years
<1%, postmarketing and/or case reports: Hypersensi- Local Anesthetic/Vasoconstrictor Precautions
tivity reaction No information available to require special precautions
Mechanism of Action Collagenase is an enzyme Effects on Dental Treatment No significant effects or
derived from the fermentation by Clostridium histolyti- complications reported
cum and differs from other proteolytic enzymes in that Effects on Bleeding No information available to
its enzymatic action has a high specificity for native and require special precautions
denatured collagen in necrotic tissue; collagenase will
not attack collagen in healthy tissue or newly formed
Dermatologic: Urticaria (allergic)
granulation tissue. Therefore, collagenase is effective
Endocrine & metabolic: Hypermenorrhea, spotty men-
for the removal of detritus, formation of granulation
tissue, and subsequent epithelization of dermal ulcers struation
and severely burned areas. Genitourinary: Abnormal vaginal hemorrhage, cervical
perforation, dysmenorrhea, dyspareunia, ectopic
Pregnancy Considerations It is not known if collage-
nase is absorbed systemically following topical applica- pregnancy, embedment of intrauterine system in the
tion. myometrium, leukorrhea, pelvic cramps, pelvic pain,
spontaneous migration of the IUD, uterine perforation,
vaginitis
Collagen Hemostat (KOL la jen HEE moe stat) Hematologic & oncologic: Anemia
Miscellaneous: Device expulsion
Related Information Neuromuscular & skeletal: Back pain
Antiplatelet and Anticoagulation Considerations in Den- Mechanism of Action The mechanism of action is not
tistry on page 1454 well defined but may involve interfering with sperm
Brand Names: US Actifoam Collagen Sponge; Avi- transport, fertilization, and prevention of implantation.
tene; Avitene Flour; Endo Avitene; Syringe Avitene; A copper IUD may prevent fertilization by interfering
Ultrafoam Sponge 2x6.25x7CM; Ultrafoam Sponge with the ability of sperm to reach the fallopian tube, or
8x12.5x1CM; Ultrafoam Sponge 8x12.5x3CM; Ultra- decrease the sperm's ability to fertilize by causing a
foam Sponge 8x25x1CM; Ultrafoam Sponge
foreign body reaction and chemical changes that may
8x6.25x1CM
be toxic. Implantation can rarely occur with a copper
Brand Names: Canada Avitene IUD; however, the number of fertilized ova is decreased
Pharmacologic Category Hemostatic Agent when compared to sexually active women not using a
Use Hemostasis: Adjunct to hemostasis in surgical contraceptive. When fertilized ova are present, they do
procedures when control of bleeding by ligature or not develop normally (Rivera, 1999). The number of
conventional procedures is ineffective or impractical. women with a copper IUD who have an unintended
Local Anesthetic/Vasoconstrictor Precautions pregnancy within the first year of insertion following
No information available to require special precautions typical use and perfect use is <1%.
Effects on Dental Treatment No significant effects or Pregnancy Considerations Use during pregnancy is
complications reported contraindicated. An increased risk of birth defects has
Effects on Bleeding Used in surgical procedures as not been observed from the copper released from the
an adjunct to hemostasis when control of bleeding by device. However, the risk of spontaneous abortion,
ligature or conventional procedures is ineffective or premature delivery, sepsis, septic shock, and death
impractical. (rare) are increased if an intrauterine pregnancy occurs
Adverse Reactions Frequency not defined. with the IUD in place. Premature labor and delivery may
Miscellaneous: Adhesion formation, allergic reaction, also occur.
edema, foreign body reaction, hematoma, inflamma-
tion, potentiation of infection
Postmarketing and/or case reports: Numbness, pain, Corticorelin (kor ti koe REL in)
paralysis, subgaleal seroma; alveolalgia and transient
laryngospasm with dental use Brand Names: US Acthrel
Mechanism of Action Collagen hemostat is an Pharmacologic Category Diagnostic Agent
absorbable topical hemostatic agent prepared from Use Cushing syndrome, differential diagnosis: Used
purified bovine corium collagen and shredded into as a diagnostic aid to differentiate between pituitary and
fibrils. Physically, microfibrillar collagen hemostat yields ectopic production of ACTH in patients with ACTH-
a large surface area. Chemically, it is collagen with dependent disease
hydrochloric acid noncovalently bound to some of the Local Anesthetic/Vasoconstrictor Precautions
available amino groups in the collagen molecules. No information available to require special precautions
When in contact with a bleeding surface, collagen Effects on Dental Treatment No significant effects or
hemostat attracts platelets which adhere to its fibrils complications reported
363
CORTICORELIN
Effects on Bleeding No information available to Infantile spasms: Treatment of infantile spasms in

require special precautions infants and children younger than 2 years. Note:
Adverse Reactions Frequency not always defined. Corticotropin is the preferred treatment in most
Incidence of adverse effects is dependent upon dose. patients (AAN [Go 2012])
Cardiovascular: Decreased blood pressure (7%), asys- Multiple sclerosis: Treatment of acute exacerbations
tole, flushing (face, neck, and upper chest), palpita- of multiple sclerosis in adults. Note: Treatment guide-
tions (Corticorelin 2004) lines recommend the use of high dose IV or oral
Central nervous system: Tonic-clonic seizures (1%), methylprednisolone for acute exacerbations of multi-
dizziness, (Corticorelin 2004), metallic taste (Cortico- ple sclerosis (AAN [Scott 2011]; NICE 2014). Cortico-
relin 2004) tropin may be an alternative therapy if IV
Gastrointestinal: Vomiting (Corticorelin 2004), xerosto- corticosteroids cannot be administered or are not
mia (Corticorelin 2004) tolerated (Simsarian 2011).
Respiratory: Dyspnea (urge to inspire) Ophthalmic diseases: Treatment of severe acute and
<1%, postmarketing, and/or case reports: Angioedema, chronic allergic and inflammatory processes involving
chest tightness, hypotension (severe), increased heart the eye and its adnexa (eg, keratitis, iritis, iridocyclitis,
rate, loss of consciousness, tachycardia (severe), diffuse posterior uveitis, choroiditis, optic neuritis,
wheezing chorioretinitis, anterior segment inflammation). Note:
Mechanism of Action Corticorelin ovine, a peptide of FDA approved use; however, available data to support
ovine corticotropin-releasing hormone (oCRH) and an use in these conditions is limited.
analogue of human CRH (hCRH), stimulates adreno- Symptomatic sarcoidosis: Treatment of symptomatic
corticotropic hormone (ACTH) release from the anterior sarcoidosis. Note: FDA approved use; however, avail-
pituitary. ACTH stimulates the adrenal cortex to produce able data to support use in this condition is limited.
cortisol. Depending on the plasma ACTH and cortisol Glucocorticoids (eg, prednisone) are generally recom-
response following the corticorelin stimulation test, the mended as first-line treatment for sarcoidosis (Soto-
results aid the clinician in the differentiation between the Gomez 2016).
source of ACTH-dependent hypercortisolism (pituitary Local Anesthetic/Vasoconstrictor Precautions
vs ectopic). No information available to require special precautions
Pharmacodynamics/Kinetics Effects on Dental Treatment No significant effects or
Onset of Action IV: complications reported
Plasma ACTH concentration: Increases 2 minutes Effects on Bleeding No information available to
after injection require special precautions
Plasma cortisol concentration: Increases within 10 Adverse Reactions Adverse events associated with
minutes after injection infantile spasm treatment unless otherwise indicated.
Peak effect: Response to injection is biphasic with a Other adverse events associated with corticosteroids
second lower peak 2 to 3 hours postinjection; basal may also occur.
and peak response levels vary depending on AM or >10%:
PM administration. In general, baseline ACTH and Cardiovascular: Hypertension (11%)
cortisol concentrations are higher in the AM. Central nervous system: Convulsions (12%)
Plasma ACTH concentration: Initial peak: 15 to 60 Infection: Infection (20%)
minutes after injection 1% to 10%:
Plasma cortisol concentration: Initial peak at 30 to Cardiovascular: Cardiac abnormality (3%)
120 minutes after injection Central nervous system: Irritability (7%)
Duration of Action IV: Plasma ACTH and cortisol Endocrine & metabolic: Cushingoid state (3%)
concentrations remain elevated for up to 2 hours after Gastrointestinal: Decreased appetite (3%), diarrhea
injection. (3%), vomiting (3%), weight gain (1%)
Half-life Elimination t1/2: Exhibits biexponential Infection: Candidiasis (≥2%)
decay; Fast component: 11.6 ± 1.5 minutes; slow Otic: Otitis media (≥2%)
component: 73 ± 8 minutes Respiratory: Pneumonia (≥2%), upper respiratory tract
infection (≥2%), nasal congestion (1%)
Pregnancy Considerations Animal reproduction
studies have not been conducted.
Cardiovascular: Increased blood pressure (associated
Corticotropin (kor ti koe TROE pin) with cortisol elevation)
Central nervous system: Behavioral changes (associ-
Brand Names: US HP Acthar ated with cortisol elevation), mood changes (associ-
Pharmacologic Category Adrenocorticotropin Stimu- ated with cortisol elevation)
lating Hormone Endocrine & metabolic: Decreased glucose tolerance
Use (associated with cortisol elevation), fluid retention
Diuresis in nephrotic syndrome: To induce a diuresis (associated with cortisol elevation)
or remission of proteinuria in patients with nephrotic Gastrointestinal: Increased appetite (associated with
syndrome without uremia of the idiopathic type or due cortisol elevation), weight gain (associated with cor-
to lupus erythematosus. Note: Based on the 2012 tisol elevation)
KDIGO clinical practice guidelines for glomeruloneph- <1%, postmarketing and/or case reports: Abdominal
ritis, recommendations cannot be made for the use of distention, carbohydrate intolerance (infants), cardiac
corticotropin for initial therapy or relapses of idiopathic failure, diaphoresis (adults), dizziness, epidermal thin-
membranous nephropathy until more randomized, ning (adults), facial erythema, headache (adults),
controlled trials are conducted. The KDIGO guidelines hirsutism (adults), hypersensitivity reaction, hypokale-
do not include recommendations for use of cortico- mic alkalosis (infants), impaired intestinal carbohy-
tropin in the treatment of proteinuria due to lupus drate absorption, injection site reaction, intracranial
nephritis (KDIGO 2012). hemorrhage (adults), myasthenia, nausea, necrotizing
364
CORTISONE
angiitis (adults), pancreatitis (adults), reversible cere- choice; synthetic analogs may be used in conjunction
bral atrophy (infants; usually secondary to hyperten- with mineralocorticoids when applicable; in infancy,
sion), shock (adults), subdural hematoma, ulcerative mineralocorticoid supplementation is of particular
esophagitis, vertebral compression fracture (infants), importance).
vertigo (adults) Gastrointestinal diseases: To tide the patient over a
Mechanism of Action Stimulates the adrenal cortex to critical period of the disease in regional enteritis and
secrete adrenal steroids (including cortisol), weakly ulcerative colitis.
androgenic substances, and aldosterone Hematologic disorders: Acquired (autoimmune)
Pharmacodynamics/Kinetics hemolytic anemia, congenital (erythroid) hypoplastic
Onset of Action Maximum effect: Cortisol serum anemia, erythroblastopenia (red blood cell [RBC] ane-
concentration: IM, SubQ: 3-12 hours mia), immune thrombocytopenia (formerly known as
Duration of Action Repository: 10-25 hours, up to 3 idiopathic thrombocytopenic purpura) in adults, sec-
days ondary thrombocytopenia in adults.
Half-life Elimination ACTH: 15 minutes Neoplastic diseases: Palliative management of leuke-
Pregnancy Risk Factor C mias and lymphomas in adults; acute leukemia of
Pregnancy Considerations Adverse events were childhood.
observed in animal reproduction studies. Endogenous Ophthalmic diseases: Severe acute and chronic aller-
corticotropin concentrations are increased near delivery gic and inflammatory processes involving the eye and
(Smith, 2007). its adnexa (eg, allergic conjunctivitis, allergic corneal
marginal ulcers, anterior segment inflammation, cho-
Some studies have shown an association between first rioretinitis, diffuse posterior uveitis and choroiditis,
trimester systemic corticosteroid use and oral clefts keratitis, herpes zoster ophthalmicus, iritis and irido-
(Park-Wyllie 2000; Prada, 2003). Systemic corticoste- cyclitis, optic neuritis, sympathetic ophthalmia).
roids may also influence fetal growth (decreased birth Renal diseases: To induce diuresis or remission of
weight); however, information is conflicting (Lunghi proteinuria in nephrotic syndrome, without uremia, of
2010). When systemic corticosteroids are needed in the idiopathic type or that is caused by lupus eryth-
pregnancy, it is generally recommended to use the ematosus.
lowest effective dose for the shortest duration of time, Respiratory diseases: Aspiration pneumonitis, beryl-
avoiding high doses during the first trimester (Leach- liosis, fulminating or disseminated pulmonary tuber-
man 2006; Lunghi 2010; Makol 2011; Østensen 2009). culosis when used concurrently with appropriate
Prescribing and Access Restrictions H.P. Acthar® antituberculosis chemotherapy, Loeffler syndrome
Gel is only available through specialty pharmacy dis- not manageable by other means, symptomatic sarcoi-
tribution and not through traditional distribution sources dosis.
(eg, wholesalers, retail pharmacies). Hospitals wishing Rheumatic disorders: Adjunctive therapy for short-
to acquire H.P. Acthar® Gel should contact CuraScript term administration (to tide the patient over an acute
Specialty Distribution (1-877-599-7748). episode or exacerbation) in acute and subacute bursi-
After treatment is initiated, discharge or outpatient pre- tis; acute gouty arthritis; acute nonspecific tenosyno-
scriptions should be submitted to the Acthar Support vitis; ankylosing spondylitis; epicondylitis;
and Access Program (A.S.A.P.) in order to ensure an posttraumatic osteoarthritis; psoriatic arthritis; rheu-
uninterrupted supply of the medication. The Acthar matoid arthritis (RA), including juvenile RA (select
Referral/Prescription form is available online at http:// cases may require low-dose maintenance therapy);
www.acthar.com/files/Acthar-Prescription-Referral- and synovitis of osteoarthritis. During an exacerbation
Form.pdf. or as maintenance therapy in select cases of acute
rheumatic carditis, systemic dermatomyositis (poly-
Additional information is available for the A.S.A.P. at myositis), and systemic lupus erythematosus.
http://www.acthar.com/healthcare-professionals/physi- Miscellaneous: Tuberculous meningitis with subarach-
cian-patient-referrals or by calling 1-888-435-2284. noid block or impending block when used concurrently
with appropriate antituberculous chemotherapy; trich-
Cortisone (KOR ti sone) inosis with neurologic or myocardial involvement.
Related Information No information available to require special precautions
Respiratory Diseases on page 1467 Effects on Dental Treatment A compromised
Triamcinolone (Systemic) on page 1296 immune response may occur if patient has been taking
Pharmacologic Category Corticosteroid, Systemic systemic cortisone. The need for corticosteroid cover-
Use age in these patients should be considered before any
Allergic states: Control of severe or incapacitating dental treatment; consult with physician.
allergic conditions intractable to adequate trials of Effects on Bleeding Variable effects on anticoagulant
conventional treatment of atopic dermatitis, bronchial therapy are observed with glucocorticoids, such as
asthma, contact dermatitis, drug hypersensitivity reac- cortisone.
tions, seasonal or perennial allergic rhinitis, and serum Adverse Reactions Frequency not defined.
sickness. >10%:
Dermatologic diseases: Bullous dermatitis herpetifor- Central nervous system: Insomnia, nervousness
mis, exfoliative dermatitis, mycosis fungoides, pem- Gastrointestinal: Dyspepsia, increased appetite
phigus, severe erythema multiforme (Stevens- 1% to 10%:
Johnson syndrome), severe psoriasis, severe sebor- Endocrine & metabolic: Diabetes mellitus, hirsutism
rheic dermatitis. Neuromuscular & skeletal: Arthralgia
Endocrine disorders: Congenital adrenal hyperplasia, Ophthalmic: Cataract, glaucoma
hypercalcemia associated with cancer, nonsuppura- Respiratory: Epistaxis
tive thyroiditis, primary or secondary adrenocortical <1%, postmarketing, and/or case reports: Abdominal
insufficiency (hydrocortisone or cortisone is the first distention, acne vulgaris, alkalosis, amenorrhea,
365
CORTISONE
amyotrophy, bone fracture, bruise, Cushing's syn- Effects on Dental Treatment Key adverse event(s)
drome, decreased glucose tolerance, delirium, related to dental treatment: Stomatitis and taste alter-
edema, emotional lability, euphoria, fluid retention, ation have been reported
growth suppression, hallucination, headache, HPA- Effects on Bleeding No reports of bleeding or throm-
axis suppression, hyperglycemia, hyperpigmentation, bocytopenia
hypersensitivity reaction, hypertension, hypokalemia, Adverse Reactions
myalgia, nausea, osteoporosis, pancreatitis, peptic >10%:
ulcer, pseudotumor cerebri, psychosis, seizure, skin Cardiovascular: Edema (31% to 49%), bradycardia
atrophy, sodium retention, ulcerative esophagitis, ver- (5% to 14%)
tigo, vomiting Central nervous system: Fatigue (27% to 29%), neu-
Mechanism of Action Decreases inflammation by ropathy (19% to 25%; includes dysesthesia, gait
suppression of migration of polymorphonuclear leuko- disturbance, hypoesthesia, muscular weakness,
cytes and reversal of increased capillary permeability neuralgia, peripheral neuropathy, parasthesia,
Pharmacodynamics/Kinetics peripheral sensory neuropathy, polyneuropathy,
Half-life Elimination ~0.5 hours burning sensation in skin), headache (22%), dizzi-
ness (18% to 22%)
Time to Peak ~2 hours
Pregnancy Considerations Adverse events have Endocrine & metabolic: Hypophosphatemia (28% to
been observed with corticosteroids in animal reproduc- 32%), hypokalemia (18%)
tion studies. Cortisone crosses the placenta (Migeon Gastrointestinal: Diarrhea (60% to 61%), nausea (55%
1957). Some studies have shown an association to 56%), vomiting (46% to 47%), constipation (42%
between first trimester systemic corticosteroid use and to 43%), decreased appetite (30%), abdominal pain
oral clefts (Park-Wyllie 2000; Pradat 2003). Systemic (26%), dysgeusia (26%), dyspepsia (8% to 14%)
corticosteroids may also influence fetal growth Genitourinary: Decreased estimated GFR (eGFR)
(decreased birth weight); however, information is con- (<90 mL/min/1.73 m2: 76%; <60 mL/min/1.73 m2:
flicting (Lunghi 2010). Hypoadrenalism may occur in 38%; <30 mL/min/1.73 m2: 4%)
newborns following maternal use of corticosteroids in Hematologic & oncologic: Neutropenia (49% to 52%;
pregnancy (monitor). When systemic corticosteroids grades 3/4: 11% to 12%), lymphocytopenia (48% to
are needed in pregnancy, it is generally recommended 51%; grades 3/4: 7% to 9%)
to use the lowest effective dose for the shortest duration Hepatic: Increased serum ALT (76% to 79%),
of time, avoiding high doses during the first trimester increased serum AST (61% to 66%)
(Leachman 2006; Lunghi 2010; Makol 2011; Østensen Neuromuscular & skeletal: Limb pain (16%)
2009). Cortisone may be used (alternative agent) to Ophthalmic: Visual disturbance (60% to 71%; onset:
treat primary adrenal insufficiency (PAI) in pregnant <2 weeks; includes blurred vision, diplopia, photo-
women. Pregnant women with PAI should be monitored phobia, photopsia, visual acuity decreased, visual
at least once each trimester (Bornstein 2016). brightness, visual field defect, visual impairment,
vitreous floaters)
Respiratory: Upper respiratory tract infection (26%
Crizotinib (kriz OH ti nib) to 32%)
Related Information 1% to 10%:
Clinical Risk Related to Drugs Prolonging QT Interval Cardiovascular: Pulmonary embolism (6%), prolonged
on page 1462 Q-T interval on ECG (5% to 6%), syncope (1%
Brand Names: US Xalkori to 3%)
Brand Names: Canada Xalkori Endocrine & metabolic: Weight loss (10%), weight
Pharmacologic Category Antineoplastic Agent, Ana- gain (8%), diabetic ketoacidosis (≤2%), decreased
plastic Lymphoma Kinase Inhibitor; Antineoplastic plasma testosterone (1%; hypogonadism)
Agent, Tyrosine Kinase Inhibitor Gastrointestinal: Dysphagia (10%), esophagitis (2%
Use Non-small cell lung cancer, metastatic: Treat- to 6%)
ment of metastatic non-small cell lung cancer (NSCLC) Hepatic: Hepatic failure (1%)
in patients whose tumors are anaplastic lymphoma Infection: Sepsis (≤5%)
kinase (ALK)-positive or are ROS1-positive (as Neuromuscular & skeletal: Muscle spasm (8%)
detected by an approved test) Renal: Renal cyst (3% to 5%)
Respiratory: Adult respiratory distress syndrome
(≤5%), interstitial pulmonary disease (≤5%; grades
Crizotinib is one of the drugs confirmed to prolong the
3/4: 1%; includes acute respiratory distress syn-
QT interval and is accepted as having a risk of causing
drome, pneumonitis), pneumonia (≤5%), respiratory
torsade de pointes. The risk of drug-induced torsade de failure (≤5%), dyspnea (2%)
pointes is extremely low when a single QT interval Frequency not defined:
prolonging drug is prescribed. In terms of epinephrine, Cardiovascular: Cardiac arrhythmia, septic shock
it is not known what effect vasoconstrictors in the local <1%, postmarketing, and/or case reports: Hepatotox-
anesthetic regimen will have in patients with a known icity
history of congenital prolonged QT interval or in patients Mechanism of Action Crizotinib is a tyrosine kinase
taking any medication that prolongs the QT interval. receptor inhibitor which inhibits anaplastic lymphoma
Until more information is obtained, it is suggested that kinase (ALK), Hepatocyte Growth Factor Receptor
the clinician consult with the physician prior to the use of (HGFR, c-MET), ROS1 (c-ros), and Recepteur d’Ori-
a vasoconstrictor in suspected patients, and that the gine Nantais (RON). ALK gene abnormalities due to
vasoconstrictor (epinephrine, mepivacaine, and levo- mutations or translocations may result in expression of
nordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be oncogenic fusion proteins (eg, ALK fusion protein)
used with caution. which alter signaling and expression and result in
366
CROMOLYN (ORAL INHALATION)
increased cellular proliferation and survival in tumors Neuromuscular & skeletal: Myalgia (3%), arthralgia,
which express these fusion proteins. Approximately 2% lower extremity weakness, lupus erythematosus, stiff-
to 7% of patients with NSCLC have the abnormal ness of legs
echinoderm microtubule-associated protein-like 4, or Otic: Tinnitus
EML4-ALK gene (which has a higher prevalence in Respiratory: Dyspnea, pharyngitis
never smokers or light smokers and in patients with Mechanism of Action Prevents the mast cell release
adenocarcinoma). Inhibition of ALK, ROS1, and c-Met of histamine, leukotrienes, and slow-reacting substance
phosphorylation is concentration-dependent. Crizotinib of anaphylaxis by inhibiting degranulation after contact
selectively inhibits ALK tyrosine kinase, which reduces
with antigens
proliferation of cells expressing the genetic alteration. Pharmacodynamics/Kinetics
Onset of Action Response to treatment: Oral: May
Half-life Elimination Terminal: 42 hours
occur within 2 to 6 weeks
Time to Peak 4 to 6 hours
Half-life Elimination 80 to 90 minutes
Pregnancy Considerations Based on the mecha-
nism of action and data from animal reproduction Pregnancy Considerations Adverse events were not
studies, crizotinib may cause fetal harm if administered observed in animal reproduction studies. Systemic
during pregnancy. Females of reproductive potential absorption following oral administration is <1%.
should use adequate contraception during treatment
and for at least 45 days after the last crizotinib dose; Cromolyn (Oral Inhalation) (KROE moe lin)
males with female partners of reproductive potential
should use condoms during treatment and for at least Brand Names: Canada Nu-Cromolyn; PMS-Sodium
90 days after the final crizotinib dose. Crizotinib may Cromoglycate
cause reduced fertility in females and males of repro- Pharmacologic Category Mast Cell Stabilizer
ductive potential (based on animal studies). Use Prophylactic agent used for long-term (chronic)
Prescribing and Access Restrictions Available control of asthma; prevention of exercise-induced bron-
through specialty pharmacies. Further information may chospasm
be obtained from the manufacturer, Pfizer, at
1-877-744-5675, or at http://www.pfizerpro.com
Inhalation: Unpleasant taste.
Cromolyn (Systemic) (KROE moe lin) Effects on Bleeding No information available to
Brand Names: US Gastrocrom
Brand Names: Canada Nalcrom Adverse Reactions Frequency not always defined.
Central nervous system: Drowsiness
Pharmacologic Category Mast Cell Stabilizer
Dermatologic: Burning sensation of the nose, pruritus
Use
of nose
Food allergy: Nalcrom [Canadian product]: Treatment
of food allergy in conjunction with restriction of main Gastrointestinal: Nausea, stomach pain
causative allergens Hypersensitivity: Serum sickness
Systemic mastocytosis: Management of systemic Respiratory: Cough (20%; transient), wheezing (4%;
mastocytosis mild), epistaxis, nasal congestion, sneezing
Local Anesthetic/Vasoconstrictor Precautions <1%, postmarketing, and/or case reports: Anaphylaxis,
No information available to require special precautions anemia, angioedema, arthralgia, bronchospasm, diz-
Effects on Dental Treatment Key adverse event(s) ziness, dysuria, exfoliative dermatitis, headache,
related to dental treatment: hemoptysis, hoarseness, joint swelling, lacrimation,
Systemic: Glossitis, stomatitis, and unpleasant taste. laryngeal edema, nephrosis, myalgia, parotid gland
Effects on Bleeding No information available to enlargement, pericarditis, peripheral neuritis, photo-
require special precautions dermatitis, polymyositis, pulmonary infiltrates (with
Adverse Reactions eosinophilia), skin rash, urinary frequency, urticaria,
Cardiovascular: Chest pain, edema, flushing, palpita- vasculitis (periarteritis), vertigo
tions, tachycardia, ventricular premature contractions Mechanism of Action Prevents the mast cell release
Central nervous system: Headache (5%), irritability of histamine, leukotrienes, and slow-reacting substance
(2%), malaise (1%), anxiety, behavioral changes, of anaphylaxis by inhibiting degranulation after contact
burning sensation, convulsions, depression, dizzi- with antigens
ness, dizziness (postprandial), fatigue, hallucination, Pharmacodynamics/Kinetics
hypoesthesia, insomnia, lethargy, migraine, nervous- Half-life Elimination 80 to 90 minutes
ness, paresthesia, psychosis Time to Peak Serum: Inhalation: ~15 minutes
Dermatologic: Pruritus (3%), skin rash (2%), erythema,
skin photosensitivity, urticaria
Gastrointestinal: Diarrhea (5%), nausea (3%), abdomi- Pregnancy Considerations Adverse events were not
nal pain (2%), constipation, dyspepsia, dysphagia, observed in animal reproduction studies following SubQ
esophageal spasm, flatulence, glossitis, stomatitis, administration. Limited data suggest little or no placen-
unpleasant taste, vomiting tal transfer (Brogden 1974). Uncontrolled asthma is
Genitourinary: Dysuria, urinary frequency associated with adverse events on pregnancy. Although
Hematologic & oncologic: Neutropenia, pancytopenia, cromolyn sodium is considered to have a good safety
polycythemia, purpura profile, due to decreased efficacy, other agents are
Hepatic: Abnormal hepatic function tests preferred for the control of asthma in pregnancy (GINA
Hypersensitivity: Anaphylaxis, angioedema 2018).
367
CYANOCOBALAMIN
Cyanocobalamin (sye an oh koe BAL a min) Cyclobenzaprine (sye kloe BEN za preen)
Brand Names: US B-12 Compliance Injection; Nasco- Related Information

bal; Physicians EZ Use B-12; Vitamin Deficiency Sys- Dentin Hypersensitivity, Acid Erosion, High Caries
tem-B12 Index, Management of Alveolar Osteitis, and Xerosto-
Pharmacologic Category Vitamin, Water Soluble mia on page 1548
Use Vitamin B12 deficiency: Treatment of pernicious Temporomandibular Dysfunction (TMD), Chronic Pain,
anemia, vitamin B12 deficiency due to dietary deficien- and Fibromyalgia on page 1559
cies, gastrointestinal malabsorption, folic acid defi- Brand Names: US Amrix; Fexmid
ciency, parasitic infestation, inadequate secretion of Generic Availability (US) Yes
intrinsic factor, and inadequate utilization of B12 (eg, Pharmacologic Category Skeletal Muscle Relaxant
during neoplastic treatment); treatment of increased B12 Dental Use Treatment of muscle spasm associated with
requirements due to pregnancy, thyrotoxicosis, hemor- acute temporomandibular joint pain (TMJ)
rhage, malignancy, liver or kidney disease Use Muscle spasm: As an adjunct to rest and physical
Local Anesthetic/Vasoconstrictor Precautions therapy for short-term (2 to 3 weeks) relief of muscle
No information available to require special precautions spasm associated with acute, painful musculoskeletal
Effects on Dental Treatment No significant effects or conditions.
Adverse Reactions related to dental treatment: Xerostomia and changes in
>10%:
tinuation).
Central nervous system: Headache (IM: 20%; intra-
nasal: 4%)
Adverse Reactions
Neuromuscular & skeletal: Asthenia (IM: 16%; intra-
>10%:
nasal: 4%)
Central nervous system: Drowsiness (1% to 39%),
1% to 10%:
dizziness (1% to 11%)
Central nervous system: Paresthesia (4%) Gastrointestinal: Xerostomia (6% to 32%)
Gastrointestinal: Glossitis (nasal: 4%), nausea (4%) 1% to 10%:
Respiratory: Rhinitis (4% to 8%) Central nervous system: Fatigue (1% to 6%), head-
Frequency not defined: ache (1% to 5%), confusion (1% to 3%), decreased
Cardiovascular: Cardia c fai lur e, th ro mbo sis mental acuity (1% to 3%), irritability (1% to 3%),
(peripheral) nervousness (1% to 3%)
Dermatologic: Pruritus, skin rash (transient) Gastrointestinal: Dyspepsia (≤4%), abdominal pain
Endocrine & metabolic: Hypokalemia (1% to 3%), acid regurgitation (1% to 3%), constipa-
Gastrointestinal: Diarrhea tion (1% to 3%), diarrhea (1% to 3%), nausea (1% to
Hematologic & oncologic: Polycythemia vera, throm- 3%), unpleasant taste (1% to 3%)
bocythemia Neuromuscular & skeletal: Weakness (1% to 3%)
Hypersensitivity: Anaphylactic shock (IM/SubQ) Ophthalmic: Blurred vision (1% to 3%)
Respiratory: Pulmonary edema Respiratory: Pharyngitis (1% to 3%), upper respiratory
Miscellaneous: Swelling tract infection (1% to 3%)
Mechanism of Action Coenzyme for various meta- <1%, postmarketing, and/or case reports: Abnormal
bolic functions, including fat and carbohydrate metabo- dreams, abnormal hepatic function tests, abnormality
lism and protein synthesis, used in cell replication and in thinking, ageusia, agitation, anaphylaxis, angioe-
hematopoiesis dema, anorexia, anxiety, ataxia, cardiac arrhythmia,
Pharmacodynamics/Kinetics cholestasis, convulsions, depression, diaphoresis,
Onset of Action diplopia, disorientation, dysarthria, excitement (para-
Megaloblastic anemia: IM: doxical, children), facial edema, flatulence, gastritis,
Conversion of megaloblastic to normoblastic eryth- gastrointestinal pain, hallucination, hepatitis (rare),
roid hyperplasia within bone marrow: 8 hours hypertonia, hypotension, increased thirst, insomnia,
jaundice, malaise, muscle twitching, palpitations, par-
Increased reticulocytes: 2 to 5 days
esthesia, pruritus, psychosis, seizure, serotonin syn-
Complicated vitamin B12 deficiency: IM, SubQ: Reso-
drome, skin rash, syncope, tachycardia, tinnitus,
lution of:
tongue edema, tremor, urinary frequency, urinary
Psychiatric sequelae: 24 hours
retention, urticaria, vasodilation, vertigo, vomiting
Thrombocytopenia: 10 days
Dental Usual Dosage Treatment of muscle spasm
Granulocytopenia: 2 weeks
associated with acute TMJ pain (Burket 2008) (Note:
Time to Peak Serum: IM, SubQ: 30 minutes to 2 Do not use longer than 2-3 weeks): Oral:
hours; Intranasal: 1.25 ± 1.9 hours Adults: Initial: 5 mg 3 times/day; may increase to
Pregnancy Considerations Animal reproduction 7.5-10 mg 3 times/day if needed
studies have not been conducted. Water soluble vita- Elderly: 5 mg 3 times/day; plasma concentration and
mins cross the placenta. Absorption of vitamin B12 may incidence of adverse effects are increased in the
increase during pregnancy. Vitamin B12 requirements elderly; dose should be titrated slowly
may be increased in pregnant women compared to Dosing
nonpregnant women. Serum concentrations of vitamin Adult
B12 are higher in the neonate at birth than the mother Jaw pain due to temporomandibular disorder,
(IOM 1998). acute (off-label): Immediate release: Usual: 10 mg
368
CYCLOBENZAPRINE
once daily administered 1 to 2 hours before bedtime immediately if signs/symptoms arise. Concomitant use
(Alencar 2014; Herman 2002) or use within 14 days of discontinuing an MAO inhibitor
Muscle spasm: Oral: Note: Do not use longer than 2 is contraindicated.
to 3 weeks.
Extended release capsules not recommended for use in
Extended release: Usual: 15 mg once daily; some
mild-to-severe hepatic impairment or in the elderly.
patients may require up to 30 mg once daily
Potentially significant drug-drug interactions may exist,
Immediate release: Initial: 5 mg 3 times daily; may
increase up to 10 mg 3 times daily if needed
itoring, and/or selection of alternative therapy. Effects
Geriatric may be potentiated when used with other CNS depres-
Extended release: Use not recommended. sants or ethanol.
Immediate release: Initial: 5 mg; titrate dose slowly
and consider less frequent dosing.
Not effective in the treatment of spasticity due to cere-
Renal Impairment: Adult There are no dosage bral or spinal cord disease or in children with cerebral
adjustment provided in the manufacturer's labeling. palsy.
Hepatic Impairment: Adult Drug Interactions
Extended release: Mild to severe impairment: Use not Metabolism/Transport Effects Substrate of
recommended. CYP1A2 (major), CYP2D6 (minor), CYP3A4 (minor);
Immediate release: Note: Assignment of Major/Minor substrate status
Mild impairment: Initial: 5 mg; use with caution; based on clinically relevant drug interaction potential
titrate slowly and consider less frequent dosing Avoid Concomitant Use
Moderate to severe impairment: Use not recom- Avoid concomitant use of Cyclobenzaprine with any of
mended. the following: Aclidinium; Azelastine (Nasal); Bromper-
Pediatric Muscle spasm, treatment: Adolescents idol; Cimetropium; Dapoxetine; Eluxadoline; Glycopyr-
≥15 years: Oral: Immediate release tablet: Initial: rolate (Oral Inhalation); Glycopyrronium (Topical);
5 mg 3 times daily; may increase up to 10 mg 3 times Ipratropium (Oral Inhalation); Levosulpiride; Methyl-
daily if needed. Do not use longer than 2 to 3 weeks. ene Blue; Monoamine Oxidase Inhibitors; Orphena-
Renal Impairment: Pediatric There are no dosage drine; Oxatomide; Oxomemazine; Paraldehyde;
adjustments provided in the manufacturer's labeling. Potassium Chloride; Potassium Citrate; Revefenacin;
Hepatic Impairment: Pediatric Thalidomide; Tiotropium; Umeclidinium
Immediate release tablet: Adolescents ≥15 years: Increased Effect/Toxicity
Mild impairment: Initial: 5 mg; use with caution; Cyclobenzaprine may increase the levels/effects of:
titrate slowly and consider less frequent dosing Alcohol (Ethyl); Anticholinergic Agents; Antipsychotic
Moderate to severe impairment: Use not recom- Agents; Azelastine (Nasal); Blonanserin; Botulinum
mended Toxin-Containing Products; Brexanolone; Buprenor-
Mechanism of Action Centrally-acting skeletal muscle phine; Cimetropium; CNS Depressants; Eluxadoline;
relaxant pharmacologically related to tricyclic antide- Flunitrazepam; Glucagon; Glycopyrrolate (Oral Inha-
pressants; reduces tonic somatic motor activity influ- lation); HYDROcodone; Methotrimeprazine; Metoclo-
encing both alpha and gamma motor neurons pramide; MetyroSINE; Mirabegron; Mirtazapine;
Contraindications Hypersensitivity to cyclobenzaprine Monoamine Oxidase Inhibitors; Opioid Agonists;
or any component of the formulation; during or within 14 Orphenadrine; OxyCODONE; Paraldehyde; Piribedil;
days of MAO inhibitors; hyperthyroidism; heart failure; Potassium Chloride; Potassium Citrate; Pramipexole;
arrhythmias; heart block or conduction disturbances; Ramosetron; Revefenacin; ROPINIRole; Rotigotine;
acute recovery phase of MI Selective Serotonin Reuptake Inhibitors; Serotonin
Warnings/Precautions May cause CNS depression, Modulators; Suvorexant; Thalidomide; Thiazide and
which may impair physical or mental abilities; ethanol Thiazide-Like Diuretics; Tiotropium; Topiramate; Zolpi-
and/or other CNS depressants may enhance these dem
effects. Patients must be cautioned about performing
The levels/effects of Cyclobenzaprine may be
tasks which require mental alertness (eg, operating
increased by: Abiraterone Acetate; Aclidinium; Ali-
machinery or driving). Cyclobenzaprine shares the toxic
zapride; Amantadine; Antiemetics (5HT3 Antago-
potentials of the tricyclic antidepressants (including
nists); Antipsychotic Agents; Botulinum Toxin-
arrhythmias, tachycardia, and conduction time prolon-
Containing Products; Brimonidine (Topical); Bromopr-
gation) and the usual precautions of tricyclic antidepres-
ide; Bromperidol; Cannabidiol; Cannabis; Chloral
sant therapy should be observed; use with caution in
Betaine; Chlormethiazole; Chlorphenesin Carbamate;
patients with urinary hesitancy or retention, angle-clo-
CYP1A2 Inhibitors (Moderate); CYP1A2 Inhibitors
sure glaucoma or increased intraocular pressure, hep-
(Strong); Dapoxetine; Deferasirox; Dimethindene
atic impairment, or in the elderly.
(Topical); Doxylamine; Dronabinol; Droperidol; Esket-
Potentially life-threatening serotonin syndrome has amine; Glycopyrronium (Topical); HydrOXYzine; Ipra-
occurred with cyclobenzaprine when used in combina- tropium (Oral Inhalation); Kava Kava; Lofexidine;
tion with other serotonergic agents (eg, SSRIs, SNRIs, Magnesium Sulfate; Metaxalone; Methotrimeprazine;
TCAs, meperidine, tramadol, buspirone, MAO inhibi- Methylene Blue; Methylphenidate; Mianserin; Minocy-
tors), bupropion, and verapamil. Monitor patients cline; Nabilone; Obeticholic Acid; Oxatomide; Oxome-
closely especially during initiation/dose titration for mazine; Peginterferon Alfa-2b; Perampanel;
signs/symptoms of serotonin syndrome such as mental Pramlintide; Rufinamide; Sodium Oxybate; Tapenta-
status changes (eg, agitation, hallucinations); auto- dol; Tetrahydrocannabinol; Tetrahydrocannabinol and
nomic instability (eg, tachycardia, labile blood pressure, Cannabidiol; Tolperisone; Trimeprazine; Umeclidi-
diaphoresis); neuromuscular changes (eg, tremor, nium; Vemurafenib
rigidity, myoclonus); GI symptoms (eg, nausea, vomit- Decreased Effect
ing, diarrhea); and/or seizures. Discontinue cyclobenza- Cyclobenzaprine may decrease the levels/effects of:
prine and any concomitant serotonergic agent Acetylcholinesterase Inhibitors; Gastrointestinal
369
CYCLOBENZAPRINE
Agents (Prokinetic); Itopride; Levosulpiride; Nitrogly- Local Anesthetic/Vasoconstrictor Precautions

cerin; Secretin No information available to require special precautions
The levels/effects of Cyclobenzaprine may be Effects on Dental Treatment Key adverse event(s)
decreased by: Acetylcholinesterase Inhibitors; Ombi- related to dental treatment: Mucositis and stomatitis.
tasvir, Paritaprevir, and Ritonavir; Ombitasvir, Paritap- Effects on Bleeding Hematologic toxicities including
revir, Ritonavir, and Dasabuvir thrombocytopenia are among the important dose-limit-
Food Interactions Food increases bioavailability (peak ing effects of cyclophosphamide. A medical consult is
plasma concentrations increased by 35% and area recommended.
under the curve by 20%) of the extended release Adverse Reactions Frequency not defined.
capsule. Management: Monitor for increased effects if Dermatologic: Alopecia (reversible; onset: 3 to 6 weeks
taken with food. after start of treatment)
Pharmacodynamics/Kinetics Endocrine & metabolic: Altered hormone level
Onset of Action Immediate release: Within 1 hour (increased gonadotropin secretion), amenorrhea
Duration of Action Immediate release: 12 to 24 Gastrointestinal: Abdominal pain, anorexia, diarrhea,
hours mucositis, nausea and vomiting (dose-related), stoma-
titis
Half-life Elimination Normal hepatic function:
Genitourinary: Azoospermia, defective oogenesis, hem-
Range: 8 to 37 hours; Immediate release: 18 hours;
orrhagic cystitis, oligospermia, sterility
Extended release: 32 hours; Impaired hepatic func-
Hematologic & oncologic: Anemia, bone marrow
tion: 46.2 hours (range: 22.4 to 188 hours) (Winchell
depression, febrile neutropenia, leukopenia (dose-
2002)
related; recovery: 7 to 10 days after cessation), neu-
Time to Peak Immediate release: ~4 hours (Winchell
tropenia, thrombocytopenia
2002); Extended release: 7 to 8 hours
Infection: Infection
Pregnancy Risk Factor B <1%, postmarketing, and/or case reports: Acute respi-
Pregnancy Considerations Adverse events have not ratory distress, anaphylaxis, auditory disturbance,
been observed in animal reproduction studies. The blurred vision, cardiac arrhythmia (with high-dose
manufacturer recommends avoiding use during preg- [HSCT] therapy), cardiac failure (with high-dose
nancy unless clearly needed. [HSCT] therapy), cardiac tamponade (with high-dose
Breastfeeding Considerations It is not known if [HSCT] therapy), cardiotoxicity, confusion, C-reactive
cyclobenzaprine is excreted in breast milk. Because protein increased, dizziness, dyschromia (skin/finger-
cyclobenzaprine is closely related to tricyclic antide- nails), dyspnea, erythema multiforme, gastrointestinal
pressants, some of which are excreted in breast milk, hemorrhage, heart block, hematuria, hemopericar-
the manufacturer recommends that caution be exer- dium, hemorrhagic colitis, hemorrhagic myocarditis
cised when administering cyclobenzaprine to breast- (with high-dose [HSCT] therapy), hemorrhagic ureter-
feeding women. itis, hepatic sinusoidal obstruction syndrome (formerly
Dosage Forms: US known as hepatic veno-occlusive disease), hepatitis,
Capsule Extended Release 24 Hour, Oral: hepatotoxicity, hypersensitivity reaction, hyperurice-
Amrix: 15 mg, 30 mg mia, hypokalemia, hyponatremia, increased lactate
Generic: 15 mg, 30 mg dehydrogenase, interstitial pneumonitis, jaundice,
Tablet, Oral: malaise, mesenteric ischemia (acute), metastases,
Fexmid: 7.5 mg methemoglobinemia (with high-dose [HSCT] therapy),
Generic: 5 mg, 7.5 mg, 10 mg multi-organ failure, myocardial necrosis (with high-
dose [HSCT] therapy), neurotoxicity, neutrophilic
Cyclophosphamide (sye kloe FOS fa mide) eccrine hidradenitis, ovarian fibrosis, pancreatitis,
pericarditis, pneumonia, pulmonary hypertension, pul-
Brand Names: Canada Procytox monary infiltrates, pulmonary interstitial fibrosis (with
Pharmacologic Category Antineoplastic Agent, Alky- high doses), pulmonary veno-occlusive disease, pye-
lating Agent; Antineoplastic Agent, Alkylating Agent lonephritis, radiation recall phenomenon, reactivation
(Nitrogen Mustard); Antirheumatic Miscellaneous; of disease, reduced ejection fraction, renal tubular
Immunosuppressant Agent necrosis, reversible posterior leukoencephalopathy
Use syndrome, rhabdomyolysis, sepsis, septic shock,
Oncology uses: Treatment of acute lymphoblastic SIADH, skin rash, Stevens-Johnson syndrome, testic-
leukemia (ALL), acute myelocytic leukemia (AML), ular atrophy, thrombocytopenia (immune-mediated),
breast cancer, chronic lymphocytic leukemia (CLL), thrombosis (arterial and venous), toxic epidermal nec-
chronic myeloid leukemia (CML), Hodgkin lymphoma, rolysis, toxic megacolon, tumor lysis syndrome, uri-
mycosis fungoides, multiple myeloma, neuroblastoma, nary fibrosis, weakness, wound healing impairment
non-Hodgkin lymphomas (including Burkitt lym- Mechanism of Action Cyclophosphamide is an alky-
phoma), ovarian adenocarcinoma, and retinoblastoma lating agent that prevents cell division by cross-linking
Limitations of use: Although potentially effective as a DNA strands and decreasing DNA synthesis. It is a cell
single-agent in susceptible malignancies, cyclophos- cycle phase nonspecific agent. Cyclophosphamide also
phamide is more frequently used in combination with possesses potent immunosuppressive activity. Cyclo-
other chemotherapy drugs phosphamide is a prodrug that must be metabolized to
Nononcology uses: Nephrotic syndrome: Treatment active metabolites in the liver.
of minimal change nephrotic syndrome (biopsy pro- Pharmacodynamics/Kinetics
ven) in children who are unresponsive or intolerant to Half-life Elimination IV: 3 to 12 hours; Children: 4
corticosteroid therapy hours; Adults: 6 to 8 hours
Limitations of use: The safety and efficacy for the Time to Peak Oral: ~1 hour; IV: Metabolites: 2 to 3
treatment of nephrotic syndrome in adults or in other hours
renal diseases has not been established. Pregnancy Risk Factor D
370
CYCLOSPORINE (SYSTEMIC)
Pregnancy Considerations Cyclophosphamide Endocrine & metabolic: Cyanocobalamin deficiency,

crosses the placenta and can be detected in amniotic folate deficiency
fluid (D'Incalci 1982). Based on the mechanism of Hepatic: Increased liver enzymes
action, cyclophosphamide may cause fetal harm if Hypersensitivity: Hypersensitivity reaction
administered during pregnancy. Adverse events (includ- Neuromuscular & skeletal: Tremor
ing ectrodactylia) were observed in human studies Mechanism of Action Inhibits bacterial cell wall syn-
following exposure to cyclophosphamide. Women of thesis by competing with amino acid (D-alanine) for
childbearing potential should avoid pregnancy while incorporation into the bacterial cell wall; bacteriostatic
receiving cyclophosphamide and for up to 1 year after or bactericidal
completion of treatment. Males with female partners Pharmacodynamics/Kinetics
who are or may become pregnant should use a condom Half-life Elimination Normal renal function: 12 hours
during and for at least 4 months after cyclophospha- Time to Peak Serum: 4 to 8 hours
mide treatment. Cyclophosphamide may cause sterility Pregnancy Risk Factor C
in males and females (may be irreversible) and amenor- Pregnancy Considerations Adverse events have not
rhea in females. When treatment is needed for lupus
been observed in animal reproduction studies. Cyclo-
nephritis, cyclophosphamide should be avoided in
serine crosses the placenta and can be detected in the
women who are pregnant or those who wish to preserve
fetal blood and amniotic fluid. The American Thoracic
their fertility (Hahn 2012).
Society recommends use in pregnant women only if
Chemotherapy, if indicated, may be administered to there are no alternatives (CDC 2003).
pregnant women with breast cancer as part of a combi-
nation chemotherapy regimen (common regimens
administered during pregnancy include doxorubicin (or
CycloSPORINE (Systemic) (SYE kloe spor een)
epirubicin), cyclophosphamide, and fluorouracil); che- Brand Names: US Gengraf; Neoral; SandIMMUNE
motherapy should not be administered during the first Brand Names: Canada Neoral; Sandimmune I.V.
trimester, after 35 weeks gestation, or within 3 weeks of Pharmacologic Category Calcineurin Inhibitor;
planned delivery (Amant 2010; Loibl 2006). The Euro-
Immunosuppressant Agent
pean Society for Medical Oncology has published
Use
guidelines for diagnosis, treatment, and follow-up of
Cyclosporine modified:
cancer during pregnancy. The guidelines recommend
Transplant rejection prophylaxis: Prophylaxis of
referral to a facility with expertise in cancer during
pregnancy and encourage a multidisciplinary team organ rejection in kidney, liver, and heart transplants
(obstetrician, neonatologist, oncology team). In general, (commonly used in combination with an antiprolifer-
if chemotherapy is indicated, it should be avoided ative immunosuppressive agent and corticosteroid).
during in the first trimester, there should be a 3-week Rheumatoid arthritis: Treatment of severe, active
time period between the last chemotherapy dose and rheumatoid arthritis (RA) not responsive to metho-
anticipated delivery, and chemotherapy should not be trexate alone
administered beyond week 33 of gestation (Pecca- Psoriasis: Treatment of severe, recalcitrant plaque
tori 2013). psoriasis in non-immunocompromised adults unre-
sponsive to or unable to tolerate other systemic
therapy
CycloSERINE (sye kloe SER een) Cyclosporine non-modified:
Pharmacologic Category Antibiotic, Miscellaneous; Transplant rejection (prophylaxis): Prophylaxis of
Antitubercular Agent organ rejection in kidney, liver, and heart transplants
(commonly used in combination with an antiprolifer-
Use
ative agent and a corticosteroid)
Tuberculosis: Treatment of active pulmonary or
extrapulmonary tuberculosis, in combination with Transplant rejection, chronic (treatment): May be
other agents, when treatment with primary tuberculo- used for the treatment of chronic rejection (kidney,
sis therapy has proved inadequate liver, and heart) in patients previously treated with
Urinary tract infections: May be effective in treatment other immunosuppressive agents. Note: While
of acute urinary tract infections caused by susceptible approved for the treatment of chronic organ rejec-
strains of gram-positive and gram-negative bacteria, tion, other therapies are clinically preferred in this
especially Enterobacter spp. and Escherichia coli. setting.
Note: Should be considered only when more conven- Local Anesthetic/Vasoconstrictor Precautions
tional therapy has failed and when the organism has No information available to require special precautions
been demonstrated to be susceptible to the drug. Effects on Dental Treatment Key adverse event(s)
Local Anesthetic/Vasoconstrictor Precautions related to dental treatment: Mouth sores, swallowing
No information available to require special precautions difficulty, gingivitis, gum hyperplasia, xerostomia (nor-
Effects on Dental Treatment No significant effects or mal salivary flow resumes upon discontinuation), abnor-
complications reported mal taste, tongue disorder, and gingival bleeding (see
Effects on Bleeding No information available to Dental Health Professional Considerations)
require special precautions Effects on Bleeding No information available to
Adverse Reactions Frequency not defined. require special precautions
Cardiovascular: Cardiac arrhythmia, cardiac failure Adverse Reactions Adverse reactions reported with
Central nervous system: Coma, confusion, dizziness, systemic use, including rheumatoid arthritis, psoriasis,
drowsiness, dysarthria, headache, hyperreflexia, and transplantation (kidney, liver, and heart). Percen-
paresis, paresthesia, psychosis, restlessness, seiz- tages noted include the highest frequency regardless of
ure, vertigo indication/dosage. Frequencies may vary for specific
Dermatologic: Skin rash conditions or formulation.
371
CYCLOSPORINE (SYSTEMIC)
>10%: Gastrointestinal: Vomiting (9%), flatulence (5%), gin-

Cardiovascular: Hypertension (8% to 53%), edema givitis (4%), constipation, dysgeusia, dysphagia,
(5% to 14%) enlargement of salivary glands, eructation, esopha-
Central nervous system: Headache (2% to 25%), gitis, gastric ulcer, gastritis, gastroenteritis, gingival
paresthesia (1% to 11%) hemorrhage, glossitis, peptic ulcer, tongue disease,
Dermatologic: Hypertrichosis (5% to 19%) xerostomia
Endocrine & metabolic: Hirsutism (21% to 45%), Genitourinary: Leukorrhea (1%), breast fibroadenosis,
increased serum triglycerides (15%), female genital hematuria, mastalgia, nocturia, urine abnormality,
tract disease (9% to 11%) urinary incontinence, urinary urgency, uterine hem-
Gastrointestinal: Nausea (2% to 23%), diarrhea (3% to orrhage
13%), gingival hyperplasia (2% to 16%), abdominal Hematologic & oncologic: Purpura (3% to 4%), ane-
distress (<1% to 15%), dyspepsia (2% to 12%) mia, carcinoma, leukopenia, lymphadenopathy
Genitourinary: Urinary tract infection (kidney trans- Hepatic: Hyperbilirubinemia
plant: 21%) Infection: Abscess (including renal), bacterial infec-
Infection: Increased susceptibility to infection (3% to tion, candidiasis, fungal infection, herpes simplex
25%), viral infection (kidney transplant: 16%) infection, herpes zoster, viral infection
Neuromuscular & skeletal: Tremor (7% to 55%), leg Neuromuscular & skeletal: Arthralgia, bone fracture,
cramps (2% to 12%) dislocation, myalgia, stiffness, synovial cyst, tendon
Renal: Increased serum creatinine (16% to ≥50%), disease, weakness
renal insufficiency (10% to 38%) Ophthalmic: Cataract, conjunctivitis, eye pain, visual
Respiratory: Upper respiratory tract infection (1% disturbance
to 14%) Otic: Tinnitus, deafness, vestibular disturbance
Kidney, liver, and heart transplant only (≤2% unless Renal: Abscess (renal), increased blood urea nitro-
otherwise noted): gen, polyuria, pyelonephritis
Cardiovascular: Chest pain (≤4%), flushing (<1% to Respiratory: Cough (5%), dyspnea (5%), sinusitis
4%), glomerular capillary thrombosis, myocardial (4%), abnormal breath sounds, bronchospasm, epis-
infarction taxis, tonsillitis
Central nervous system: Convulsions (1% to 5%), Psoriasis only (1% to <3% unless otherwise noted):
anxiety, confusion, lethargy, tingling sensation Cardiovascular: Chest pain, flushing
Dermatologic: Skin infection (7%), acne vulgaris (1%
Central nervous system: Psychiatric disturbance (4%
to 6%), nail disease (brittle fingernails), hair break-
to 5%), pain (3% to 4%), dizziness, insomnia, nerv-
age, night sweats, pruritus
ousness, vertigo
Endocrine & metabolic: Gynecomastia (<1% to 4%),
Dermatologic: Acne vulgaris, folliculitis, hyperkerato-
hyperglycemia, hypomagnesemia, weight loss
sis, pruritus, skin rash, xeroderma
Gastrointestinal: Vomiting (2% to 10%), anorexia,
Endocrine & metabolic: Hot flash
aphthous stomatitis, constipation, dysphagia, gastri-
Gastrointestinal: Abdominal distention, constipation,
tis, hiccups, pancreatitis
gingival hemorrhage, increased appetite
Genitourinary: Hematuria
Genitourinary: Urinary frequency
Hematologic & oncologic: Leukopenia (<1% to 6%),
Hematologic & oncologic: Abnormal erythrocytes,
lymphoma (<1% to 6%), anemia, thrombocytopenia,
upper gastrointestinal hemorrhage altered platelet function, blood coagulation disorder,
Hepatic: Hepatotoxicity (<1% to 7%) carcinoma, hemorrhagic diathesis
Infection: Localized fungal infection (8%), cytomega- Hepatic: Hyperbilirubinemia
lovirus disease (5%), septicemia (5%), abscess Neuromuscular & skeletal: Arthralgia (1% to 6%)
(4%), fungal infection (systemic: 2%) Ophthalmic: Visual disturbance
Neuromuscular & skeletal: Arthralgia, myalgia, Respiratory: Flu-like symptoms (8% to 10%), broncho-
weakness spasm (5%), cough (5%), dyspnea (5%), rhinitis
Ophthalmic: Conjunctivitis, visual disturbance (5%), respiratory tract infection
Otic: Hearing loss, tinnitus Miscellaneous: Fever
Respiratory: Sinusitis (<1% to 7%), pneumonia (6%) Postmarketing and/or case reports (any indication):
Miscellaneous: Fever Anaphylaxis/anaphylactoid reaction (possibly associ-
Rheumatoid arthritis only (1% to <3% unless other- ated with Cremophor EL vehicle in injection formula-
wise noted): tion), brain disease, central nervous system toxicity,
Cardiovascular: Chest pain (4%), cardiac arrhythmia cholestasis, cholesterol increased, exacerbation of
(2%), abnormal heart sounds, cardiac failure, myo- psoriasis (transformation to erythrodermic or pustular
cardial infarction, peripheral ischemia psoriasis), fatigue, gout, haemolytic uremic syndrome,
Central nervous system: Dizziness (8%), pain (6%), hepatic insufficiency, hepatitis, hyperbilirubinemia,
insomnia (4%), depression (3%), migraine (2% to hyperkalemia, hyperlipidemia, hypertrichosis, hyper-
3%), anxiety, drowsiness, emotional lability, hypoes- uricemia, hypomagnesemia, impaired consciousness,
thesia, lack of concentration, malaise, neuropathy, increased susceptibility to infection (including JC virus
nervousness, paranoia, vertigo and BK virus), jaundice, leg pain (possibly a manifes-
Dermatologic: Cellulitis, dermatological reaction, der- tation of Calcineurin-Inhibitor Induced Pain Syn-
matitis, diaphoresis, dyschromia, eczema, enan- drome), malignant lymphoma, migraine, myalgia,
thema, folliculitis, nail disease, pruritus, urticaria, myopathy, myositis, papilledema, progressive multi-
xeroderma focal leukoencephalopathy, pseudotumor cerebri, pul-
Endocrine & metabolic: Menstrual disease (3%), monary edema (noncardiogenic), renal disease
decreased libido, diabetes mellitus, goiter, hot flash, (polyoma virus-associated), reversible posterior leu-
hyperkalemia, hyperuricemia, hypoglycemia, koencephalopathy syndrome, rhabdomyolysis, throm-
increased libido, weight gain, weight loss botic microangiopathy
372
CYPROHEPTADINE
Mechanism of Action Inhibition of production and Pharmacologic Category Calcineurin Inhibitor;

release of interleukin II and inhibits interleukin II- Immunosuppressant Agent
induced activation of resting T-lymphocytes. Use Keratoconjunctivitis sicca: Increase tear produc-
Pharmacodynamics/Kinetics tion when suppressed tear production is presumed to
Half-life Elimination Oral: May be prolonged with be due to keratoconjunctivitis sicca-associated ocular
hepatic impairment and shorter in pediatric patients inflammation (in patients not already using topical anti-
due to the higher metabolism rate inflammatory drugs or punctal plugs)
Cyclosporine (non-modified): Biphasic: Alpha: 1.4 Local Anesthetic/Vasoconstrictor Precautions
hours; Terminal: 19 hours (range: 10-27 hours) No information available to require special precautions
Cyclosporine (modified): Biphasic: Terminal: 8.4 hours Effects on Dental Treatment No significant effects or
(range: 5-18 hours) complications reported
Time to Peak Serum: Oral: Effects on Bleeding No information available to
Cyclosporine (non-modified): 2-6 hours; some patients require special precautions
have a second peak at 5-6 hours Adverse Reactions
Cyclosporine (modified): Renal transplant: 1.5-2 hours >10%: Ophthalmic: Eye pain (1% to 22%), burning
Pregnancy Considerations sensation of eyes (17%)
Adverse events were not observed following the use of 1% to 10%:
oral cyclosporine in animal reproduction studies (using Central nervous system: Foreign body sensation of
doses that were not maternally toxic). In humans, cyclo- eye (1% to 5%), headache (1% to 5%)
sporine crosses the placenta; maternal concentrations Genitourinary: Urinary tract infection (1% to 5%)
do not correlate with those found in the umbilical cord. Ophthalmic: Conjunctival hyperemia (1% to 6%), ble-
Cyclosporine may be detected in the serum of new- pharitis (1% to 5%), blurred vision (1% to 5%),
borns for several days after birth (Claris 1993). Based epiphora (1% to 5%), eye discharge (1% to 5%),
on clinical use, premature births and low birth weight eye irritation (1% to 5%), eye pruritus (1% to 5%),
were consistently observed in pregnant transplant stinging of eyes (1% to 5%), visual disturbance (1%
patients (additional pregnancy complications also to 5%)
present). Formulations may contain alcohol; the alcohol <1%, postmarketing and/or case reports: Hypersensi-
content should be taken into consideration in pregnant tivity reaction
women. Pregnancy Considerations Adverse events were not
The pharmacokinetics of cyclosporine may be influ- observed following the use of oral cyclosporine in
enced by pregnancy (Grimer 2007). Cyclosporine may animal reproduction studies. Serum concentrations
be used in pregnant renal, liver, or heart transplant are below the limit of detection (<0.1 ng/mL) following
patients (Cowan 2012; EBPG Expert Group on Renal ophthalmic use; fetal exposure following ophthalmic
Transplantation 2002; McGuire 2009; Parhar 2012). If administration is not expected.
therapy is needed for psoriasis, other agents are pre-
ferred; however, cyclosporine may be used as an Cyproheptadine (si proe HEP ta deen)
alternative agent along with close clinical monitoring;
use should be avoided during the first trimester if Brand Names: Canada Euro-Cyproheptadine; PMS-
possible (Bae 2012). If treatment is needed for lupus Cyproheptadine
nephritis, other agents are recommended to be used in Pharmacologic Category Histamine H1 Antagonist;
pregnant women (Hahn 2012). Histamine H1 Antagonist, First Generation; Piperidine
Derivative
Following transplant, normal menstruation and fertility
Use Allergic conditions: Perennial and seasonal aller-
may be restored within months; however, appropriate
gic rhinitis; vasomotor rhinitis; allergic conjunctivitis
contraception is recommended to prevent pregnancy
caused by inhalant allergens and foods; mild, uncom-
until 1-2 years following the transplant to improve
plicated allergic skin manifestations of urticaria and
pregnancy outcomes (Cowan 2012; EBPG Expert
angioedema; amelioration of allergic reactions to blood
Group on Renal Transplantation 2002; McGuire 2009;
or plasma; cold urticaria; dermatographism; adjunctive
Parhar 2012).
anaphylactic therapy.
The Transplant Pregnancy Registry International (TPR) Local Anesthetic/Vasoconstrictor Precautions
is a registry that follows pregnancies that occur in No information available to require special precautions
maternal transplant recipients or those fathered by male Effects on Dental Treatment Key adverse event(s)
transplant recipients. The TPR encourages reporting of related to dental treatment: Xerostomia (normal salivary
pregnancies following solid organ transplant by contact- flow resumes upon discontinuation)
ing them at 1-877-955-6877 or https://www.- Effects on Bleeding No information available to
transplantpregnancyregistry.org. require special precautions
Dental Health Professional Considerations Con- Adverse Reactions Frequency not defined.
sider a medical consultation prior to any invasive dental Cardiovascular: Extrasystoles, hypotension, palpita-
procedure in patients who have received an organ tions, tachycardia
transplant; delayed wound healing due to the immuno- Central nervous system: Ataxia, chills, confusion, dizzi-
suppressive effects and an increased potential for post- ness, drowsiness, euphoria, excitement, fatigue, hal-
operative infection may be of concern. lucination, headache, hysteria, insomnia, irritability,
nervousness, neuritis, paresthesia, restlessness,
CycloSPORINE (Ophthalmic) sedation, seizure, vertigo
(SYE kloe spor een) Dermatologic: Diaphoresis, skin photosensitivity, skin
rash, urticaria
Brand Names: US Cequa; Restasis; Restasis Multi- Gastrointestinal: Abdominal pain, anorexia, cholestasis,
dose constipation, diarrhea, increased appetite, nausea,
Brand Names: Canada Restasis vomiting, xerostomia
373
CYPROHEPTADINE
Genitourinary: Difficulty in micturition, urinary fre- neurotoxicity, paralysis (intrathecal and IV combina-
quency, urinary retention tion therapy), reversible posterior leukoencephalop-
Hematologic & oncologic: Agranulocytosis, hemolytic athy syndrome
anemia, leukopenia, thrombocytopenia Dermatologic: Acute generalized exanthematous pus-
Hepatic: Hepatic failure, hepatitis, jaundice tulosis, alopecia, dermal ulcer, ephelis, pruritus, skin
Hypersensitivity: Anaphylactic shock, angioedema, rash, urticaria
hypersensitivity reaction Endocrine & metabolic: Hyperuricemia
Neuromuscular & skeletal: Tremor Gastrointestinal: Abdominal pain, anal fissure, ano-
Ophthalmic: Blurred vision, diplopia rexia, diarrhea, esophageal ulcer, esophagitis,
Otic: Labyrinthitis (acute), tinnitus increased serum amylase, increased serum lipase,
Respiratory: Nasal congestion, pharyngitis, thickening intestinal necrosis, mucositis, nausea, pancreatitis,
of bronchial secretions sore throat, toxic megacolon, vomiting
Mechanism of Action A potent antihistamine and Genitourinary: Urinary retention
serotonin antagonist with anticholinergic effects; com- Hematologic & oncologic: Anemia, bone marrow
petes with histamine for H1-receptor sites on effector depression, hemorrhage, leukopenia, megaloblastic
cells in the gastrointestinal tract, blood vessels, and anemia, neutropenia (onset: 1 to 7 days; nadir [bipha-
respiratory tract (Paton 1985). sic]: 7 to 9 days and at 15 to 24 days; recovery
Pharmacodynamics/Kinetics [biphasic]: 9 to 12 days and at 24 to 34 days),
Half-life Elimination Metabolites: ~16 hours (Paton reticulocytopenia, thrombocytopenia (onset: 5 days;
1985) nadir: 12 to 15 days; recovery 15 to 25 days)
Time to Peak Plasma: 6 to 9 hours (Paton 1985) Hepatic: Hepatic insufficiency, hepatic sinusoidal
Pregnancy Risk Factor B obstruction syndrome (formerly known as hepatic
Pregnancy Considerations Adverse events were veno-occlusive disease), increased serum transami-
observed in some animal reproduction studies. Per nases (acute), jaundice
the product labeling, an increased risk of congenital Hypersensitivity: Allergic edema, anaphylaxis
abnormalities was not observed following maternal Infection: Sepsis
use of cyproheptadine during the first, second, or third Local: Cellulitis at injection site, inflammation at injec-
trimesters in two studies of pregnant women; however tion site (SC injection), local inflammation (anus), pain
the possibility of harm cannot be ruled out. Although at injection site (SC injection)
cyproheptadine is approved for the treatment of allergic Neuromuscular & skeletal: Rhabdomyolysis
conditions such as rhinitis and uritcaria, other agents Ophthalmic: Conjunctivitis
are preferred for use in pregnant women (Scadding Renal: Renal insufficiency
2008; Wallace 2008; Zuberbier 2014). Antihistamines Respiratory: Acute respiratory distress, dyspnea, inter-
are not recommended for treatment of pruritus associ- stitial pneumonitis
ated with intrahepatic cholestasis in pregnancy Miscellaneous: Drug toxicity (cytarabine syndrome;
(Ambros-Rudolph 2011; Kremer 2014). chest pain, conjunctivitis, fever, maculopapular rash,
malaise, myalgia, ostealgia), fever
Cytarabine (Conventional) Adverse events associated with high-dose cytar-
(sye TARE a been con VEN sha nal) abine
Brand Names: Canada Cytarabine Injection; Cytosar Cardiovascular: Cardiomegaly, cardiomyopathy (in
combination with cyclophosphamide)
Central nervous system: Neurotoxicity (patients with
metabolite; Antineoplastic Agent, Antimetabolite (Pyri-
renal impairment: ≤55%), coma, drowsiness, neuro-
midine Analog)
cerebellar toxicity, peripheral neuropathy (motor and
Use
sensory), personality changes
Acute myeloid leukemia: Remission induction (in
Dermatologic: Alopecia (complete), desquamation,
combination with other chemotherapy medications)
skin rash (severe)
in acute myeloid leukemia (AML)
Gastrointestinal: Gastrointestinal ulcer, necrotizing
Acute lymphocytic leukemia: Treatment of acute
enterocolitis, pancreatitis, peritonitis, pneumatosis
lymphocytic leukemia (ALL)
cystoides intestinalis
Chronic myeloid leukemia: Treatment of chronic mye-
Hepatic: Hepatic abscess, hepatic injury, hyperbiliru-
loid leukemia (CML; blast phase)
binemia
Meningeal leukemia: Prophylaxis and treatment of
Infection: Sepsis
meningeal leukemia
Ophthalmic: Corneal toxicity, hemorrhagic conjuncti-
vitis
Respiratory: Acute respiratory distress, pulmonary
Effects on Dental Treatment Key adverse event(s) edema
related to dental treatment: Mucositis
Effects on Bleeding Hematologic effects depend on Adverse events associated with intrathecal cytara-
dose and schedule of treatment. Platelets are one of the bine administration
primary cell lines affected. Patients will develop throm- Central nervous system: Aphonia, leukoencephalop-
bocytopenia on approximately day 7 which resolves athy (necrotizing; with concurrent cranial irradiation,
about day 21-28. A medical consult is recommended. intrathecal methotrexate, and intrathecal hydrocorti-
Adverse Reactions Frequency not always defined. sone), nerve palsy (accessory nerve), neurotoxicity,
CNS, gastrointestinal, ophthalmic, and pulmonary tox- paraplegia
icities are more common with high-dose regimens. Gastrointestinal: Dysphagia, nausea, vomiting
Cardiovascular: Angina pectoris, chest pain, local Ophthalmic: Blindness (with concurrent systemic che-
thrombophlebitis, pericarditis motherapy and cranial irradiation), diplopia
Central nervous system: Aseptic meningitis, cerebral Respiratory: Cough, hoarseness
dysfunction, dizziness, headache, neuritis, Miscellaneous: Fever
374
DABIGATRAN ETEXILATE
Mechanism of Action Cytarabine inhibits DNA syn- Neuromuscular & skeletal: Weakness (40%), back
thesis. Cytarabine gains entry into cells by a carrier pain (24%), limb pain (15%), neck pain (14%),
process, and then must be converted to its active arthralgia (11%), neck stiffness (11%)
compound, aracytidine triphosphate. Cytarabine is a Ophthalmic: Blurred vision (11%)
pyrimidine analog and is incorporated into DNA; how- Miscellaneous: Fever (32%)
ever, the primary action is inhibition of DNA polymerase 1% to 10%:
resulting in decreased DNA synthesis and repair. The Cardiovascular: Tachycardia (9%), hypotension (8%),
degree of cytotoxicity correlates linearly with incorpo- hypertension (6%), syncope (3%), edema (2%)
ration into DNA; therefore, incorporation into the DNA is Central nervous system: Agitation (10%), hypoesthe-
responsible for drug activity and toxicity. Cytarabine is sia (10%), myasthenia (10%), depression (8%), anxi-
specific for the S phase of the cell cycle (blocks pro- ety (7%), peripheral neuropathy (3% to 4%),
gression from the G1 to the S phase). abnormal reflexes (3%), sensorimotor neuropa-
Pharmacodynamics/Kinetics thy (3%)
Half-life Elimination IV: Initial: 7 to 20 minutes; Dermatologic: Diaphoresis (2%), pruritus (2%)
Terminal: 1 to 3 hours; Intrathecal: 2 to 6 hours Endocrine & metabolic: Hypokalemia (7%), hypona-
Time to Peak IM, SubQ: 20 to 60 minutes tremia (7%), hyperglycemia (6%)
Gastrointestinal: Abdominal pain (9%), dysphagia
(8%), anorexia (5%), hemorrhoids (3%), mucosal
Based on the mechanism of action and findings from
inflammation (3%)
animal reproduction studies, fetal harm may occur if
Genitourinary: Urinary incontinence (7%), urinary
cytarabine is administered during pregnancy. Limb and
retention (5%)
ear defects have been noted in case reports of cytar-
Hematologic & oncologic: Neutropenia (10%),
abine exposure during the first trimester of pregnancy. bruise (2%)
The following have also been noted in the neonate: Neuromuscular & skeletal: Tremor (9%)
Pancytopenia, WBC depression, electrolyte abnormal- Otic: Hypoacusis (6%)
ities, prematurity, low birth weight, decreased hematoc- Respiratory: Dyspnea (10%), cough (7%), pneumo-
rit or platelets. Risk to the fetus is decreased if nia (6%)
treatment can be avoided during the first trimester; <1%, postmarketing, and/or case reports: Anaphylaxis,
however, females of reproductive potential should avoid bladder disease (bladder control impaired), blindness,
becoming pregnant during treatment and be advised of brain disease, cauda equina syndrome, cranial nerve
the potential risks. palsy, deafness, drowsiness, fecal incontinence, hemi-
plegia, hydrocephalus, increased intracranial pres-
Cytarabine (Liposomal) sure, leukocytosis (in CSF), meningitis (infectious),
(sye TARE a been lye po SO mal) myelopathy, nervous system disease (neurologic def-
icit), numbness, papilledema, visual disturbance
Brand Names: US DepoCyt [DSC] Mechanism of Action Cytarabine liposomal is a sus-
Brand Names: Canada DepoCyt [DSC] tained-release formulation of the active ingredient cytar-
Pharmacologic Category Antineoplastic Agent, Anti- abine, an antimetabolite which acts through inhibition of
metabolite; Antineoplastic Agent, Antimetabolite (Pyri- DNA synthesis and is cell cycle-specific for the S phase
midine Analog) of cell division. Cytarabine is converted intracellularly to
Use Lymphomatous meningitis: Intrathecal treatment its active metabolite cytarabine-5’-triphosphate (ara-
of lymphomatous meningitis CTP). Ara-CTP also appears to be incorporated into
Local Anesthetic/Vasoconstrictor Precautions DNA and RNA; however, the primary action is inhibition
No information available to require special precautions of DNA polymerase, resulting in decreased DNA syn-
Effects on Dental Treatment No significant effects or thesis and repair. The liposomal formulation allows for
complications reported gradual release, resulting in prolonged exposure.
Effects on Bleeding Hematologic effects depend on Pharmacodynamics/Kinetics
dose and schedule of treatment. Platelets are one of the Half-life Elimination CSF: 6 to 82 hours
primary cell lines affected. Patients will develop throm- Time to Peak CSF: Intrathecal: <1 hour
bocytopenia on approximately day 7 which resolves Pregnancy Risk Factor D
about day 21-28. A medical consult is recommended. Pregnancy Considerations Adverse effects were
Adverse Reactions observed in animal reproductive studies with conven-
>10%: tional cytarabine. Conventional cytarabine has been
Cardiovascular: Peripheral edema (11%) associated with fetal malformations when given as a
Central nervous system: Chemical arachnoiditis (with- component of systemic combination chemotherapy dur-
out dexamethasone premedication: 100%; with dex- ing the first trimester. Systemic exposure following intra-
amethasone premedication: 33% to 42%; grade 4: thecal administration of cytarabine liposomal is
19% to 30%; onset: ≤5 days), headache (56%), negligible; however, women of childbearing potential
confusion (33%), fatigue (25%), abnormal gait should avoid becoming pregnant during treatment.
(23%), seizure (20% to 22%), dizziness (18%), leth- Product Availability DepoCyt is no longer available in
argy (16%), insomnia (14%), memory impairment the US.
(14%), pain (14%)
Endocrine & metabolic: Dehydration (13%) Dabigatran Etexilate (da BIG a tran ett EX ill ate)
Gastrointestinal: Nausea (46%), vomiting (44%), con-
stipation (25%), diarrhea (12%), decreased appe- Related Information
tite (11%) Antiplatelet and Anticoagulation Considerations in Den-
Genitourinary: Urinary tract infection (14%) tistry on page 1454
Hematologic & oncologic: Anemia (12%), thrombocy- Cardiovascular Diseases on page 1442
topenia (3% to 11%) Brand Names: US Pradaxa
375
DABIGATRAN ETEXILATE
Brand Names: Canada Pradaxa a specific, reversible, direct thrombin inhibitor that inhib-
Pharmacologic Category Anticoagulant; Anticoagu- its both free and fibrin-bound thrombin. Inhibits coagu-
lant, Direct Thrombin Inhibitor; Direct Oral Anticoagu- lation by preventing thrombin-mediated effects,
lant (DOAC) including cleavage of fibrinogen to fibrin monomers,
Use activation of factors V, VIII, XI, and XIII, and inhibition
Deep venous thrombosis and pulmonary embolism of thrombin-induced platelet aggregation.
treatment and prevention: Treatment of deep Pharmacodynamics/Kinetics
venous thrombosis (DVT) and pulmonary embolism Half-life Elimination 12 to 17 hours; Elderly: 14 to 17
(PE) in patients who have been treated with a paren- hours; Mild-to-moderate renal impairment: 15 to 18
teral anticoagulant for 5 to 10 days; to reduce the risk hours; Severe renal impairment: 28 hours (Stangier
of recurrence of DVT and pulmonary embolism in 2010)
patients who have been previously treated. Time to Peak Plasma: Dabigatran: 1 hour; delayed 2
Nonvalvular atrial fibrillation: Prevention of stroke hours by food (no effect on bioavailability)
and systemic embolism in patients with nonvalvular Pregnancy Considerations
atrial fibrillation (AF) An ex vivo human placenta dual perfusion model illus-
VTE prophylaxis in total hip arthroplasty: Prophy- trated that dabigatran crossed the placenta at term;
laxis of DVT and PE in patients who have undergone dabigatran etexilate mesylate (prodrug) had limited
total hip arthroplasty (THA). placental transfer (Bapat 2014).
Local Anesthetic/Vasoconstrictor Precautions Data are insufficient to evaluate the safety of direct
No information available to require special precautions thrombin inhibitors during pregnancy (Guyatt 2012).
Effects on Dental Treatment Dabigatran etexilate is Other agents are preferred for the treatment of AF or
converted in vivo to the active dabigatran, a specific, VTE in pregnant patients (ESG/AEPC/DGesGM/ESC
reversible, direct thrombin inhibitor. It causes bleeding 2011; Kearon 2016). Monitor the neonate for bleeding
by preventing thrombin-mediated effects, and by inhibit- if in utero exposure occurs.
ing thrombin-induced platelet aggregation. Patients tak- Dental Health Professional Considerations At rec-
ing dabigatran etexilate are at increased risk of ommended therapeutic doses, dabigatran etexilate pro-
bleeding. See Effects on Bleeding. longs the activated partial thromboplastin time (aPTT).
Effects on Bleeding Dabigatran etexilate inhibits clot With an oral dose of 150 mg twice daily, the median
formation via direct inhibition of thrombin (factor IIa). peak aPTT is approximately twice that of control values.
Dabigatran increases the risk of bleeding and can Twelve hours after the last dose, the median aPTT is
cause significant and sometimes fatal bleeding. Hem- 1.5 x control. The INR test is relatively insensitive to the
orrhage may occur at virtually any site; risk is depend- activity of dabigatran etexilate and may not be elevated
ent on multiple variables, including the intensity of in patients on dabigatran etexilate. Medical consult is
anticoagulation and patient susceptibility. Medical con- suggested. Routine coagulation testing (INR) is not
sult is suggested. required, or necessary, for Direct-Acting Oral Antico-
Adverse Reactions agulants (DOAC).
>10%:
Gastrointestinal: Gastrointestinal symptoms (eg, dys-
pepsia, gastritis-like symptoms; 25% to 40%; dose Dacarbazine (da KAR ba zeen)
dependent)
Hematologic & oncologic: Hemorrhage (11% to 19%; Brand Names: Canada Dacarbazine for Injection, BP
major hemorrhage: ≤3%; hemorrhage [life-threaten- Pharmacologic Category Antineoplastic Agent, Alky-
ing]: 2%) lating Agent (Triazene)
1% to 10%: Gastrointestinal: Dyspepsia (8%; includes Use
abdominal pain, abdominal discomfort, epigastric dis- Hodgkin lymphoma: Treatment of Hodgkin lymphoma
comfort), gastrointestinal hemorrhage (≤6%; major: (in combination with other chemotherapy agents)
≤2%), gastritis (3%; includes gastroesophageal reflux Metastatic malignant melanoma: Treatment of meta-
disease, esophagitis, erosive gastritis, gastrointestinal static malignant melanoma
hemorrhage, hemorrhagic gastritis, gastrointestinal Local Anesthetic/Vasoconstrictor Precautions
ulcer) No information available to require special precautions
<1%, postmarketing, and/or case reports: Allergic Effects on Dental Treatment Key adverse event(s)
edema, anaphylactic shock, anaphylaxis, angioe- related to dental treatment: Metallic taste.
dema, catheter site hemorrhage, cerebrovascular Effects on Bleeding Hematopoietic suppression
accident (in patients with prosthetic heart valve), (including platelets) is the most common toxicity of
decreased hematocrit, epidural hematoma (with spinal dacarbazine. Risk of thrombocytopenia, which can be
puncture or spinal/epidural anesthesia), esophageal life-threatening, reaches a nadir at 7-10 days. A medical
ulcer, genitourinary tract hemorrhage, hemarthrosis, consult is recommended.
hypersensitivity reaction, intracranial hemorrhage Adverse Reactions Frequency not always defined.
(includes hemorrhagic stroke, subarachnoid bleeding, Central nervous system: Infusion-site pain
subdural hematoma), muscle hemorrhage, myocardial Dermatologic: Alopecia
infarction, pericardial effusion (severe hemorrhagic; Gastrointestinal: Nausea and vomiting (>90%), ano-
occurred postoperatively in patients with prosthetic rexia
heart valve; required intervention for hemodynamic Hematologic & oncologic: Bone marrow depression
compromise), retroperitoneal hemorrhage, spinal (onset: 5 to 7 days; nadir: 7 to 10 days; recovery: 21
hematoma (with spinal puncture or spinal/epidural to 28 days), leukopenia, thrombocytopenia
anesthesia), thrombocytopenia, thromboembolism (in <1%, postmarketing, and/or case reports: Anaphylaxis,
patients with prosthetic heart valve), transient ische- anemia, diarrhea, dysgeusia, eosinophilia, erythema,
mic attacks (in patients with prosthetic heart valve) facial flushing, facial paresthesia, flu-like symptoms
Mechanism of Action Prodrug lacking anticoagulant (fever, myalgia, malaise), hepatic necrosis, increased
activity that is converted in vivo to the active dabigatran, liver enzymes (transient), paresthesia, renal function
376
DACLIZUMAB
test abnormality, skin photosensitivity, skin rash, urti- Gastrointestinal: Nausea (8% to 15%)
caria, venous obstruction (hepatic vein) Hematologic & Oncologic: Anemia (20%)
Mechanism of Action Dacarbazine is an alkylating 1% to 10%:
agent which is converted to the active alkylating metab- Central nervous system: Drowsiness (5%), insom-
olite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxa- nia (3%)
mide] via the cytochrome P450 system. The cytotoxic Dermatologic: Skin rash (8%)
effects of MTIC are manifested through alkylation Gastrointestinal: Diarrhea (3% to 5%), increased
(methylation) of DNA at the O6, N7 guanine positions serum lipase (>3x ULN, transient)
which lead to DNA double strand breaks and apoptosis. <1%, postmarketing, and/or case reports: Reactivation
Dacarbazine is non-cell cycle specific (Marchesi 2007). of HBV (FDA Safety Alert Dec. 8, 2016)
Pharmacodynamics/Kinetics Mechanism of Action Daclatasvir binds to the N-
Half-life Elimination Biphasic: Initial: 19 minutes, 55 terminus within Domain 1 of HCV nonstructural protein
minutes (renal and hepatic dysfunction); Terminal: 5 5A (NS5A) and inhibits viral RNA replication and virion
hours, 7.2 hours (renal and hepatic dysfunction) assembly.
Pregnancy Risk Factor C Pharmacodynamics/Kinetics
Pregnancy Considerations [US Boxed Warning]: Half-life Elimination ~12 to 15 hours
Studies have demonstrated this agent to be carci- Time to Peak Plasma: ≤2 hours
nogenic and/or teratogenic when used in animals; Pregnancy Considerations
adverse effects have been observed in animal repro- Daclatasvir must not be used as monotherapy. If used
duction studies. Females of reproductive potential in combination with ribavirin, use is contraindicated in
should avoid becoming pregnant during treatment. pregnant females and males whose female partners are
The European Society for Medical Oncology has pub- pregnant. All warnings related to the use of ribavirin and
lished guidelines for diagnosis, treatment, and follow-up pregnancy and/or contraception should be followed.
of cancer during pregnancy. The guidelines recommend Treatment of hepatitis C is not currently recommended
referral to a facility with expertise in cancer during to treat maternal infection or to decrease the risk of
pregnancy and encourage a multidisciplinary team mother-to-child transmission during pregnancy (Tran
(obstetrician, neonatologist, oncology team). In general, 2016). HCV-infected females of childbearing potential
if chemotherapy is indicated, it should be avoided should consider postponing pregnancy until therapy is
during in the first trimester, there should be a 3-week complete to reduce the risk of HCV transmission
time period between the last chemotherapy dose and (AASLD/IDSA 2017). When HCV infection is detected
anticipated delivery, and chemotherapy should not be during pregnancy, treatment should be deferred until
administered beyond week 33 of gestation (Peccatori after delivery. Direct-acting antiviral medications should
2013). An international consensus panel has published not be used in pregnant females outside of clinical trials
guidelines for hematologic malignancies during preg- until safety and efficacy information is available (SMFM
nancy. Dacarbazine is a component of the ABVD regi- [Hughes 2017]).
men, which is used for the treatment of Hodgkin Product Availability The manufacturer of Daklinza,
lymphoma. If treatment cannot be deferred until after Bristol Myers Squibb, plans to cease distribution of
delivery in patients with early stage Hodgkin lymphoma, the 90 mg tablets as of December 2018 and the
ABVD may be administered safely and effectively in the 30 mg and 60 mg tablets as of June 2019.
latter phase of pregnancy (based on limited data); for
patients with advanced-stage disease, ABVD can be
administered in the second and third trimesters (Lishner Daclizumab (dac KLYE zue mab)
2016).
Brand Names: US Zinbryta [DSC]
Brand Names: Canada Zinbryta
Daclatasvir (dak LAT as vir) Pharmacologic Category Immunosuppressant
Agent; Interleukin-2 Inhibitor; Monoclonal Antibody
Brand Names: US Daklinza Use Multiple sclerosis, relapsing: Treatment of relaps-
Brand Names: Canada Daklinza ing forms of multiple sclerosis (MS) in adults. Daclizu-
Pharmacologic Category Antihepaciviral, NS5A mab should generally be reserved for patients who
Inhibitor; NS5A Inhibitor have had an inadequate response to 2 or more medi-
Use cations indicated for the treatment of MS.
Chronic hepatitis C: Treatment of chronic hepatitis C Local Anesthetic/Vasoconstrictor Precautions
virus (HCV) genotype 1 or genotype 3 infection in No information available to require special precautions
combination with sofosbuvir, with or without ribavirin Effects on Dental Treatment Key adverse event(s)
Limitations of use: Sustained virologic response rates related to dental treatment: Oropharyngeal pain, bron-
are reduced in HCV genotype 3-infected patients with chitis, pharyngitis, rhinitis, tonsillitis have been reported
cirrhosis receiving daclatasvir in combination with Effects on Bleeding No information available to
sofosbuvir for 12 weeks. require special precautions
Effects on Dental Treatment No significant effects or Dermatologic: Allergic skin reaction (18% to 37%),
complications reported skin rash (7% to 11%)
Effects on Bleeding No information available to Immunologic: Autoimmune disease (13% to 32%)
require special precautions Infection: Infection (50% to 65%)
Adverse Reactions All adverse drug reactions are Respiratory: Nasopharyngitis (25%), upper respiratory
from combination therapy trials with sofosbuvir. tract infection (9% to 17%)
>10%: 1% to 10%:
Central nervous system: Fatigue (14% to 15%), head- Central nervous system: Depression (7% to 10%),
ache (12% to 14%) seizure (1%)
377
DACLIZUMAB
Dermatologic: Dermatitis (3% to 9%), eczema (5%),

acne vulgaris (3%) Dacomitinib (DAK oh MI ti nib)
Hematologic & oncologic: Lymphadenopathy (5%),
anemia (3%) Brand Names: US Vizimpro
Hepatic: Increased serum ALT (5% to 6%), increased Pharmacologic Category Antineoplastic Agent, Epi-
serum AST (3% to 6%), hepatic injury (≤1%) dermal Growth Factor Receptor (EGFR) Inhibitor; Anti-
Infection: Influenza (9%) neoplastic Agent, Tyrosine Kinase Inhibitor
Respiratory: Oropharyngeal pain (8%), bronchitis Use Non-small cell lung cancer, metastatic: First-line
(7%), pharyngitis (6%), rhinitis (4%), tonsillitis (4%) treatment of metastatic non-small cell lung cancer
Miscellaneous: Fever (3%) (NSCLC) in patients with epidermal growth factor
Frequency not defined: receptor (EGFR) exon 19 deletion or exon 21 L858R
Dermatologic: Desquamation, erythema, folliculitis, substitution mutations as detected by an approved test.
pruritus, psoriasis, skin photosensitivity, skin rash Local Anesthetic/Vasoconstrictor Precautions
(toxic), xeroderma No information available to require special precautions
Gastrointestinal: Diarrhea Effects on Dental Treatment Key adverse event(s)
Hematologic & oncologic: Decreased absolute lym- related to dental treatment: Frequent occurrence of
phocyte count, lymphadenitis stomatitis, oral mucosa ulcers
Hepatic: Abnormal hepatic function tests, increased Effects on Bleeding No information available to
liver enzymes require special precautions
Hypersensitivity: Hypersensitivity reaction (including Adverse Reactions
anaphylaxis, angioedema, and urticaria) >10%:
Infection: Cytomegalovirus disease, viral infection Cardiovascular: Chest pain (10%)
Respiratory: Laryngitis, pneumonia, respiratory tract Central nervous system: Insomnia (11%)
infection Dermatologic: Skin rash (69% to 78%), paronychia
(64%), xeroderma (30%), alopecia (23%), pruritus
<1%, postmarketing, and/or case reports: Autoimmune
(21%), palmar-plantar erythrodysesthesia (15%),
hepatitis, colitis (serious; noninfectious), increased
dermatitis (11%)
serum alkaline phosphatase (<2 x ULN), increased
Endocrine & metabolic: Hypoalbuminemia (44%),
serum bilirubin (≥2 x ULN), increased serum trans-
hyperglycemia (36%), hypocalcemia (33%), hypoka-
aminases (≥3 x ULN), malignant neoplasm of breast
lemia (29%), hyponatremia (26%), weight loss
(more common in women), suicidal ideation
(26%), hypomagnesemia (22%)
Mechanism of Action Daclizumab is a humanized Gastrointestinal: Diarrhea (87%), stomatitis (45%;
monoclonal antibody which binds to the CD25 subunit grades 3/4: 4%), decreased appetite (31%), nausea
of the high-affinity interleukin-2 (IL-2) receptor to pre- (19%), constipation (13%), oral mucosa ulcer (12%)
vent signaling at the high-affinity IL-2 receptor while Hematologic & oncologic: Anemia (44%; grades 3/4:
allowing increased IL-2 availability for signaling at the <1%), lymphocytopenia (42%; grades 3/4: 6%)
intermediate-affinity IL-2 receptor (Gold 2013, Kappos Hepatic: Increased serum alanine aminotransferase
2015). Because IL-2 has a role in activating and regu- (40%), increased serum aspartate aminotransferase
lating the immune system; CD25 antagonism may (35%), increased serum alkaline phosphatase
result in therapeutic benefit in multiple sclerosis (Gold (22%), hyperbilirubinemia (16%)
2013). Neuromuscular & skeletal: Limb pain (14%), asthenia
Pharmacodynamics/Kinetics (13%), musculoskeletal pain (12%)
Half-life Elimination SubQ: 21 days Ophthalmic: Conjunctivitis (19%)
Time to Peak SubQ: 5 to 7 days Renal: Increased creatinine clearance (24%)
Pregnancy Considerations Adverse events were Respiratory: Cough (21%), nasal signs and symptoms
observed in animal reproduction studies. Daclizumab (19%), dyspnea (13%), upper respiratory tract infec-
is a monoclonal antibody; monoclonal antibodies are tion (12%)
known to cross the placenta, with increasing amounts 1% to 10%:
during the second and third trimesters. Use of similar Central nervous system: Fatigue (9%)
agents is not recommended for the treatment of multiple Dermatologic: Skin fissure (9%), exfoliation of skin
sclerosis in pregnant women (Coyle 2016, Pozzilli (4% to 7%), hypertrichosis (1%)
2015). Endocrine & metabolic: Dehydration (1%)
Product Availability Gastrointestinal: Vomiting (9%), dysgeusia (7%)
As of March 2, 2018, Biogen and AbbVie have Ophthalmic: Keratitis (2%)
announced the voluntary worldwide withdrawal of Zin- Respiratory: Interstitial pulmonary disease (3%)
bryta (daclizumab) for the treatment of adult patients <1%, postmarketing, and/or case reports: Pneumonitis
with relapsing forms of multiple sclerosis. The drug will Mechanism of Action Dacomitinib is an irreversible
be available in the United States and Canada for epidermal growth factor receptor (EGFR) tyrosine kin-
patients as needed until April 30, 2018. ase inhibitor which has activity against EGFR/HER1,
HER2, and HER4, as well as some EGFR-activating
More information may be found at http://media.biogen. mutations (exon 19 deletion or exon 21 L858R sub-
com/press-release/autoimmune-diseases/biogen% stitution mutation). Dacomitinib also has activity against
C2%A0and-abbvie-announce%C2%A0-voluntary% DDR1, EPHA6, LCK, DDR2, and MNK1 (in vitro).
C2%A0worldwide-withdrawal-marketi or https://www.- Pharmacodynamics/Kinetics
fda.gov/Drugs/DrugSafety/ucm600999.htm?utm_cam- Half-life Elimination 70 hours
paign=FDA%20working%20with%20manufacturers% Time to Peak ~6 hours (range: 2 to 24 hours)
20to%20withdraw%20Zinbryta%20from%20the% Pregnancy Considerations Based on data from ani-
20market%20in&utm_medium=email&utm_source=E- mal reproduction studies and the mechanism of action,
loqua or http://healthycanadians.gc.ca/recall-alert-rap- dacomitinib use during pregnancy may cause fetal
pel-avis/hc-sc/2018/66214a-eng.php. harm. Verify pregnancy status in females of
378
DALBAVANCIN
reproductive potential prior to initiating dacomitinib. and cytosine base pairs inhibiting DNA and RNA syn-
Females of reproductive potential should use effective thesis and protein synthesis
contraception during therapy and for at least 17 days Pharmacodynamics/Kinetics
after the last dacomitinib dose. Half-life Elimination 30 to 40 hours (Perry 2012);
Children: Range: 14 to 43 hours (Veal 2005)
Pregnancy Considerations Based on data from ani-
DACTINomycin (dak ti noe MYE sin)
mal reproduction studies and its mechanism of action,
Brand Names: US Cosmegen dactinomycin may cause fetal harm if administered to a
Brand Names: Canada Cosmegen pregnant female. Verify pregnancy status of females of
reproductive potential prior to initiating dactinomycin
therapy; effective contraception should be used during
biotic
therapy and for at least 6 months after the last dactino-
Use mycin dose. When used for gestational trophoblastic
Ewing sarcoma: Treatment of Ewing sarcoma (as part neoplasm, unfavorable outcomes have been reported
of a multi-phase, combination chemotherapy regimen) when subsequent pregnancies occur within 6 months of
Gestational trophoblastic neoplasia: Treatment of treatment. It is recommended to use effective contra-
gestational trophoblastic neoplasia in post-menarchal ception for 6 months to 1 year after therapy (Matsui
patients (as a single agent or as part of a combination 2004; Seckl 2013). Males with female partners of
chemotherapy regimen) reproductive potential should use effective contracep-
Rhabdomyosarcoma: Treatment of rhabdomyosar- tion during therapy and for 3 months after the last
coma (as part of a multi-phase, combination chemo- dactinomycin dose.
therapy regimen)
Solid tumors: Palliative and/or adjunctive treatment of
locally recurrent or locoregional solid malignancies (as Dalbavancin (dal ba VAN sin)
a component of regional perfusion) in adult patients
Wilms tumor: Treatment of Wilms tumor (as part of a
Brand Names: US Dalvance
multi-phase, combination chemotherapy regimen) Pharmacologic Category Glycopeptide
Local Anesthetic/Vasoconstrictor Precautions Use Acute bacterial skin and skin structure infec-
No information available to require special precautions tions: Treatment of adult patients with acute bacterial
skin and skin structure infections (ABSSSI) caused by
susceptible isolates of the following gram-positive
related to dental treatment: Stomatitis and mucositis
microorganisms: Staphylococcus aureus (including
Effects on Bleeding Onset of thrombocytopenia, methicillin-susceptible and methicillin-resistant strains),
which can be severe, occurs at 7 days with the nadir Streptococcus pyogenes, Streptococcus agalactiae, S.
at 14-21 days. A medical consult is recommended. dysgalactiae, Streptococcus anginosus group (includ-
Adverse Reactions ing S. anginosus, S. intermedius, S. constellatus), and
Frequency not defined: Enterococcus faecalis (vancomycin-susceptible strains)
Cardiovascular: Thrombophlebitis Local Anesthetic/Vasoconstrictor Precautions
Central nervous system: Fatigue, malaise, peripheral No information available to require special precautions
neuropathy Effects on Dental Treatment Key adverse event(s)
Dermatologic: Acne vulgaris, alopecia, cheilitis, der- related to dental treatment: Use may result in fungal
matitis, erythema multiforme, skin rash, Stevens- superinfection including Candida albicans in the oral
Johnson syndrome, toxic epidermal necrolysis cavity.
Endocrine & metabolic: Growth suppression, hypocal- Effects on Bleeding Dalbavancin may affect bleeding
cemia times including spontaneous hematoma and wound
Gastrointestinal: Abdominal pain, anorexia, aphthous hemorrhage; may interfere with test used to monitor
stomatitis, constipation, diarrhea, dysphagia, esoph- coagulation such as INR.
agitis, gastrointestinal ulcer, mucositis, nausea, proc- Adverse Reactions
titis, vomiting 1% to 10%:
Hematologic & oncologic: Anemia, bone marrow Cardiovascular: Flushing (<2%), phlebitis (<2%)
depression, disseminated intravascular coagulation, Central nervous system: Headache (5%), dizzi-
febrile neutropenia, hemorrhage, leukopenia, neutro- ness (<2%)
penia (nadir: 14 to 21 days), pancytopenia, reticulo- Dermatologic: Skin rash (3%), pruritus (2%), urtica-
cytopenia, second primary malignant neoplasm ria (<2%)
(including leukemia), thrombocytopenia, tumor lysis Endocrine & metabolic: Hypoglycemia (<2%),
syndrome increased gamma-glutamyl transferase (<2%),
Hepatic: Abnormal hepatic function tests, ascites, increased lactate dehydrogenase (<2%)
hepatic failure, hepatic sinusoidal obstruction syn- Gastrointestinal: Nausea (6%), diarrhea (4%), vomit-
drome, hepatitis, hepatomegaly, hepatotoxicity, ing (3%), abdominal pain (<2%), Clostridioides (for-
severe hepatic disease (hepatopathy-thrombocyto- merly Clostridium) difficile colitis (<2%),
penia syndrome, Farruggia 2011) gastrointestinal hemorrhage (<2%), hematochezia
Hypersensitivity: Hypersensitivity reaction (<2%), melena (<2%), oral candidiasis (<2%)
Infection: Infection, sepsis Hematologic & oncologic: Acute posthemorrhagic
Neuromuscular & skeletal: Myalgia anemia (<2%), anemia (<2%), eosinophilia (<2%),
Ophthalmic: Optic neuropathy hematoma (spontaneous; <2%), increased INR
Renal: Renal function abnormality, renal failure syn- (<2%), leukopenia (<2%), neutropenia (<2%), pete-
drome, renal insufficiency chia (<2%), thrombocythemia (<2%), thrombocyto-
Respiratory: Pneumonitis, pneumothorax penia (<2%), wound hemorrhage (<2%)
Miscellaneous: Fever, radiation recall phenomenon Hepatic: Hepatotoxicity (<2%)
Mechanism of Action Dactinomycin binds to the Hepatic: Increased serum alkaline phosphatase
guanine portion of DNA intercalating between guanine (<2%), increased serum transaminases (<2%)
379
DALBAVANCIN
Hypersensitivity: Anaphylactoid reaction (<2%)

Infection: Vulvovaginal infection (mycotic; <2%) Dalteparin (dal TE pa rin)
Respiratory: Bronchospasm (<2%)
Related Information
Miscellaneous: Infusion related reaction (<2%; includ-
ing red man syndrome)
Brand Names: US Fragmin
Brand Names: Canada Fragmin
back pain, Clostridioides (formerly Clostridium) diffi-
cile-associated diarrhea, hypersensitivity reaction,
lant, Low Molecular Weight Heparin
increased serum alanine aminotransferase
Use
Mechanism of Action Dalbavancin is a lipoglycopep- Anticoagulant for hemodialysis and hemofiltration
tide which binds to the D-alanyl-D-alanine terminus of (Fragmin [Canadian product only]): Prevention of
the stem pentapeptide in nascent cell wall peptidogly- clotting in the extracorporeal system during hemodial-
can, preventing cross-linking and interfering with cell ysis and hemofiltration in connection with acute renal
wall synthesis. It is bactericidal in vitro against Staph- failure or chronic renal insufficiency
ylococcus aureus and Streptococcus pyogenes Non-ST elevation acute coronary syndromes: Pre-
Pharmacodynamics/Kinetics vention of ischemic complications in patients with
Half-life Elimination 346 hours unstable angina or non-Q-wave myocardial infarction
Pregnancy Considerations Adverse events have on concurrent aspirin therapy.
been observed in animal reproduction studies. The long Venous thromboembolism prophylaxis: Prevention
half-life of dalbavancin should be considered when of DVT which may lead to PE, in patients requiring
evaluating potential exposure to the fetus. abdominal surgery who are at risk for thromboembo-
lism complications (eg, >40 years, obesity, malig-
nancy, history of DVT or PE, surgical procedures
Dalfampridine (dal FAM pri deen) requiring general anesthesia lasting >30 minutes);
patients undergoing total hip arthroplasty; or in
Brand Names: US Ampyra patients who are at risk for thromboembolism compli-
Brand Names: Canada Fampyra cations due to severe immobility during an acute
Pharmacologic Category Potassium Channel illness.
Blocker Venous thromboembolism treatment in patients
Use Treatment to improve walking in patients with multi- with active cancer: Extended treatment (6 months)
ple sclerosis (MS) of acute symptomatic VTE (ie, DVT and/or PE) to
Local Anesthetic/Vasoconstrictor Precautions reduce the recurrence of VTE in cancer patients.
Note: In patients with VTE (ie, DVT and/or PE) and
cancer, ACCP guidelines recommend low molecular
Effects on Dental Treatment No significant effects or weight heparin (LMWH) over oral anticoagulants for
complications reported initial and long-term treatment (ACCP [Kearon 2012];
Effects on Bleeding No information available to ACCP [Kearon 2016]).
>10%: Genitourinary: Urinary tract infection (12%)
1% to 10%:
related to dental treatment: Bleeding is the major
Central nervous system: Insomnia (9%), dizziness adverse effect of dalteparin. Adverse reactions reported
(7%), headache (7%), equilibrium disturbance (5%), were generally less than those seen with heparin. See
paresthesia (4%) Effects on Bleeding.
Gastrointestinal: Nausea (7%), constipation (3%), dys-
Effects on Bleeding The risk of bleeding and throm-
pepsia (2%)
bocytopenia is high with low molecular weight heparin
Neuromuscular & skeletal: Weakness (7%), back pain anticoagulants such as dalteparin. The use of NSAIDs
(5%), acute exacerbations of multiple sclerosis (4%) and aspirin should be avoided. A medical consult is
Respiratory: Nasopharyngitis (4%), pharyngolaryng- recommended.
eal pain (2%)
Adverse Reactions Note: As with all anticoagulants,
<1%, postmarketing and/or case reports: Hypersensi- bleeding is the major adverse effect of dalteparin.
tivity reaction, seizure, vomiting Hemorrhage may occur at virtually any site. Risk is
Mechanism of Action Nonspecific potassium channel dependent on multiple variables.
blocker which improves conduction in focally demyeli- >10%: Hematologic & oncologic: Hemorrhage (3% to
nated axons by delaying repolarization and prolonging 14%), thrombocytopenia (including heparin-induced
the duration of action potentials. Enhanced neuronal thrombocytopenia, <1%; cancer clinical trials: ~11%)
conduction is thought to strengthen skeletal muscle 1% to 10%:
fiber twitch activity, thereby, improving peripheral motor Hematologic & oncologic: Major hemorrhage (≤6%),
neurologic function. wound hematoma (3%)
Pharmacodynamics/Kinetics Hepatic: Increased serum ALT (>3 x ULN: 4% to 10%),
Half-life Elimination 5.2-6.5 hours; prolonged in increased serum AST (>3 x ULN: 5% to 9%)
severe renal impairment (~3 times longer) Local: Pain at injection site (≤12%), hematoma at
injection site (≤7%)
Time to Peak Plasma: 3-4 hours
<1% (Limited to important or life-threatening): Alopecia,
Pregnancy Risk Factor C anaphylactoid reaction, gastrointestinal hemorrhage,
Pregnancy Considerations Adverse events have hemoptysis, hypersensitivity reaction (fever, pruritus,
been observed in animal reproduction studies, including rash, injections site reaction, bullous eruption), post-
decreased growth and death. operative wound bleeding, skin necrosis, subdural
380
DANAPAROID
hematoma, thrombosis (associated with heparin- Heparin-induced thrombocytopenia: Management of

induced thrombocytopenia). Spinal or epidural hema- heparin-induced thrombocytopenia (HIT)
tomas can occur following neuraxial anesthesia or Local Anesthetic/Vasoconstrictor Precautions
spinal puncture, resulting in paralysis. No information available to require special precautions
Mechanism of Action Low molecular weight heparin Effects on Dental Treatment Key adverse event(s)
analog with a molecular weight of 4,000 to 6,000 related to dental treatment: Bleeding is the major
daltons; the commercial product contains 3% to 15% adverse effect of danaparoid. See Effects on Bleeding.
heparin with a molecular weight <3,000 daltons, 65% to Effects on Bleeding As with all anticoagulants, bleed-
78% with a molecular weight of 3,000 to 8,000 daltons ing is the major adverse effect of danaparoid. Hemor-
and 14% to 26% with a molecular weight >8,000 rhage may occur at virtually any site; risk is dependent
daltons; while dalteparin has been shown to inhibit both on multiple variables including the intensity of antico-
factor Xa and factor IIa (thrombin), the antithrombotic agulation and patient susceptibility. At the recom-
effect of dalteparin is characterized by a higher ratio of mended doses, LMWHs do not significantly influence
antifactor Xa to antifactor IIa activity (ratio = 4) platelet aggregation or affect global clotting time (ie, PT
Pharmacodynamics/Kinetics or aPTT). Medical consult is suggested.
Onset of Action Anti-Xa activity: Within 1 to 2 hours Adverse Reactions Frequency not always defined. As
Duration of Action >12 hours with all anticoagulants, bleeding is the major adverse
Half-life Elimination Route dependent: effect of danaparoid. Hemorrhage may occur at virtually
IV: Mean terminal half-life: 2.1 ± 0.3 hours (40 unit/kg/ any site. Risk is dependent on multiple variables.
1% to 10%:
dose) to 2.3 ± 0.4 hours (60 unit/kg/dose); mean
Central nervous system: Pain (5%)
terminal half-life (anti-Xa activity): 5.7 ± 2.0 hours
(5,000 unit dose in chronic renal impairment requir-
Gastrointestinal: Nausea (3%), constipation (2%)
ing hemodialysis)
Genitourinary: Urinary retention (1%)
SubQ: Mean terminal half-life: 3 to 5 hours
Hematologic & oncologic: Leukocytosis (1%)
Time to Peak Serum: SubQ: Anti-Xa activity: ~4 hours Infection: Infection (2%)
Pregnancy Considerations Low molecular weight Local: Hematoma at injection site (≤5%)
heparin (LMWH) does not cross the placenta; increased Respiratory: Pneumonia (1%)
risks of fetal bleeding or teratogenic effects have not Miscellaneous: Fever (2% to 5%)
been reported (ACCP [Bates 2012]). Frequency not defined:
LMWH is recommended over unfractionated heparin for Cardiovascular: Atrial fibrillation, cerebral infarction,
the treatment of acute VTE in pregnant women. LMWH decreased blood pressure (arterial), deep vein
is also recommended over unfractionated heparin for thrombosis, hypotension, peripheral edema
Central nervous system: Cerebral hemorrhage, con-
VTE prophylaxis in pregnant women with certain risk
fusion, fatigue, hemiparesis, insomnia, loss of con-
factors. LMWH should be discontinued at least 24 hours
sciousness, restlessness
prior to induction of labor or a planned cesarean deliv-
Genitourinary: Hematuria, urinary incontinence, uri-
ery. For women undergoing cesarean section and who
nary tract hemorrhage (including microscopic), urine
have additional risk factors for developing VTE, the
abnormality
prophylactic use of LMWH may be considered. For
Hematologic & oncologic: Bruise, hematoma, hemor-
women who require long-term anticoagulation with war- rhage (dose-related), thrombocytopenia
farin and who are considering pregnancy, LMWH sub- Hypersensitivity: Hypersensitivity reaction
stitution should be done prior to conception when Infection: Sepsis
possible. When choosing therapy, fetal outcomes (ie, Neuromuscular & skeletal: Muscle spasm, tremor
pregnancy loss, malformations), maternal outcomes (ie, Respiratory: Apnea, asthma
VTE, hemorrhage), burden of therapy, and maternal <1%, postmarketing, and/or case reports: Increased
preference should be considered (ACCP [Guyatt serum alkaline phosphatase, increased serum ALT
2012]). LMWH may also be used in women with (transient), increased serum AST (transient)
mechanical heart valves (consult current guidelines for Mechanism of Action Inhibits factor Xa and IIa (anti-
details) (ACC/AHA [Nishimura 2014]; ACCP Xa effects >20 times anti-IIa effects). Prevents fibrin
[Bates 2012]). formation in the coagulation pathway via thrombin gen-
Multiple-dose vials contain benzyl alcohol (avoid in eration inhibition.
pregnant women due to association with gasping syn- Pharmacodynamics/Kinetics
drome in premature infants); use of preservative-free Onset of Action Peak effect: SubQ: Maximum anti-
formulation is recommended. factor Xa activities occur in 4-5 hours
Half-life Elimination Anti-Xa activity: ~25 hours
(renal impairment: 29-35 hours); Thrombin generation
Danaparoid (da NAP a roid) inhibition activity: ~7 hours
Brand Names: Canada Orgaran been observed in animal reproduction studies. The
Pharmacologic Category Anticoagulant; Anticoagu- manufacturer labeling states that incidental observa-
lant, Heparinoid tions in pregnant women during the last trimesters,
Use Note: Not approved in the US gave no indication that use during pregnancy results
Catheter patency: Intermittent flushing to maintain in fetal abnormalities or exacerbation of bleeding in the
patency of catheters/IV lines and/or access ports mother or infant during delivery. Use in pregnant
Deep vein thrombosis: Prevention of postoperative women however is generally not recommended unless
deep vein thrombosis (DVT) following orthopedic or deemed medically necessary and alternative therapy is
major abdominal and thoracic surgery; prevention of unavailable. Danaparoid does not cross the placenta
DVT in patients with confirmed diagnosis of non-hem- and is the preferred anticoagulant in pregnant women
orrhagic stroke with HIT (Guyatt 2012).
381
DANAPAROID
Product Availability Not available in the US peliosis), skin photosensitivity, Stevens-Johnson syn-
drome
Mechanism of Action Suppresses pituitary output of
Danazol (DA na zole)
follicle-stimulating hormone (FSH) and luteinizing hor-
Brand Names: Canada Cyclomen mone (LH), resulting in regression and atrophy of
Pharmacologic Category Androgen normal and ectopic endometrial tissue; decreases rate
of growth of abnormal breast tissue; reduces attacks
Use
associated with hereditary angioedema by increasing
Endometriosis: Treatment of endometriosis amenable
levels of C4 component of complement
to hormonal management. Pharmacodynamics/Kinetics
Hereditary angioedema (HAE), prophylaxis: Preven-
Onset of Action Immune thrombocytopenia (off-label
tion of attacks of angioedema of all types (cutaneous, use): Initial response: 14 to 90 days; Peak response:
abdominal, laryngeal) in males and females. 28 to 180 days (Neunert 2011)
Guideline recommendations:Danazol may be con-
Half-life Elimination 9.7 ± 3.29 hours (variable; up to
sidered for short-term pre-procedural and long-term
24 hours following long-term use for endometriosis)
HAE prophylaxis as an alternative to CI inhibitor
Time to Peak Serum: 4 hours (range: 2 to 8 hours)
(human). Danazol is not recommended for treatment
of acute HAE attacks (WAO/EAACI [Maurer 2018]).
[US Boxed Warning]: Danazol use is contraindi-
cated in pregnancy. Pregnancy should be ruled
out immediately prior to starting treatment using a
Effects on Dental Treatment No significant effects or sensitive test (eg, beta subunit test if available)
complications reported capable of determining early pregnancy. A nonhor-
Effects on Bleeding Thrombocytopenia and throm- monal method of contraception should also be
botic events have been reported. used during therapy. If a patient becomes pregnant
Adverse Reactions Frequency not defined. during danazol treatment, discontinue danazol and
Cardiovascular: Edema, flushing, hypertension, myo- apprise the patient of the potential risk to the fetus.
cardial infarction, palpitations, syncope, tachycardia Exposure to danazol in utero may result in andro-
Central nervous system: Depression, dizziness, emo- genic effects on the female fetus; reports of clitoral
tional lability, fatigue, headache, nervousness, pares- hypertrophy, labial fusion, urogenital sinus defect,
thesia, sleep disorder, voice disorder (deepening of vaginal atresia, and ambiguous genitalia have been
the voice, hoarseness, instability, sore throat) received.
Dermatologic: Acne vulgaris, alopecia, diaphoresis,
maculopapular rash, papular rash, pruritus, sebor- The use of danazol for the management of hereditary
rhea, urticaria, vesicular eruption angioedema (HAE) in pregnancy that is not responsive
Endocrine & metabolic: Amenorrhea (may continue to preferred therapy has been described in case reports
post-therapy), change in libido, decreased glucose (Altman 2006; Boulos 1994; González-Quevedo 2016;
tolerance (and glucagon changes), decreased HDL Milingos 2009). However, danazol is contraindicated
cholesterol, decreased thyroxine binding globulin, during pregnancy; current guidelines recommend use
hirsutism (mild), increased LDL cholesterol, increased of other agents in pregnant females (WAO/EAACI
thyroxine binding globulin, menstrual disease (altered [Maurer 2018]).
timing of cycle, spotting), weight gain
Gastrointestinal: Constipation, gastroenteritis, nausea, Dantrolene (DAN troe leen)
vomiting
Genitourinary: Asthenospermia, breast atrophy, Brand Names: US Dantrium; Revonto; Ryanodex
decreased ejaculate volume, hematuria, inhibition of Brand Names: Canada Dantrium
spermatogenesis, spermatozoa disorder (changes in Pharmacologic Category Skeletal Muscle Relaxant
sperm count and semen viscosity), vaginal dryness, Use
vaginal irritation Chronic spasticity: Oral: Treatment of spasticity asso-
Hematologic & oncologic: Abnormal erythrocytes ciated with upper motor neuron disorders (eg, spinal
(increased), decreased sex hormone binding globulin, cord injury, stroke, cerebral palsy, or multiple sclero-
eosinophilia, increased sex hormone-binding globulin, sis).
leukocytosis, leukopenia, malignant neoplasm (after Malignant hyperthermia:
prolonged use), petechial rash, polycythemia, purpuric IV: Management of malignant hyperthermia (MH);
rash, thrombocythemia, thrombocytopenia prevention of MH in susceptible individuals (preop-
Hepatic: Cholestatic jaundice, hepatic adenoma, hep- erative/postoperative administration)
atic neoplasm (malignant; after prolonged use), Oral: Prevention of MH preoperatively in susceptible
increased liver enzymes, jaundice, peliosis hepatitis individuals who require anesthesia and/or surgery;
Neuromuscular & skeletal: Ankylosing spondylitis, following a malignant hyperthermic crisis to prevent
arthralgia, back pain, increased creatine phosphoki- recurrence of signs of malignant hyperthermia.
nase, joint swelling, limb pain, muscle cramps, muscle Note: Dantrolene prophylaxis is not recommended for
spasm, neck pain, tremor, weakness most MH-susceptible patients, provided nontrigger-
Ophthalmic: Visual disturbance ing anesthetics are used and an adequate supply of
Respiratory: Interstitial pneumonitis dantrolene is available.
<1%, postmarketing, and/or case reports: Anxiety, car- Local Anesthetic/Vasoconstrictor Precautions
pal tunnel syndrome, cataract, change in appetite, No information available to require special precautions
chills, clitoromegaly, convulsions, erythema multi- Effects on Dental Treatment No significant effects or
forme, fever, gingival hemorrhage, Guillain-Barre syn- complications reported
drome, hepatotoxicity (idiosyncratic) (Chalasani Effects on Bleeding No information available to
2014), nasal congestion, nipple discharge, pancreati- require special precautions
tis, pelvic pain, pseudotumor cerebri, purpura (splenic Adverse Reactions Frequency not always defined.
382
DAPAGLIFLOZIN
Cardiovascular: Flushing (intravenous: 27%), atrioven- needed, close monitoring of the mother and newborn is
tricular block (intravenous: 3%), tachycardia (3%), recommended (Krause 2004; Norman 1995).
cardiac failure, phlebitis, variable blood pressure
Central nervous system: Drowsiness (17%; drowsiness
may persist for 48 hours post dose), voice disorder
Dapagliflozin (dap a gli FLOE zin)
(intravenous: 13%), feeling abnormal (intravenous: Brand Names: US Farxiga
10%), dizziness (3%), headache (3%), myasthenia Brand Names: Canada Forxiga
(3%), chills, choking sensation, confusion, depression,
Pharmacologic Category Antidiabetic Agent,
fatigue, insomnia, malaise, nervousness, seizure,
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor;
speech disturbance
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
Dermatologic: Acneiform eruption (capsules), diaphore-
sis, eczematous rash, erythema (intravenous), hair Use Diabetes mellitus, type 2: As an adjunct to diet
disease (abnormal growth), pruritus, urticaria and exercise to improve glycemic control in adults with
Gastrointestinal: Dysphagia (10%; use caution at meal type 2 diabetes mellitus
time on day of administration as swallowing may be Local Anesthetic/Vasoconstrictor Precautions
difficult), nausea (10%), vomiting (3%), abdominal No information available to require special precautions
cramps, anorexia, constipation, diarrhea, dysgeusia, Effects on Dental Treatment Key adverse event(s)
gastric irritation, gastrointestinal hemorrhage, sia- related to dental treatment: Dizziness and syncope
lorrhea have been reported; patients may experience ortho-
Genitourinary: Crystalluria, difficulty in micturition, erec- static hypotension as they stand up after treatment;
tile dysfunction, hematuria, nocturia, urinary fre- especially if lying in dental chair for extended periods
quency, urinary incontinence, urinary retention of time. Use caution with sudden changes in position
Hematologic & oncologic: Anemia, aplastic anemia, during and after dental treatment.
leukopenia, lymphocytic lymphoma, thrombocyto- Dapagliflozin-dependent patients with diabetes (non-
penia insulin dependent, type 2) should be questioned by
Hepatic: Hepatitis the dental professional at each dental visit to assess
Hypersensitivity: Anaphylaxis their risk for stress-induced hypoglycemia. The dental
Local: Injection site reaction (intravenous: 3%; pain,
professional should inquire about the patient’s routine
erythema, swelling), local tissue necrosis (with extrav-
(ie, work, sleep schedule, eating patterns), history of
asation due to high product pH)
hypoglycemia, time of last medication dose, last meal,
Neuromuscular & skeletal: Limb pain (intravenous: 3%),
and most recent blood sugar assessment. Keep a
back pain, myalgia
supply of glucose tablets and other carbohydrates in
Ophthalmic: Blurred vision (intravenous: 3%), diplopia,
the office to prepare for a hypoglycemic event. Seek
epiphora, visual disturbance
medical attention when necessary (American Diabetes
Respiratory: Dyspnea (intravenous), pleural effusion
Association 2016).
(with pericarditis), pulmonary edema (rare), respira-
tory depression Effects on Bleeding No information available to
Miscellaneous: Fever require special precautions
<1%, postmarketing, and/or case reports: Decrease in Adverse Reactions
forced vital capacity (intravenous), dyspnea (intrave- 1% to 10%:
nous), hepatic disease, hepatotoxicity (oral), Endocrine & metabolic: Dyslipidemia (3%), hyper-
increased liver enzymes (oral), respiratory muscle phosphatemia (2%), hypovolemia (1%)
failure (intravenous) Gastrointestinal: Nausea (3%)
Mechanism of Action Acts directly on skeletal muscle Genitourinary: Urinary tract infection (6%), increased
by interfering with release of calcium ion from the urine output (3% to 4%), dysuria (2%)
sarcoplasmic reticulum; prevents or reduces the Hematologic & oncologic: Increased hematocrit (1%)
increase in myoplasmic calcium ion concentration that Infection: Genitourinary fungal infection (3% to 8%),
activates the acute catabolic processes associated with influenza (3%)
malignant hyperthermia Neuromuscular & skeletal: Back pain (4%), limb
Pharmacodynamics/Kinetics pain (2%)
Half-life Elimination Renal: Renal insufficiency (2% to 7%)
Neonates (at birth): ~20 hours (Shime 1988) Respiratory: Nasopharyngitis (7%)
Children 2 to 7 years: 10 hours (range: 8.1 to 14.8 Frequency not defined:
hours) (Lerman 1989) Hypersensitivity: Angioedema, hypersensitivity
Adults: 4 to 11 hours reaction
Pregnancy Risk Factor C Neuromuscular & skeletal: Bone fracture
Pregnancy Considerations Adverse events have Renal: Decreased estimated GFR (eGFR), increased
been observed in animal reproduction studies. Dantro- serum creatinine
lene crosses the human placenta. Cord blood concen- <1%, postmarketing, and/or case reports: Acute renal
trations are similar to those in the maternal plasma at failure, allergic skin reaction (severe), anaphylaxis,
term. and dantrolene can be detected in the newborn increased LDL cholesterol, ketoacidosis, necrotizing
serum at delivery. Adverse events were not observed in fasciitis (perineum), pyelonephritis, renal insufficiency,
the newborn following maternal doses of 100 mg/day skin rash, urinary tract infection with sepsis
administered orally prior to delivery (Shime, 1988). Mechanism of Action By inhibiting sodium-glucose
Uterine atony has been reported following dantrolene cotransporter 2 (SGLT2) in the proximal renal tubules,
injection after delivery; however, this may be due in part dapagliflozin reduces reabsorption of filtered glucose
to the mannitol contained in the IV preparation (Shin, from the tubular lumen and lowers the renal threshold
1995; Weingarten, 1987). Prophylactic use of dantro- for glucose (RTG). SGLT2 is the main site of filtered
lene is not routinely recommended in pregnant women glucose reabsorption; reduction of filtered glucose reab-
susceptible to MH prior to obstetric surgery, if use is sorption and lowering of RTG result in increased urinary
383
DAPAGLIFLOZIN
excretion of glucose, thereby reducing plasma glucose Gastrointestinal: Nausea (3% to 4%), constipa-
concentrations. tion (3%)
Pharmacodynamics/Kinetics Genitourinary: Urinary tract infection (6%), increased
Half-life Elimination ~12.9 hours urine output (2% to 3%), dysuria (2%)
Time to Peak 2 hours Respiratory: Cough (3%), pharyngitis (2% to 3%)
Pregnancy Considerations <1%, postmarketing, and/or case reports: Ketoacidosis
Based on animal data, adverse fetal effects on renal (FDA Safety Communication, December 4, 2015),
development may occur in humans following in utero pyelonephritis (FDA Safety Communication, Decem-
exposure during the second and third trimesters. ber 4, 2015), urosepsis (FDA Safety Communication,
December 4, 2015)
In women with diabetes, maternal hyperglycemia can Mechanism of Action
be associated with congenital malformations as well as Dapagliflozin: By inhibiting sodium-glucose cotrans-
adverse effects in the fetus, neonate, and the mother porter 2 (SGLT2) in the proximal renal tubules, dapa-
(ACOG 201 2018; ADA 2019; Metzger 2007). To pre- gliflozin reduces reabsorption of filtered glucose from
vent adverse outcomes prior to conception and the tubular lumen and lowers the renal threshold for
throughout pregnancy, maternal blood glucose and glucose (RTG). SGLT2 is the main site of filtered
HbA1c should be kept as close to target goals as glucose reabsorption; reduction of filtered glucose
possible but without causing significant hypoglycemia
reabsorption and lowering of RTG result in increased
(ADA 2019; Blumer 2013). Agents other than dapagli-
urinary excretion of glucose, thereby reducing plasma
flozin are currently recommended to treat diabetes in
glucose concentrations.
pregnant women (ADA 2019).
Metformin: Decreases hepatic glucose production,
decreases intestinal absorption of glucose, improves
Dapagliflozin and Metformin insulin sensitivity by increasing peripheral glucose
(dap a gli FLOE zin & met FOR min) uptake and utilization.
Brand Names: US Xigduo XR
Metformin crosses the placenta (ADA 2019).
Brand Names: Canada Xigduo
Pharmacologic Category Antidiabetic Agent, Bigua- Refer to individual monographs for additional infor-
nide; Antidiabetic Agent, Sodium-Glucose Cotrans- mation.
p o r t e r 2 ( S G LT 2 ) I n h i b i t o r ; S o d i u m - G l u c o s e
Cotransporter 2 (SGLT2) Inhibitor Dapsone (Systemic) (DAP sone)
Use Diabetes mellitus, type 2: As an adjunct to diet
and exercise to improve glycemic control in adults with Related Information
type 2 diabetes mellitus when treatment with both HIV Infection and AIDS on page 1477
dapagliflozin and metformin is appropriate. Pharmacologic Category Antibiotic, Miscellaneous
Local Anesthetic/Vasoconstrictor Precautions Use Treatment of leprosy (due to susceptible strains of
No information available to require special precautions Mycobacterium leprae) and dermatitis herpetiformis
related to dental treatment: Dizziness and syncope No information available to require special precautions
have been reported; patients may experience ortho- Effects on Dental Treatment No significant effects or
static hypotension as they stand up after treatment; complications reported
especially if lying in dental chair for extended periods
of time. Use caution with sudden changes in position
during and after dental treatment.
Dapagliflozin-dependent patients with diabetes (non- >10%: Hematologic: Reticulocyte increase (2% to
insulin dependent, type 2) should be questioned by 12%), hemolysis (>10%; dose related; seen in patients
the dental professional at each dental visit to assess with and without G6PD deficiency), hemoglobin
their risk for stress-induced hypoglycemia. The dental decrease (>10%; 1-2 g/dL; almost all patients), meth-
professional should inquire about the patient’s routine emoglobinemia (>10%), red cell life span shortened
(ie, work, sleep schedule, eating patterns), history of (>10%), Agranulocytosis, anemia, leukopenia, pure
hypoglycemia, time of last medication dose, last meal, red cell aplasia (case report)
and most recent blood sugar assessment. Keep a Cardiovascular: Tachycardia
supply of glucose tablets and other carbohydrates in Central nervous system: Fever, headache, insomnia,
the office to prepare for a hypoglycemic event. Seek psychosis, vertigo
medical attention when necessary (American Diabetes Dermatologic: Bullous and exfoliative dermatitis, eryth-
Association 2016). ema nodosum, exfoliative dermatitis, morbilliform and
Effects on Bleeding No information available to scarlatiniform reactions, phototoxicity, Stevens-John-
require special precautions son syndrome, toxic epidermal necrolysis, urticaria
Adverse Reactions See individual monographs for Endocrine & metabolic: Hypoalbuminemia (without pro-
additional adverse effects reported with each agent teinuria), male infertility
1% to 10%: Gastrointestinal: Abdominal pain, nausea, pancreatitis,
Central nervous system: Headache (5%), dizzi- vomiting
ness (3%) Hepatic: Cholestatic jaundice, hepatitis
Endocrine & metabolic: Dyslipidemia (2% to 3%) Neuromuscular & skeletal: Lower motor neuron toxicity
Infection: Genitourinary fungal infection (female: 9%, (prolonged therapy), lupus-like syndrome, peripheral
includes bacterial vaginosis, female genital tract neuropathy (rare, nonleprosy patients)
infection, genital abscess, vaginal infection, vulvova- Ophthalmic: Blurred vision
ginal candidiasis; male: 4%, includes balanitis, bal- Otic: Tinnitus
anitis [candida], balanoposthitis, posthitis), influenza Renal: Albuminuria, nephrotic syndrome, renal papillary
(3% to 4%) necrosis
384
DAPTOMYCIN
Respiratory: Interstitial pneumonitis, pulmonary eosino-

philia DAPTOmycin (DAP toe mye sin)
Miscellaneous: Infectious mononucleosis-like syn-
drome (rash, fever, lymphadenopathy, hepatic dys- Brand Names: US Cubicin; Cubicin RF
function) Brand Names: Canada Cubicin
Mechanism of Action Competitive antagonist of para- Pharmacologic Category Antibiotic, Cyclic Lipopep-
aminobenzoic acid (PABA) and prevents normal bacte- tide
rial utilization of PABA for the synthesis of folic acid Use
Pharmacodynamics/Kinetics Skin and skin structure infections, complicated:
Half-life Elimination Children: 15.1 hours (Miroch- Treatment of complicated skin and skin structure
nick 1993); Adults: 28 hours (range: 10 to 50 hours) infections caused by Staphylococcus aureus (includ-
Time to Peak 4 to 8 hours ing methicillin-resistant isolates), Streptococcus pyo-
Pregnancy Risk Factor C genes, Streptococcus agalactiae, Streptococcus
Pregnancy Considerations Dapsone crosses the dysgalactiae subspecies equisimilis, and Enterococ-
placenta (Brabin 2004). Per the manufacturer, dapsone cus faecalis (vancomycin-susceptible isolates only) in
has not shown an increased risk of congenital anoma- adult and pediatric patients 1 to 17 years of age.
lies when given during all trimesters of pregnancy. S. aureus bacteremia: Treatment of S. aureus (methi-
Several reports have described adverse effects in the cillin-susceptible and methicillin-resistant isolates)
newborn after in utero exposure to dapsone, including bacteremia in adults, including those with right-sided
neonatal hemolytic disease, methemoglobinemia, and infective endocarditis; treatment of S. aureus bacter-
hyperbilirubinemia (Hocking 1968; Kabra 1998; Thorn- emia in pediatric patients 1 to 17 years of age.
ton 1989). Dapsone may be used in pregnant women Limitations of use: Not indicated for the treatment of
requiring maintenance therapy of either leprosy or pneumonia.
dermatitis herpetiformis. Dapsone may be used as an Local Anesthetic/Vasoconstrictor Precautions
alternative agent for management of Pneumocystis No information available to require special precautions
jirovecii pneumonia (PCP) or Toxoplasma gondii ence- Effects on Dental Treatment No significant effects or
phalitis in pregnant, HIV-infected patients (HHS [OI complications reported
Adult] 2016). Because of the theoretical increased risk Effects on Bleeding No information available to
for hyperbilirubinemia and kernicterus, neonatal care require special precautions
providers should be informed if maternal dapsone is Adverse Reactions
used near term (HHS [OI Adult] 2016). 1% to 10%:
Cardiovascular: Chest pain (adults: 7%), edema
Dapsone (Topical) (DAP sone)
(adults: 7%), hypertension (adults: 6%), hypotension
(adults: 2%)
Brand Names: US Aczone Central nervous system: Insomnia (adults: 9%), head-
Brand Names: Canada Aczone ache (3% to 5%), dizziness (adults: 2%)
Pharmacologic Category Topical Skin Product, Acne Dermatologic: Pruritus (3% to 6%), diaphoresis
Use Acne vulgaris: Topical treatment of acne vulgaris (adults: 5%), skin rash (adults: 4%)
Guideline recommendations: American Academy of Gastrointestinal: Diarrhea (5% to 7%), abdominal pain
Dermatology (AAD) acne guidelines recommend dap- (adults: 6%; children and adolescents: 2%), vomiting
sone 5% topical gel for inflammatory acne, particularly (children and adolescents: 3% to 11%; adults: <1%)
in adult females with acne (AAD [Zaenglein 2016]). Genitourinary: Urinary tract infection (adults: 2%)
Local Anesthetic/Vasoconstrictor Precautions Hepatic: Abnormal hepatic function tests (adults: 3%),
No information available to require special precautions increased serum alkaline phosphatase (adults: 2%)
Effects on Dental Treatment No significant effects or Infection: Gram-negative organism infection (adults:
complications reported 8%), bacteremia (adults: 5%), sepsis (adults: 5%)
phokinase (3% to 9%)
Respiratory: Pharyngolaryngeal pain (adults: 8%),
Adverse Reactions
dyspnea (adults: 2%)
1% to 10%:
Miscellaneous: Fever (≤4%)
Respiratory: Sinusitis (2%)
Cardiovascular: Atrial fibrillation, atrial flutter
Central nervous system: Attempted suicide, tonic-clonic
Central nervous system: Hallucination, hypoesthesia
movements
(including oral)
Gastrointestinal: Abdominal pain, pancreatitis, severe
Endocrine & metabolic: Increased serum phosphate
vomiting
Gastrointestinal: Decreased appetite, epigastric dis-
Respiratory: Pharyngitis
tress, gingival pain, oral candidiasis, xerostomia
<1%, postmarketing, and/or case reports: Application
Genitourinary: Fungal urinary tract infection, proteinu-
site rash, depression, erythema, erythematous rash,
ria, vulvovaginal candidiasis
facial edema, lip edema, methemoglobinemia, perior-
Hematologic & oncologic: Lymphadenopathy
bital swelling, psychosis, skin rash
Hepatic: Increased serum ALT, increased serum AST
Pregnancy Considerations The amount of topical
Infection: Candidiasis, fungal septicemia
dapsone available systemically is minimal compared
Neuromuscular & skeletal: Dyskinesia
to oral administration.
Topical products are recommended as initial therapy for Otic: Tinnitus
the treatment of acne vulgaris in pregnant females; Renal: Renal insufficiency
however, information specific to dapsone is lacking <1%, postmarketing, and/or case reports: Abdominal
(Kong 2013). Agents other than topical dapsone are distension, acute generalized exanthematous pustu-
preferred (Chien 2016). losis, acute renal failure, anaphylaxis, anemia,
385
DAPTOMYCIN
arthralgia, bronchiolitis obliterans organizing pneumo- Local Anesthetic/Vasoconstrictor Precautions

nia, Clostridioides (formerly Clostridium) difficile-asso- No information available to require special precautions
ciated diarrhea, cough, decreased appetite, Effects on Dental Treatment No significant effects or
dysgeusia, eczema, electrolyte disturbance, eosino- complications reported
philia, eosinophilic pneumonitis, eye irritation, fatigue, Effects on Bleeding Chemotherapy may result in
flushing, hypomagnesemia, hypersensitivity reaction significant myelosuppression, including thrombocytope-
(including angioedema, drug rash with eosinophilia nia. In patients under active treatment a medical consult
and systemic symptoms [DRESS], dysphagia, hives, is suggested.
pulmonary eosinophilia, truncal erythema), increased
Adverse Reactions
lactate dehydrogenase, increased myoglobin,
>10%:
increased serum bicarbonate, jaundice, leukocytosis,
Central nervous system: Fatigue (39%), head-
mental status changes, muscle cramps, myalgia,
myasthenia, myopathy, nausea, neutropenia (Knoll ache (12%)
2013), paresthesia, peripheral neuropathy, renal fail- Gastrointestinal: Nausea (27%), diarrhea (16%), con-
ure, rhabdomyolysis, rigors, Stevens-Johnson syn- stipation (15%), decreased appetite (15%), vomit-
drome, stomatitis, supraventricular cardiac ing (14%)
arrhythmia, thrombocythemia, thrombocytopenia, ver- Hematologic & oncologic: Lymphocytopenia (72%;
tigo, vesiculobullous dermatitis, visual disturbance, grade: 3: 30%; grade 4: 10%), neutropenia (60%;
weakness grade 3: 17%; grade 4: 3%), thrombocytopenia
Mechanism of Action Daptomycin binds to compo- (48%; grade 3: 10%; grade 4: 8%), anemia (45%;
nents of the cell membrane of susceptible organisms grade 3: 19%)
and causes rapid depolarization, inhibiting intracellular Neuromuscular & skeletal: Back pain (23%), arthralgia
synthesis of DNA, RNA, and protein. Daptomycin is (17%), limb pain (15%), musculoskeletal chest
bactericidal in a concentration-dependent manner. pain (12%)
Pharmacodynamics/Kinetics Respiratory: Cough (21%), upper respiratory tract
Half-life Elimination infection (20%), nasal congestion (17%), dyspnea
Neonates and Infants <3 months: Median: 6.2 hours (15%), nasopharyngitis (15%), pneumonia (11%)
(range: 3.7 to 9 hours) (Cohen-Wolkowiez 2012) Miscellaneous: Infusion related reaction (48%),
Children 2 to 6 years: Mean range: 5.3 to 5.7 hours fever (21%)
(Abdel-Rahman 2008; Abdel-Rahman 2011) 1% to 10%:
Children 7 to 11 years: 5.6 ± 2.2 hours (Abdel-Rah- Cardiovascular: Hypertension (10%)
man 2008) Central nervous system: Chills (10%)
Children 12 to 17 years: 6.7 ± 2.2 hours (Abdel-Rah- Infection: Herpes zoster infection (3%)
man 2008) Miscellaneous: Physical health deterioration (3%)
Adults: 8 to 9 hours (up to 28 hours in renal <1%, postmarketing, and/or case reports: Anaphylaxis,
impairment) positive indirect Coombs test
Pregnancy Considerations Adverse events were not Mechanism of Action Daratumumab is an IgG1κ
observed in animal reproduction studies. Successful human monoclonal antibody directed against CD38.
use of daptomycin during the second and third trimes- CD38 is a cell surface glycoprotein which is highly
ters of pregnancy has been described; however, only expressed on myeloma cells, yet is expressed at low
limited information is available from case reports. levels on normal lymphoid and myeloid cells (Lokhorst
2015). By binding to CD38, daratumumab inhibits the
Daratumumab (dar a TOOM ue mab) growth of CD38 expressing tumor cells by inducing
apoptosis directly through Fc mediated cross linking
Brand Names: US Darzalex as well as by immune-mediated tumor cell lysis through
Brand Names: Canada Darzalex complement dependent cytotoxicity, antibody depend-
Pharmacologic Category Antineoplastic Agent, Anti- ent cell mediated cytotoxicity, and antibody dependent
CD38; Antineoplastic Agent, Monoclonal Antibody cellular phagocytosis.
Use Pharmacodynamics/Kinetics
Multiple myeloma (newly diagnosed): Treatment of Half-life Elimination Monotherapy: 18 ± 9 days;
newly diagnosed multiple myeloma (in combination Combination therapy: 22 to 23 days
with bortezomib, melphalan, and prednisone) in Pregnancy Considerations Animal reproduction
patients who are ineligible for autologous stem cell studies have not been conducted. Daratumumab is a
transplant. monoclonal antibody; monoclonal antibodies are known
Multiple myeloma (relapsed/refractory): to cross the placenta. Based on the mechanism of
Treatment of multiple myeloma (in combination with action, daratumumab may cause myeloid or lymphoid
dexamethasone and either lenalidomide or bortezo-
cell depletion and decreased bone density in the fetus.
mib) in patients who have received at least one prior
Females of reproduction potential should use effective
therapy.
contraception during therapy and for 3 months after
Treatment of multiple myeloma (in combination with
treatment is complete. The administration of live vac-
dexamethasone and pomalidomide) in patients who
cines should be deferred for neonates and infants
have received at least two prior therapies, including
lenalidomide and a proteasome inhibitor. exposed to daratumumab in utero until a hematology
Treatment of multiple myeloma (as monotherapy) in evaluation can be completed.
patients who have received at least 3 prior lines of
therapy, including a proteasome inhibitor and an Darbepoetin Alfa (dar be POE e tin AL fa)
immunomodulatory agent or who are double refrac-
tory to a proteasome inhibitor and an immunomodu- Brand Names: US Aranesp (Albumin Free)
latory agent. Brand Names: Canada Aranesp
386
DARIFENACIN
Pharmacologic Category Colony Stimulating Factor; Mechanism of Action Darbepoetin alfa induces eryth-
Erythropoiesis-Stimulating Agent (ESA); Hematopoietic ropoiesis by stimulating the division and differentiation
Agent of committed erythroid progenitor cells; induces the
Use release of reticulocytes from the bone marrow into the
Anemia due to chemotherapy in patients with can- bloodstream, where they mature to erythrocytes. There
cer: Treatment of anemia in patients with nonmyeloid is a dose-response relationship with this effect. This
malignancies when anemia is due to the effect of results in an increase in reticulocyte counts followed
concomitant myelosuppressive chemotherapy, and by a rise in hematocrit and hemoglobin levels. When
upon initiation, there is a minimum of 2 additional administered SubQ or IV, darbepoetin alfa's half-life is
months of planned chemotherapy. ~3 times that of epoetin alfa concentrations.
Anemia due to chronic kidney disease: Treatment of Pharmacodynamics/Kinetics
anemia due to chronic kidney disease, including Onset of Action Increased hemoglobin levels not
patients on dialysis and patients not on dialysis. generally observed until 2 to 6 weeks after initiating
Limitations of use: Darbepoetin alfa has not demon- treatment
strated improved quality of life, fatigue, or well-being. Half-life Elimination Note: Darbepoetin alfa half-life
Darbepoetin alfa is not indicated for use under the is approximately 3-fold longer than epoetin alfa follow-
following conditions: ing IV administration
- Cancer patients receiving hormonal therapy, thera- CKD:
peutic biologic products, or radiation therapy unless Children and Adolescents: (Lerner 2002):
also receiving concurrent myelosuppressive chemo- IV: Terminal: 22.1 ± 4.8 hours
therapy SubQ: Terminal: 42.8 ± 23 hours
- Cancer patients receiving myelosuppressive chemo- Adults:
therapy when the expected outcome is curative
IV: 21 hours
- Cancer patients receiving myelosuppressive chemo-
SubQ: Nondialysis patients: 70 hours (range: 35 to
therapy when anemia can be managed by trans-
139 hours), Dialysis patients: 46 hours (range: 12
fusion
to 89 hours)
- As a substitute for red blood cell (RBC) transfusion in
Cancer:
patients requiring immediate correction of anemia
Children and Adolescents: SubQ: 49.4 ± 32 hours
(Blumer 2007)
Adults: SubQ: 74 hours (range: 24 to 144 hours)
Time to Peak SubQ:
CKD:
Effects on Bleeding Erythropoiesis-stimulating agents
Children and Adolescents: 36.2 ± 14.1 hours
have been associated with thromboembolic events.
(Lerner 2002)
Adverse Reactions Adverse reactions occurred in
Adults: 48 hours (range: 12 to 72 hours; independent
adults with chronic kidney disease unless otherwise
specified. of dialysis)
>10%: Cancer:
Cardiovascular: Hypertension (31%; children and ado- Children and Adolescents: 87.5 ± 53 hours
lescents: frequency not defined), peripheral edema (Blumer 2007)
(17%), edema (cancer patients: 13%) Adults: 71 hours (range: 28 to 120 hours)
Gastrointestinal: Abdominal pain (cancer Pregnancy Considerations Use of darbepoetin alfa
patients: 13%) in pregnancy has been described in case reports
Respiratory: Dyspnea (17%), cough (12%) (Ghosh 2007; Goshorn 2005; Macciò 2009; Sobiło-
1% to 10%: Jarek 2006).
Cardiovascular: Procedural hypotension (10%),
angina pectoris (8%), thrombosis (cancer patients: Darifenacin (dar i FEN a sin)
5%), thrombosis of vascular graft (arteriovenous:
5%), thromboembolism (cancer patients, venous: Brand Names: US Enablex
4%), pulmonary embolism (cancer patients: 2%), Brand Names: Canada Enablex
arterial thromboembolism (cancer patients: 1%) Pharmacologic Category Anticholinergic Agent
Dermatologic: Erythema of skin (≤5%), skin Use Overactive bladder: Treatment of overactive blad-
rash (≤5%) der with symptoms of urinary frequency, urgency, or
Endocrine & metabolic: Hypervolemia (7%) urge incontinence.
Immunologic: Antibody development (children & ado-
lescents: 4% to 6%, adults: <1%)
Cardiovascular: Myocardial infarction, significant car- Effects on Dental Treatment Key adverse event(s)
diovascular event related to dental treatment: Xerostomia (normal salivary
Central nervous system: Cerebrovascular disease flow resumes upon discontinuation). Prolonged xero-
Local: Pain at injection site stomia may contribute to discomfort and dental disease
<1%, postmarketing, and/or case reports: Anaphylaxis, (eg, caries, periodontal disease, and oral candidiasis).
angioedema, bronchospasm, cardiac failure, cerebro- Effects on Bleeding No information available to
vascular accident, erythema multiforme, exfoliation of require special precautions
skin, hypertensive encephalopathy, pure red cell apla- Adverse Reactions
sia (occurs following development of antibodies to >10%: Gastrointestinal: Xerostomia (19% to 35%), con-
erythropoietin), seizure, severe dermatological reac- stipation (15% to 21%)
tion, severe hypersensitivity reaction, skin blister, Ste- 1% to 10%:
vens-Johnson syndrome, toxic epidermal necrolysis, Cardiovascular: Hypertension (≥1%), peripheral
urticaria edema (≥1%)
387
DARIFENACIN
Central nervous system: Headache (7%), dizziness Gastrointestinal: Vomiting (children & adolescents:
(<2%), pain (≥1%) 13% to 33%; adults: 2% to 5%), nausea (children:
Dermatological: Pruritus (≥1%), skin rash (≥1%), xero- 4% to 25%; adults: 4% to 7%), diarrhea (children &
derma (≥1%) adolescents: 11% to 24%; adults: 9% to 14%)
Endocrine & metabolic: Weight gain (≥1%) 1% to 10%:
Gastrointestinal: Dyspepsia (3% to 8%), abdominal Central nervous system: Headache (3% to 9%),
pain (2% to 4%), nausea (2% to 4%), vomiting (≥1%) fatigue (≤3%), abnormal dreams (<2%)
Genitourinary: Urinary tract infection (4% to 5%), Dermatologic: Pruritus (children & adolescents: 8%;
vaginitis (≥1%), urinary retention (acute) adults: <2%), Stevens-Johnson syndrome (<2%),
Neuromuscular & skeletal: Weakness (<3%), arthral- urticaria (<2%)
gia (≥1%), back pain (≥1%) Endocrine & metabolic: Increased serum triglycerides
(1% to 10%), increased amylase (≤7%), diabetes
Ophthalmic: Dry eye syndrome (2%), visual disturb-
mellitus (≤2%)
ance (≥1%)
Gastrointestinal: Abdominal pain (5% to 10%),
Respiratory: Flu-like symptoms (1% to 3%), bronchitis
decreased appetite (children & adolescents: 8%),
(≥1%), pharyngitis (≥1%), rhinitis (≥1%), sinusi- anorexia (2% to 5%), increased serum lipase (adults:
tis (≥1%) ≤3%; children & adolescents: grade 3: 1%), abdomi-
Postmarketing and/or case reports: Anaphylaxis, nal distention (2%), dyspepsia (≤2%), flatulence
angioedema, confusion, erythema multiforme, granu- (<2%), acute pancreatitis (<2%)
loma (annulare), hallucination, hypersensitivity reac- Hepatic: Increased serum ALT (adults: ≤9%; children:
tion, palpitations 1% to 3%), increased serum AST (adults: 1% to 7%;
Mechanism of Action Selective antagonist of the M3 children & adolescents: grade 3: 1%), hepatitis (<2%;
muscarinic (cholinergic) receptor subtype. Blockade of includes acute and cytolytic), increased serum alka-
the receptor limits bladder contractions, reducing the line phosphatase (≤1%)
symptoms of bladder irritability/overactivity (urge incon- Hypersensitivity: Angioedema (<2%), hypersensitivity
tinence, urgency and frequency). reaction (<2%)
Pharmacodynamics/Kinetics Immunologic: Immune reconstitution syndrome (<2%)
Half-life Elimination ~13 to 19 hours Neuromuscular & skeletal: Weakness (≤3%), myalgia
Time to Peak Plasma: ~7 hours (<2%), osteonecrosis (<2%)
Pregnancy Risk Factor C <1%, postmarketing, and/or case reports: Acute gener-
alized exanthematous pustulosis, dermatological
reaction, DRESS syndrome, erythema multiforme
been observed in animal reproduction studies.
(DHHS 2011), hepatic disease, hepatotoxicity, hyper-
bilirubinemia, hyperglycemia, hypercholesterolemia
Darunavir (dar OO na veer) (DHHS 2011), hypertriglyceridemia, redistribution of
body fat, toxic epidermal necrolysis
Related Information Mechanism of Action Binds to the site of HIV-1
HIV Infection and AIDS on page 1477 protease activity and inhibits cleavage of viral Gag-Pol
Brand Names: US Prezista polyprotein precursors into individual functional proteins
Brand Names: Canada Prezista required for infectious HIV. This results in the formation
Pharmacologic Category Antiretroviral, Protease of immature, noninfectious viral particles.
Inhibitor (Anti-HIV) Pharmacodynamics/Kinetics
Use HIV-1 infection: Treatment of HIV-1 infection, coad- Half-life Elimination ~15 hours
ministered with ritonavir and other antiretroviral agents, Pregnancy Considerations
in adults and pediatric patients 3 years and older Darunavir has a low level of transfer across the human
placenta.
No information available to require special precautions No increased risk of overall birth defects has been
Effects on Dental Treatment No significant effects or observed following first trimester exposure according
complications reported to data collected by the antiretroviral pregnancy registry.
Effects on Bleeding Increased bleeding has been Maternal antiretroviral therapy (ART) may increase the
noted with protease inhibitors, such as darunavir, in risk of preterm delivery, although available information
patients with hemophilia A or B. No other information is conflicting possibly due to variability of maternal
is available to require special precautions in other factors (disease severity; gestational age at initiation
patients. of therapy). An increased risk of stillbirth, low birth
weight, and small for gestational age infants has been
Adverse Reactions Frequency of adverse events is
observed in some but not all studies. Because there is
reported for darunavir/ritonavir in both treatment-naive
clear benefit to appropriate treatment, maternal ART
and experienced patients. Frequency, type, and
should not be withheld due to concerns for adverse
severity of adverse events in pediatric patients are neonatal outcomes. Long-term follow-up is recom-
comparable to adult patients unless otherwise noted. mended for all infants exposed to antiretroviral medi-
See also Ritonavir monograph. cations; children who develop significant organ system
>10%: abnormalities of unknown etiology (particularly of the
Dermatologic: Skin rash (children: 5% to 19%; adults: CNS or heart) should be evaluated for potential mito-
6% to 7%) chondrial dysfunction. Hyperglycemia, new onset of
Endocrine & metabolic: Increased serum cholesterol diabetes mellitus, or diabetic ketoacidosis have been
(adults: 1% to 25%; children & adolescents: grade 3: reported with PIs; it is not clear if pregnancy increases
this risk.
1%), increased LDL cholesterol (adults: 8% to 14%;
children & adolescents: grade 3: 3%), increased The Health and Human Services (HHS) Perinatal HIV
serum glucose (≤11%) Guidelines consider darunavir (when combined with
388
DASATINIB
low-dose ritonavir boosting) a preferred protease inhib- 1% to 10%:

itor for HIV-infected pregnant females who are antire- Central nervous system: Fatigue (4%), headache
troviral-naive (initial therapy), who have had ART (3%), abnormal dreams (<2%)
therapy in the past but are restarting, who require a Dermatologic: Pruritus (<2%), Stevens-Johnson syn-
new ART regimen (due to poor tolerance or poor drome (<2%)
virologic response of current regimen), and who are Endocrine & metabolic: Increased LDL cholesterol
not yet pregnant but are trying to conceive. In addition, (5% to 9%), increased serum triglycerides (≤7%),
females who become pregnant while taking darunavir increased serum glucose (≤6%), diabetes mellitus
may continue if viral suppression is effective and the (<2%), gynecomastia (<2%), lipodystrophy (<2%)
regimen is well tolerated. Gastrointestinal: Diarrhea (9%), nausea (6%),
abdominal distress (2%), flatulence (2%), acute pan-
Serum concentrations are decreased during pregnancy;
creatitis (<2%), anorexia (<2%), dyspepsia (<2%),
therefore, ritonavir-boosted twice-daily dosing should
vomiting (<2%)
be used. According to product labeling, once-daily
Hepatic: Increased serum alanine aminotransferase
dosing of darunavir should only be considered in
(2%), increased serum aspartate aminotransferase
women who are already pregnant, and virologically
(2%), hepatitis (<2%)
stable on a once daily dose, and in whom changing to
Hypersensitivity: Angioedema (<2%), hypersensitiv-
a twice-daily regimen would compromise tolerability or
ity (<2%)
compliance. However, the current HHS perinatal guide-
Immunologic: Immune reconstitution syndrome (<2%)
lines do not recommend once daily dosing during
Neuromuscular & skeletal: Myalgia (<2%), osteonec-
pregnancy.
rosis (<2%)
In general, ART is recommended for all pregnant Renal: Increased serum creatinine (≤4%)
females with HIV to keep the viral load below the limit Mechanism of Action Darunavir binds to the site of
of detection and reduce the risk of perinatal trans- HIV-1 protease activity and inhibits cleavage of viral
mission. Monitoring during pregnancy is more frequent Gag-Pol polyprotein precursors into individual func-
than in nonpregnant adults. ART should be continued tional proteins required for infectious HIV. This results
postpartum for all females living with HIV and can be in the formation of immature, noninfectious viral par-
modified after delivery. ticles. Cobicistat is a mechanism-based inhibitor of
cytochrome P450 3A (CYP3A). Inhibition of CYP3A-
mediated metabolism by cobicistat increases the sys-
temic exposure of CYP3A substrates (eg, darunavir).
early in pregnancy as possible in the Antiretroviral
Emtricitabine is a cytosine analogue and tenofovir
Pregnancy Registry (1-800-258-4263 or http://www.-
alafenamide is converted intracellularly to tenofovir
APRegistry.com). Health care providers caring for
(adenosine nucleotide analog) and subsequently phos-
HIV-infected females and their infants may contact the
phorylated by cellular kinases to the active moiety,
National Perinatal HIV Hotline (888-448-8765) for clin-
tenofovir diphosphate. Emtricitabine and tenofovir ala-
ical consultation (HHS [perinatal] 2018).
fenamide interfere with HIV viral RNA-dependent DNA
polymerase activities resulting in inhibition of viral rep-
Darunavir, Cobicistat, Emtricitabine, lication.
and Tenofovir Alafenamide Pregnancy Considerations
(dar UE na vir, koe BIK i stat, EM trye SYE ta been, and ten OF oh The Health and Human Services (HHS) Perinatal HIV
vir AL a FEN a mide) Guidelines do not recommend this fixed-dose combina-
tion for HIV-infected pregnant females who are antire-
Brand Names: US Symtuza
troviral-naive, who have had antiretroviral therapy
Brand Names: Canada Symtuza (ART) in the past but are restarting, who require a
Pharmacologic Category Antiretroviral, Protease new ART regimen (due to poor tolerance or poor
Inhibitor (Anti-HIV); Antiretroviral, Reverse Transcrip- virologic response of current regimen), and who are
tase Inhibitor, Nucleoside (Anti-HIV); Antiretroviral, not yet pregnant but are trying to conceive. For females
Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV); who become pregnant while taking this combination,
Cytochrome P-450 Inhibitor consider altering the regimen, or continue with frequent
Use HIV-1 infection, treatment: Treatment of HIV-1 monitoring if viral suppression is effective and the
infection in adults who have no prior antiretroviral treat- regimen is well tolerated (HHS [perinatal] 2018).
ment history or who are virologically suppressed (HIV-1
RNA <50 copies per mL) on a stable antiretroviral Refer to individual monographs for additional infor-
regimen for ≥6 months and have no known substitutions mation.
associated with resistance to darunavir or tenofovir.
Local Anesthetic/Vasoconstrictor Precautions Dasatinib (da SA ti nib)
Effects on Dental Treatment No significant effects or Brand Names: US Sprycel
complications reported Brand Names: Canada Sprycel
Effects on Bleeding No information available to Pharmacologic Category Antineoplastic Agent, BCR-
require special precautions ABL Tyrosine Kinase Inhibitor; Antineoplastic Agent,
Adverse Reactions Tyrosine Kinase Inhibitor
>10% Use
Dermatologic: Skin rash (8% to 15%) Acute lymphoblastic leukemia:
Endocrine & metabolic: Increased serum cholesterol Adult: Treatment of Philadelphia chromosome-positive
(2% to 17%) (Ph+) acute lymphoblastic leukemia (ALL) in adult
Neuromuscular & skeletal: Decreased bone mineral patients with resistance or intolerance to prior
density (16%) therapy.
389
DASATINIB
Pediatric: Treatment of newly diagnosed Ph+ ALL (in insomnia, myasthenia, neuropathy, peripheral neuro-
combination with chemotherapy) in pediatric patients pathy
≥1 year of age. Dermatologic: Acne vulgaris, alopecia, dermatitis,
Chronic myeloid leukemia: eczema, hyperhidrosis, urticaria, xeroderma
Adult: Treatment of newly diagnosed Ph+ chronic Endocrine & metabolic: Growth suppression, hyper-
myeloid leukemia (CML) in chronic phase; treatment uricemia, weight gain, weight loss
of chronic, accelerated, or myeloid or lymphoid blast Gastrointestinal: Constipation (10%), gastrointestinal
phase Ph+ CML with resistance or intolerance to hemorrhage (2% to 9%), abdominal distention,
prior therapy, including imatinib. change in appetite, colitis (including neutropenic
Pediatric: Treatment of Ph+ CML in chronic phase in colitis), dysgeusia, dyspepsia, enterocolitis, gastritis,
pediatric patients ≥1 year of age. mucositis, stomatitis
Local Anesthetic/Vasoconstrictor Precautions Hematologic & oncologic: Bruise
Dasatinib is one of the drugs confirmed to prolong the Hepatic: Increased serum bilirubin (grades 3/4: ≤6%),
QT interval and is accepted as having a risk of causing increased serum alanine aminotransferase (grades
torsade de pointes. The risk of drug-induced torsade de 3/4: ≤5%), increased serum aspartate aminotransfer-
pointes is extremely low when a single QT interval ase (grades 3/4: ≤4%), ascites (≤1%)
prolonging drug is prescribed. In terms of epinephrine, Infection: Herpes virus infection, sepsis
it is not known what effect vasoconstrictors in the local Neuromuscular & skeletal: Muscle spasm (5%),
anesthetic regimen will have in patients with a known abnormal bone growth (children; epiphyses delayed
history of congenital prolonged QT interval or in patients fusion), asthenia, stiffness
taking any medication that prolongs the QT interval. Ophthalmic: Blurred vision, decreased visual acuity,
Until more information is obtained, it is suggested that dry eye syndrome, visual disturbance
the clinician consult with the physician prior to the use of Otic: Tinnitus
a vasoconstrictor in suspected patients, and that the Renal: Increased serum creatinine (grades 3/4: ≤8%)
vasoconstrictor (epinephrine, mepivacaine and levonor- Respiratory: Pulmonary hypertension (≤5%), pulmo-
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used nary edema (≤4%), cough, pneumonia, pneumonitis,
with caution. pulmonary infiltrates, upper respiratory tract infection
Effects on Dental Treatment Key adverse event(s) Miscellaneous: Soft tissue injury (oral)
related to dental treatment: Mucositis/stomatitis, taste <1%, postmarketing, and/or case reports: Abnormal
perversion. gait, abnormal platelet aggregation, abnormal T waves
Effects on Bleeding Bleeding was experienced in on ECG, acute coronary syndrome, acute pancreatitis,
≤9% of patients with ≤7% severe. Thrombocytopenia acute respiratory distress, amnesia, anal fissure,
is prevalent. A medical consult is recommended. angina pectoris, anxiety, arthritis, asthma, ataxia, atrial
Adverse Reactions Adverse reactions occurred in fibrillation, atrial flutter, bronchospasm, bullous skin
adults unless otherwise indicated. disease, cardiomegaly, cerebrovascular accident,
≥10%: cholecystitis, cholestasis, confusion, conjunctivitis,
Cardiovascular: Facial edema, peripheral edema coronary artery disease, cor pulmonale, cranial nerve
Central nervous system: Headache (adults and chil-
palsy (facial), decreased libido, deep vein thrombosis,
dren: 12% to 33%), fatigue (adults: 8% to 26%;
dehydration, dementia, dermal ulcer, diabetes melli-
children: 10%), pain (11%)
tus, dyschromia, dysphagia, embolism, emotional
Dermatologic: Skin rash (adults and children: 11% to
lability, epistaxis, equilibrium disturbance, erythema
21%), pruritus (12%)
nodosum, esophagitis, fibrosis (dermal), fistula (anal),
Endocrine & metabolic: Fluid retention (adults: 19% to
gastroesophageal reflux disease, gastrointestinal dis-
48%; children: 10%; cardiac-related: 9%)
ease (protein wasting), gingival hemorrhage, gyneco-
Gastrointestinal: Diarrhea (adults: 17% to 31%; chil-
dren: 21%), nausea (adults and children: 8% to mastia (adults and children), hearing loss, hematoma,
24%), vomiting (adults and children: 5% to 16%), hematuria, hemoptysis, hemorrhage (ocular), hepati-
abdominal pain (adults and children: 7% to 16%) tis, hypercholesterolemia, hypersensitivity reaction,
Hematologic & oncologic: Thrombocytopenia (grades hypersensitivity angiitis, hyperthyroidism, hypoalbumi-
3/4: 22% to 85%), neutropenia (grades 3/4: 29% to nemia, hypotension, hypothyroidism, increased crea-
79%), anemia (grades 3/4: 13% to 74%), hemor- tine phosphokinase, increased gamma-glutamyl
rhage (8% to 26%; grades 3/4: 1% to 9%), febrile transferase, increased lacrimation, increased pulmo-
neutropenia (4% to 12%; grades 3/4: 4% to 12%) nary artery pressure, increased troponin, inflammation
Infection: Infection (9% to 14%) (panniculitis), interstitial pulmonary disease, intestinal
Local: Localized edema (3% to 22%; superficial) obstruction, livedo reticularis, lymphadenopathy, lym-
Neuromuscular & skeletal: Musculoskeletal pain phocytopenia, malaise, menstrual disease, myocardi-
(<22%), limb pain (children: 19%), myalgia (7% to tis, nail disease, nephrotic syndrome, optic neuritis,
13%), arthralgia (adults and children: ≤13%) osteonecrosis, osteopenia (children), ototoxicity (hem-
Respiratory: Pleural effusion (5% to 28%), dyspnea orrhage), palmar-plantar erythrodysesthesia, pancrea-
(3% to 24%) titis, pericarditis, petechia, photophobia,
Miscellaneous: Fever (6% to 18%) pleuropericarditis, prolongation P-R interval on ECG,
1% to <10%: proteinuria, pulmonary embolism, pure red cell apla-
Cardiovascular: Cardiac conduction disturbance (7%), sia, reactivation of HBV, renal failure syndrome, renal
ischemic heart disease (4%), cardiac disorder (≤4%), insufficiency, rhabdomyolysis, seizure, skin photosen-
edema (≤4%), pericardial effusion (≤4%), prolonged sitivity, Stevens-Johnson syndrome, Sweet's syn-
Q-T interval on ECG (≤1%), cardiac arrhythmia, drome, syncope, tendonitis, thrombophlebitis,
chest pain, flushing, hypertension, palpitations, thrombosis, thrombotic microangiopathy, thyroiditis,
tachycardia transient ischemic attacks, tremor, tumor lysis syn-
Central nervous system: Intracranial hemorrhage drome, upper gastrointestinal tract ulcer, urinary fre-
(≤3%), chills, depression, dizziness, drowsiness, quency, uterine hemorrhage, vaginal hemorrhage,
390
DAUNORUBICIN AND CYTARABINE (LIPOSOMAL)
ventricular arrhythmia, ventricular tachycardia, vertigo, Endocrine & metabolic: Hyperuricemia

voice disorder Gastrointestinal: Abdominal pain, diarrhea, discolora-
Mechanism of Action Dasatinib is a BCR-ABL tyro- tion of saliva, gastrointestinal ulcer
sine kinase inhibitor that targets most imatinib-resistant Local: Post-injection flare
BCR-ABL mutations (except the T315I and F317V Ophthalmic: Discoloration of tears
mutants) by distinctly binding to active and inactive <1%, postmarketing, and/or case reports: Anaphylac-
ABL-kinase. Kinase inhibition halts proliferation of leu- toid reaction, cardiac arrhythmia, cardiomyopathy,
kemia cells. It also inhibits SRC family (including SRC, hepatitis, hypersensitivity reaction (systemic; includes
LKC, YES, FYN); c-KIT, EPHA2 and platelet derived angioedema, dysphagia, dyspnea, pruritus, urticaria),
growth factor receptor (PDGFRβ). increased serum bilirubin, increased serum transami-
Pharmacodynamics/Kinetics nases, infertility, injection site reaction (includes injec-
Half-life Elimination Terminal: 3 to 5 hours (adults); 2 tion site cellulitis, local thrombophlebitis, pain at
to 5 hours (pediatrics) injection site), leukemia (secondary), myocardial
Time to Peak 0.5 to 6 hours infarction, myocarditis, nail bed changes (pigmenta-
Pregnancy Considerations Dasatinib crosses the tion), nail disease (banding), onycholysis, pericarditis,
placenta, with fetal plasma and amniotic concentrations skin rash, sterility, typhlitis (neutropenic)
comparable to maternal concentrations. Adverse Mechanism of Action Daunorubicin inhibits DNA and
effects, including hydrops fetalis and fetal leukopenia RNA synthesis by intercalation between DNA base
and thrombocytopenia have been reported following pairs and by steric obstruction. Daunomycin interca-
maternal exposure to dasatinib. Females of reproduc- lates at points of local uncoiling of the double helix.
tive potential should use effective contraception during Although the exact mechanism is unclear, it appears
treatment and for 30 days after the final dasatinib dose. that direct binding to DNA (intercalation) and inhibition
Pregnant females are advised to avoid exposure to of DNA repair (topoisomerase II inhibition) result in
crushed or broken tablets. blockade of DNA and RNA synthesis and fragmentation
Dental Health Professional Considerations See of DNA.
Half-life Elimination Initial: 45 minutes; Terminal:
DAUNOrubicin (Conventional) 18.5 hours; Daunorubicinol plasma half-life: ~27 hours
(daw noe ROO bi sin con VEN sha nal) Pregnancy Risk Factor D
Brand Names: Canada Cerubidine been observed in animal reproduction studies. Daunor-
Pharmacologic Category Antineoplastic Agent, ubicin crosses the placenta. Women of reproductive
Anthracycline; Antineoplastic Agent, Topoisomerase II potential should avoid pregnancy.
Inhibitor
Use
Acute lymphocytic leukemia: Treatment (remission Daunorubicin and Cytarabine
induction) of acute lymphocytic leukemia (ALL) in (Liposomal)
children and adults (in combination with other chemo- (daw noe ROO bi sin & sye TARE a been lye po SO mal)
therapy)
Brand Names: US Vyxeos
Acute myeloid leukemia: Treatment (remission induc-
tion) of acute myeloid leukemia (AML) in adults (in Pharmacologic Category Antineoplastic Agent,
combination with other chemotherapy) Anthracycline; Antineoplastic Agent, Antimetabolite;
Antineoplastic Agent, Antimetabolite (Pyrimidine Ana-
No information available to require special precautions log); Antineoplastic Agent, Topoisomerase II Inhibitor
Effects on Dental Treatment Key adverse event(s) Use Acute myeloid leukemia: Treatment of adults with
related to dental treatment: Stomatitis and discoloration newly-diagnosed therapy-related acute myeloid leuke-
of saliva. mia (t-AML) or AML with myelodysplasia-related
changes (AML-MRC)
Effects on Bleeding Thrombocytopenia occurs with
the nadir in 10-14 days and recovery in 21-28 days. A Local Anesthetic/Vasoconstrictor Precautions
medical consult is suggested. No information available to require special precautions
Adverse Reactions Effects on Dental Treatment No significant effects or
Frequency not defined. complications reported
>10%: Effects on Bleeding Thrombocytopenia
Cardiovascular: Cardiac failure (dose-related, may be Adverse Reactions
delayed for 7 to 8 years after treatment), ECG >10%:
abnormality (transient, generally asymptomatic and Cardiovascular: Edema (51%), cardiac arrhythmia
self-limiting; includes atrial premature contractions, (30%), cardiotoxicity (20%), hypotension (20%),
ST segment changes on ECG, supraventricular hypertension (18%), chest pain (17%)
tachycardia, ventricular premature contractions) Central nervous system: Headache (33%), fatigue
Dermatologic: Alopecia (reversible) (32%), sleep disorder (25%), chills (23%), dizziness
Gastrointestinal: Nausea (mild), stomatitis, vomit- (18%), delirium (16%), anxiety (14%)
ing (mild) Dermatologic: Skin rash (54%), pruritus (15%)
Genitourinary: Red urine discoloration Endocrine & metabolic: Hyponatremia (grades 3/4: 6%
Hematologic & oncologic: Bone marrow depression to 14%)
(onset: 7 days; nadir: 10 to 14 days; recovery: 21 Gastrointestinal: Diarrhea (≤66%), nausea (47%), col-
to 28 days; primarily leukopenia; anemia, thrombo- itis (≤45%), mucositis (44%), constipation (40%),
cytopenia) abdominal pain (33%), decreased appetite (29%),
Miscellaneous: Radiation recall phenomenon vomiting (24%), hemorrhoids (11%)
1% to 10%: Hematologic & oncologic: Anemia (100%), neutrope-
Dermatologic: Discoloration of sweat nia (100%; grade 4 [prolonged]: 10% to 17%),
391
DAUNORUBICIN AND CYTARABINE (LIPOSOMAL)
thrombocytopenia (100%; grade 3 [prolonged]: 25% contraception should be used during therapy and for
to 28%), hemorrhage (70%; grades 3 to 5: 10%), at least 6 months after the last dose. Male patients with
febrile neutropenia (68%; grades 3 to 5: 66%), female partners of reproductive potential should also
petechia (11%) use effective contraception during therapy and for at
Hypersensitivity: Transfusion reaction (11%) least 6 months after the last dose. Based on animal
Infection: Bacteremia (24%), fungal infection (18%), data, treatment with daunorubicin and cytarabine (lip-
sepsis (11%) osomal) may impair fertility in males.
Local: Injection site reaction (16%; includes catheter
Also refer to individual monographs.
and device site)
Neuromuscular & skeletal: Musculoskeletal
pain (38%) DAUNOrubicin (Liposomal)
Ophthalmic: Visual impairment (11%) (daw noe ROO bi sin lye po SO mal)
Renal: Renal insufficiency (11%)
Respiratory: Cough (33%), dyspnea (32%), pneumo- Brand Names: US DaunoXome [DSC]
nia (26%), hypoxia (18%), upper respiratory tract Pharmacologic Category Antineoplastic Agent,
infection (18%), pleural effusion (16%) Anthracycline; Antineoplastic Agent, Topoisomerase II
Miscellaneous: Fever (17%) Inhibitor
1% to 10%: Use
Central nervous system: Hallucination (<10%) Kaposi sarcoma: First-line treatment of advanced HIV-
Endocrine & metabolic: Hypokalemia (grades 3/4: 6% associated Kaposi sarcoma
to 9%), hypoalbuminemia (grades 3/4: 2% to 7%), Limitation of use: Daunorubicin (liposomal) is not rec-
abnormal alanine aminotransferase (grades ommended in HIV-related Kaposi sarcoma which is
3/4: ≤5%) less than advanced.
Gastrointestinal: Dyspepsia (<10%) Local Anesthetic/Vasoconstrictor Precautions
Hepatic: Hyperbilirubinemia (grades 3/4: 2% to 6%) No information available to require special precautions
Ophthalmic: Conjunctivitis (<10%), dry eye syndrome Effects on Dental Treatment Key adverse event(s)
(<10%), eye irritation (<10%), eye pain (<10%), related to dental treatment: Stomatitis.
injected sclera (<10%), ocular hyperemia (<10%), Effects on Bleeding Thrombocytopenia occurs with
periorbital edema (<10%), swelling of eye (<10%) the nadir in 14 days and recovery in 21 days. A medical
Otic: Deafness (<10%) consult is recommended.
Respiratory: Pneumonitis (<10%) Adverse Reactions Frequency not always defined.
Mechanism of Action Cardiovascular: Edema (11%), chest pain (10%),
Daunorubicin and cytarabine (liposomal) is a combina- angina pectoris (≤5%), atrial fibrillation (≤5%), cardiac
tion product with a fixed 1:5 (daunorubicin:cytarabine) arrest (≤5%), cardiac tamponade (≤5%), hypertension
molar ratio; this ratio has been shown to have syner- (≤5%), myocardial infarction (≤5%), palpitations
gistic effects in killing leukemia cells in vitro and in (≤5%), pericardial effusion (≤5%), pulmonary hyper-
animal models. tension (≤5%), sinus tachycardia (≤5%), supraventric-
Daunorubicin (conventional) inhibits DNA and RNA syn- ular tachycardia (≤5%), syncope (≤5%), tachycardia
thesis by intercalation between DNA base pairs and (≤5%), ventricular premature contractions (≤5%),
by steric obstruction. Daunomycin intercalates at decreased left ventricular ejection fraction (3%; reduc-
points of local uncoiling of the double helix. Although tion of 20% to 25%), cardiomyopathy (cumulative,
the exact mechanism is unclear, it appears that direct dose-related; total dose above 300 mg/m2)
binding to DNA (intercalation) and inhibition of DNA Central nervous system: Fatigue (49%), headache
repair (topoisomerase II inhibition) result in blockade (25%), rigors (19%), neuropathy (13%), depression
of DNA and RNA synthesis and fragmentation of DNA. (10%), malaise (10%), dizziness (8%), insomnia
Cytarabine (conventional) is a pyrimidine analog and (6%), abnormality in thinking (≤5%), amnesia (≤5%),
is incorporated into DNA; however, the primary action anxiety (≤5%), ataxia (≤5%), confusion (≤5%), drowsi-
is inhibition of DNA polymerase resulting in decreased ness (≤5%), emotional lability (≤5%), hallucination
DNA synthesis and repair. The degree of cytotoxicity (≤5%), hypertonia (≤5%), meningitis (≤5%), seiz-
correlates linearly with incorporation into DNA; there- ure (≤5%)
fore, incorporation into the DNA is responsible for drug Dermatologic: Diaphoresis (14%), alopecia (8%), pruri-
activity and toxicity. Cytarabine is specific for the S tus (7%), folliculitis (≤5%), seborrhea (≤5%), xero-
phase of the cell cycle (blocks progression from the derma (≤5%)
G1 to the S phase). Endocrine & metabolic: Dehydration (≤5%), hot flash
Per animal data, liposomes are taken up intact by bone (≤5%), increased thirst (≤5%)
marrow cells (to a greater degree in leukemia cells Gastrointestinal: Nausea (54%), diarrhea (38%),
versus normal bone marrow cells) and are degraded abdominal pain (23%), anorexia (23%), vomiting
following cellular internalization, thus releasing cytar- (23%), stomatitis (10%), constipation (7%), tenesmus
abine and daunorubicin within the cells. (5%), dental caries (≤5%), dysgeusia (≤5%), dyspha-
Pharmacodynamics/Kinetics gia (≤5%), gastritis (≤5%), gastrointestinal hemor-
Half-life Elimination 31.5 hours (daunorubicin); 40.4 rhage (≤5%), gingival hemorrhage (≤5%),
hours (cytarabine) with >99% of drug(s) remaining hemorrhoids (≤5%), hiccups (≤5%), increased appe-
encapsulated in the liposomes tite (≤5%), melena (≤5%), xerostomia (≤5%)
Pregnancy Considerations Genitourinary: Dysuria (≤5%), nocturia (≤5%)
Based on the mechanism of action, anecdotal data of Hematologic & oncologic: Neutropenia (<1,000 cells/
cytarabine use in pregnant women, and data from mm3: 36%; grade 4: 15%), lymphadenopathy (≤5%),
animal reproduction studies, use of daunorubicin and splenomegaly (≤5%), bone marrow depression (espe-
cytarabine (liposomal) in pregnancy may cause fetal cially granulocytes; platelets and erythrocytes less
harm. Women of reproductive potential should have a effected), severe granulocytopenia (may be associ-
p r e g n a n c y t e s t p r i o r t o t r e a t m e n t ; e ff e c t i v e ated with fever and result in infection)
392
DECITABINE
Hepatic: Hepatomegaly (≤5%) Adverse Reactions

Hypersensitivity: Hypersensitivity reaction (24%) >10%:
Infection: Opportunistic infection (40%; median time to Cardiovascular: Peripheral edema (25% to 27%),
first infection/illness: 214 days) edema (5% to 18%), heart murmur (16%), hypoten-
Local: Inflammation at injection site (≤5%) sion (6% to 11%)
Neuromuscular & skeletal: Back pain (16%), arthralgia Central nervous system: Fatigue (46%), headache
(7%), myalgia (7%), abnormal gait (≤5%), hyperkine- (23% to 28%), insomnia (14% to 28%), rigors
sia (≤5%), tremor (≤5%) (22%), dizziness (18% to 21%), chills (16%), pain
Ophthalmic: Visual disturbance (5%), conjunctivitis (5% to 13%), confusion (8% to 12%), lethargy (12%),
(≤5%), eye pain (≤5%) hypoesthesia (11%), anxiety (9% to 11%)
Dermatologic: Pallor (23%), skin rash (11% to 19%),
Otic: Deafness (≤5%), otalgia (≤5%), tinnitus (≤5%)
erythema (5% to 14%), cellulitis (9% to 12%), pruri-
Renal: Polyuria (≤5%)
tus (9% to 11%)
Respiratory: Cough (28%), dyspnea (26%), rhinitis
Endocrine & metabolic: Hyperglycemia (6% to 33%),
(12%), sinusitis (8%), flu-like symptoms (5%), hemopt- hypoalbuminemia (7% to 24%), hypomagnesemia
ysis (≤5%), increased bronchial secretions (≤5%), (5% to 24%), hypokalemia (12% to 22%), hypona-
pulmonary infiltrates (≤5%) tremia (19%), hyperkalemia (13%)
Miscellaneous: Fever (47%), infusion-related reaction Gastrointestinal: Nausea (40% to 42%), constipation
(14%; includes back pain, flushing, chest tightness) (30% to 35%), diarrhea (28% to 34%), vomiting (16%
Mechanism of Action Liposomal preparation of dau- to 25%), anorexia (≤8% to 23%), decreased appetite
norubicin; liposomes have been shown to penetrate (≤8% to 23%), abdominal pain (5% to 14%), stoma-
solid tumors more effectively, possibly because of their titis (11% to 12%), dyspepsia (10% to 12%)
small size and longer circulation time. Once in tissues, Hematologic & oncologic: Neutropenia (38% to 90%;
daunorubicin is released (over time). Daunorubicin grades 3/4: 37% to 87%; recovery 28 to 50 days),
inhibits DNA and RNA synthesis by intercalation thrombocytopenia (27% to 89%; grades 3/4: 24% to
between DNA base pairs and by steric obstruction; 85%), anemia (31% to 82%; grades 3/4: 22%),
and intercalates at points of local uncoiling of the double petechia (12% to 39%), febrile neutropenia (20% to
helix. Although the exact mechanism is unclear, it 29%; grades 3/4: 23%), leukopenia (6% to 28%;
appears that direct binding to DNA (intercalation) and grades 3/4: 22%), bruise (9% to 22%), oral mucosal
petechiae (13%), lymphadenopathy (12%)
inhibition of DNA repair (topoisomerase II inhibition)
Hepatic: Hyperbilirubinemia (6% to 14%), increased
result in blockade of DNA and RNA synthesis and
serum alkaline phosphatase (11%)
fragmentation of DNA. Local: Localized tenderness (11%)
Neuromuscular & skeletal: Arthralgia (17% to 20%),
Half-life Elimination Distribution: 4.4 hours limb pain (18% to 19%), back pain (17% to 18%),
Pregnancy Risk Factor D weakness (15%)
Pregnancy Considerations Adverse events were Respiratory: Cough (27% to 40%), dyspnea (29%),
observed in animal reproduction studies. pneumonia (20% to 22%), pharyngitis (16%), rales
Product Availability DaunoXome has been discontin- (8% to 14%), epistaxis (13%)
ued in the US for more than 1 year. Miscellaneous: Fever (6% to 53%), lesion (5% to 11%)
5% to 10%:
Cardiovascular: Tachycardia (8%), chest wall pain
Decitabine (de SYE ta been)
(7%), chest pain (≤6% to 7%), chest discomfort
Brand Names: US Dacogen (≤6% to 7%), facial edema (6%), hypertension
(6%), cardiac failure (5%)
Pharmacologic Category Antineoplastic Agent, Anti- Central nervous system: Depression (9%), falling
metabolite; Antineoplastic Agent, DNA Methylation (8%), malaise (5%), mouth pain (5%)
Inhibitor Dermatologic: Alopecia (8%), xeroderma (8%), urtica-
Use Myelodysplastic syndromes: Treatment of mye- ria (6%), catheter site erythema (5%), night
lodysplastic syndromes (MDS), including previously sweats (5%)
treated and untreated, de novo and secondary MDS Endocrine & metabolic: Hyperuricemia (10%), weight
of all French-American-British (FAB) subtypes (refrac- loss (9%), increased lactate dehydrogenase (8%),
tory anemia, refractory anemia with ringed sideroblasts, dehydration (6% to 8%), hypochloremia (6%),
refractory anemia with excess blasts, refractory anemia increased serum bicarbonate (6%), decreased
with excess blasts in transformation, and chronic mye- serum bicarbonate (5%), hypoproteinemia (5%)
lomonocytic leukemia) and intermediate-1, intermedi- Gastrointestinal: Mucosal inflammation (9%), gingival
ate-2, and high-risk International Prognostic Scoring hemorrhage (8%), hemorrhoids (8%), loose stools
System (IPSS) groups (7%), tongue ulcer (7%), oral candidiasis (6%), tooth-
Local Anesthetic/Vasoconstrictor Precautions ache (6%), dysphagia (5% to 6%), abdominal dis-
No information available to require special precautions tention (5%), gastroesophageal reflux disease (5%),
glossalgia (5%), oral mucosa ulcer (lip: 5%)
Genitourinary: Urinary tract infection (7%), dysu-
related to dental treatment: Oral mucosal petechiae, ria (6%)
stomatitis, gingival bleeding, tongue ulceration, oral Hematologic & oncologic: Hematoma (5%), pancyto-
candidiasis, lip ulceration, mucosal inflammation, gin- penia (5%), thrombocythemia (5%)
gival pain have been reported. Hepatic: Ascites (10%), increased serum AST (10%),
Effects on Bleeding Gingival bleeding and oral decreased serum bilirubin (5%)
mucosal petechiae have been reported with decitabine Hypersensitivity: Transfusion reaction (7%)
therapy as well as a high incidence (27% to 89%) of Infection: Candidiasis (10%), bacteremia (5% to 8%),
thrombocytopenia. A medical consult is recommended. staphylococcal infection (7%), tooth abscess (5%)
393
DECITABINE
Local: Catheter infection (8%), catheter pain (5%), Gastrointestinal: Diarrhea (24%), vomiting (18%), nau-
swelling at injection site (5%) sea (16%)
Neuromuscular & skeletal: Myalgia (5% to 9%), Hematologic & oncologic: Hemorrhage (59%;
muscle spasm (7%), ostealgia (6%), musculoskeletal any type)
pain (≤6%; includes discomfort) Respiratory: Epistaxis (14%)
Ophthalmic: Blurred vision (6%) 1% to 10%:
Otic: Otalgia (6%) Central nervous system: Intracranial hemorrhage
Renal: Polyuria (5%) (3%), cerebral hemorrhage (2%)
Respiratory: Hypoxia (10%), upper respiratory tract Endocrine & metabolic: Hyperuricemia (2%)
infection (10%), abnormal breath sounds (5% to Gastrointestinal: Gastrointestinal hemorrhage (9%)
10%), pharyngolaryngeal pain (8%), pulmonary Hematologic & oncologic: Pulmonary hemor-
edema (6%), sinusitis (5% to 6%), pleural effusion rhage (4%)
(5%), post nasal drip (5%), pulmonary signs and Hypersensitivity: Hypersensitivity reaction (<2%)
symptoms (crepitations: 5%), sinus congestion (5%) Immunologic: Graft versus host disease (6%)
<5%, postmarketing, and/or case reports: Abscess Infection: Sepsis (7%), infection (3%)
(peridiverticular), acute cardiorespiratory failure, ana- Respiratory: Pulmonary alveolar hemorrhage (7% to
phylaxis, atrial fibrillation, cardiomyopathy, catheter 9%), pulmonary infiltrates (6%), pneumonia (5%)
site hemorrhage, cholecystitis, fungal infection, gas- Frequency not defined:
trointestinal hemorrhage, gingival pain, hemoptysis, Cardiovascular: Thrombophlebitis
hypersensitivity reaction, intracranial hemorrhage, Endocrine & metabolic: Hot flash
mental status change, myocardial infarction, myco- Gastrointestinal: Abdominal cramps, abdominal pain,
bacterium avium complex, nodule (pulmonary), pul- bloody diarrhea, hematemesis
m o na r y a s p er gi l lo s i s , p u lm o n ar y e mb o li s m , Genitourinary: Hematuria
pulmonary infection (pseudomonas), pulmonary infil- Hematologic & oncologic: Oral hemorrhage
trates, renal failure, sepsis, splenomegaly, supraven- Renal: Renal failure
tricular tachycardia, Sweet’s syndrome (acute febrile Miscellaneous: Fever
neutrophilic dermatosis), urethral bleeding Mechanism of Action Defibrotide augments plasmin
Mechanism of Action Decitabine is a hypomethylating enzymatic activity to hydrolyze fibrin clots. It reduces
agent. After phosphorylation, decitabine is incorporated endothelial cell (EC) activation and increases EC-medi-
into DNA and inhibits DNA methyltransferase causing ated fibrinolysis by increasing tissue plasminogen acti-
hypomethylation and subsequent cell death (within the vator and thrombomodulin expression, as well as by
S-phase of the cell cycle). decreasing von Willebrand factor and plasminogen
Pharmacodynamics/Kinetics activator inhibitor-1 expression.
Half-life Elimination ~0.5 to 0.6 hours Pharmacodynamics/Kinetics
Pregnancy Considerations Half-life Elimination <2 hours
Based on the mechanism of action and information from Pregnancy Considerations Adverse effects have
animal reproduction studies, decitabine may cause fetal been observed in animal reproduction studies.
harm if exposure occurs during pregnancy. Information
related to the use of decitabine in pregnancy is limited.
Deflazacort (de FLAZE a kort)
reproductive potential should use effective contracep- Brand Names: US Emflaza
tion during treatment and for 6 months after the last Pharmacologic Category Corticosteroid, Systemic
decitabine dose. Males with female partners of repro- Use Duchenne muscular dystrophy: Treatment of
ductive potential should use effective contraception Duchenne muscular dystrophy (DMD) in patients ≥5
during treatment and for 3 months after the last decita- years
bine dose. Local Anesthetic/Vasoconstrictor Precautions
Defibrotide (DE fib ro tide) Effects on Dental Treatment No significant effects or
Brand Names: US Defitelio Effects on Bleeding No information available to
Pharmacologic Category Antiplatelet Agent; Throm- require special precautions
bolytic Agent Adverse Reactions
Use Hepatic sinusoidal obstruction syndrome (treat- >10%:
ment): Treatment of hepatic sinusoidal obstruction Dermatologic: Erythema (8% to 28%)
syndrome (SOS; formerly called veno-occlusive dis- Endocrine & metabolic: Cushingoid appearance (33%
ease [VOD]) with renal or pulmonary dysfunction follow- to 60%), hirsutism (10% to 35%), weight gain (20%
ing hematopoietic stem cell transplant (HSCT). to 28%), obesity (central, 10% to 25%)
Local Anesthetic/Vasoconstrictor Precautions Gastrointestinal: Abdominal pain (including upper
No information available to require special precautions abdominal pain: 18%), increased appetite (14%)
Effects on Dental Treatment Key adverse event(s) Genitourinary: Pollakiuria (12% to 15%)
related to dental treatment: Increased bleeding with Respiratory: Cough (12%), upper respiratory tract
invasive procedures (see Effects on Bleeding) infection (12%)
Effects on Bleeding Defibrotide has antiplatelet and 1% to 10%:
fibrinolytic properties; expect increased bleeding with Cardiovascular: Cardiac arrhythmia (≥1%)
invasive dental procedures; medical consult is recom- Central nervous system: Irritability (8% to 10%),
mended abnormal behavior (9%), psychomotor agitation
Adverse Reactions (6%), aggressive behavior (≥1%), depression
>10%: (≥1%), dizziness (≥1%), emotional disturbance
Cardiovascular: Hypotension (11% to 37%) (≥1%), emotional lability (≥1%), heat exhaustion
394
DEGARELIX
(≥1%), hypertonia (≥1%, hypertonic bladder), insom- newborns following maternal use of corticosteroids in
nia (≥1%), mood changes (≥1%), sleep disor- pregnancy; monitor.
der (≥1%)
Dermatologic: Skin rash (7%), atrophic striae (6%),
acneiform eruption (≥1%), acne vulgaris (≥1%), alo-
Degarelix (deg a REL ix)
pecia (≥1%), impetigo (≥1%) Brand Names: US Firmagon

Endocrine & metabolic: Glycosuria (≥1%), hot flash Brand Names: Canada Firmagon
(≥1%), increased thirst (≥1%) Pharmacologic Category Antineoplastic Agent,
Gastrointestinal: Constipation (10%), abdominal dis- Gonadotropin-Releasing Hormone Antagonist; Gona-
tress (6%), nausea (6%), dyspepsia (≥1%), gastro- dotropin Releasing Hormone Antagonist
intestinal disease (≥1%) Use Prostate cancer, advanced: Treatment of
Genitourinary: Dysuria (≥1%), testicular pain (≥1%), advanced prostate cancer
urinary tract infection (≥1%), urine discolora- Local Anesthetic/Vasoconstrictor Precautions
tion (≥1%) Degarelix may prolong QT interval; it is suggested that
Hematologic & oncologic: Bruise (6%) the clinician consult with the physician prior to use of
Infection: Influenza (≥1%), tooth abscess (≥1%), viral vasoconstrictor in suspected patients; use vasocon-
infection (≥1%) strictor (epinephrine, mepivacaine and levonordefrin
Neuromuscular & skeletal: Back pain (7%), back injury [Carbocaine® 2% with Neo-Cobefrin®]) with caution.
(≥1%), limb pain (≥1%), muscle spasm (≥1%), myal- Effects on Dental Treatment No significant effects or
gia (≥1%), neck pain (≥1%) complications reported
Ophthalmic: Hordeolum (≥1%), increased lacrima- Effects on Bleeding No information available to
tion (≥1%) require special precautions
Otic: Otitis externa (≥1%)
Adverse Reactions
Respiratory: Nasopharyngitis (10%), rhinorrhea (8%),
>10%:
epistaxis (6%), hypoventilation (≥1%), pharyngi-
Central nervous system: Fatigue (3% to ≥10%)
tis (≥1%)
Endocrine & metabolic: Hot flash (26%), increased
Miscellaneous: Fever (9%), accidental injury (≥1%,
gamma-glutamyl transferase (≥10%), weight loss
face), mass (≥1%, neck)
(≥10%), weight gain (9% to ≥10%)
Frequency not defined. Hepatic: Increased serum transaminases (47%)
Central nervous system: Myasthenia (associated with Local: Injection site reactions (35%, grade 3: ≤2%;
long-term use) pain at injection site [28%], erythema at injection site
Neuromuscular & skeletal: Bone fracture (long bones [17%], swelling at injection site [6%], induration at
including the fibula as well as greenstick fractures), injection site [4%], injection site nodule [3%], injec-
decreased bone mineral density, osteopenia (asso- tion site infection [including abscess, 1%])
ciated with long-term use), tendon disease (associ- Miscellaneous: Fever (1% to ≥10%)
ated with long-term use) 1% to 10%:
<1%, postmarketing, and/or case reports: Abnormal Cardiovascular: Hypertension (6%)
serum calcium (negative calcium balance), acute pan- Central nervous system: Chills (5%), dizziness (1% to
creatitis (especially in children), acute peptic ulcer with 5%), headache (1% to 5%), insomnia (1% to 5%)
hemorrhage and perforation, amyotrophy, anaphy- Dermatologic: Diaphoresis
laxis, anxiety, avascular necrosis of bones, carbohy- Endocrine & metabolic: Hypercholesterolemia (3%),
drate intolerance, change in serum protein (negative gynecomastia
protein balance), chorioretinitis, cognitive dysfunction Gastrointestinal: Constipation (5%), nausea (1% to
(including confusion, amnesia, delusions, hallucina- 5%), diarrhea
tions, mania, or suicidal thoughts), corneal thinning, Genitourinary: Urinary tract infection (5%), erectile
decreased serum potassium, edema, exacerbation of dysfunction, testicular atrophy
epilepsy, hemorrhage, hypersensitivity, hypokalemic Hepatic: Increased serum ALT (10%; grade 3: <1%),
alkalosis, increased intracranial pressure (with papil- increased serum AST (5%; grade 3: <1%)
ledema in children), leukocytosis, negative nitrogen Immunologic: Antibody development (antidegare-
balance, peptic ulcer, pseudotumor cerebri, scleral lix: 10%)
thinning, thromboembolism (especially in patients with Neuromuscular & skeletal: Back pain (6%), arthralgia
underlying conditions associated with increased (5%), weakness (1% to 5%)
thrombotic tendency), toxic epidermal necrolysis, ver- Miscellaneous: Night sweats (1% to 5%)
tebral compression fracture, vertigo, wound healing <1%, postmarketing, and/or case reports: Bone meta-
impairment stases (worsening), cerebrovascular accident, depres-
Mechanism of Action Deflazacort is a corticosteroid sion, hypersensitivity reaction (including anaphylaxis,
prodrug; its active metabolite, 21-desDFZ, acts on the urticaria, and angioedema), itching at injection site,
glucocorticoid receptor to exert anti-inflammatory and local soreness/soreness at injection site, malignant
immunosuppressive effects. The precise mechanism by lymphoma, mental status changes, myocardial infarc-
which deflazacort exerts its therapeutic effects in tion, osteoarthritis, prolonged Q-T interval on ECG,
patients with Duchenne muscular dystrophy is squamous cell carcinoma, unstable angina pectoris
unknown. Mechanism of Action Gonadotropin-releasing hor-
Pharmacodynamics/Kinetics mone (GnRH) antagonist which reversibly binds to
Time to Peak 1 hour (range: 0.25 to 2 hours); delayed GnRH receptors in the anterior pituitary gland, blocking
by 1 hour with a high-fat meal the receptor and decreasing secretion of luteinizing
Pregnancy Considerations Deflazacort crosses the hormone (LH) and follicle stimulation hormone (FSH),
placenta. Orofacial clefts, intrauterine growth restriction, resulting in rapid androgen deprivation by decreasing
and decreased birth weight have been reported follow- testosterone production, thereby decreasing testoster-
ing maternal use. Hypoadrenalism may occur in one levels. Testosterone levels do not exhibit an initial
395
DEGARELIX
surge, or flare, as is typical with GnRH agonists (Craw- Local: Infusion site irritation (<2%), infusion site reac-
ford 2011). tion (<2%, bruise), local pain (<2%), local swel-
Pharmacodynamics/Kinetics ling (<2%)
Onset of Action Rapid; ~96% of patients had testos- Neuromuscular & skeletal: Increased creatine phos-
terone levels ≤50 ng/dL within 3 days (Klotz 2008) phokinase (<2%), myalgia (<2%)
Half-life Elimination Loading dose: SubQ: ~53 days; Ophthalmic: Blurred vision (<2%)
Maintenance dose: SubQ: ~31 days (Canadian label- Otic: Tinnitus (<2%)
ing) Renal: Increased serum creatinine (<2%), renal failure
Time to Peak Plasma: Loading dose: SubQ: Within 2 (<2%), renal insufficiency (<2%)
days Mechanism of Action Delafloxacin inhibits DNA
Pregnancy Risk Factor X gyrase (topoisomerase II) and topoisomerase IV
enzymes, which are required for bacterial DNA repli-
cation, transcription, repair, and recombination.
Use is contraindicated in women who are or may Pharmacodynamics/Kinetics
become pregnant. Half-life Elimination IV: 3.7 hours (single dose);
Adverse events were observed in animal reproduction Oral: 4.2 to 8.5 hours (multiple dose)
studies. Time to Peak ~1 hour
Dental Health Professional Considerations See Pregnancy Considerations Adverse events were
Local Anesthetic/Vasoconstrictor Precautions observed in some animal reproduction studies.
Product Availability Baxdela: FDA approved June
Delafloxacin (del a FLOKS a sin) 2017; anticipated availability is currently undetermined
Brand Names: US Baxdela

Pharmacologic Category Antibiotic, Fluoroquinolone
Delavirdine (de la VIR deen)
Use Skin and skin structure infections: Treatment of Related Information

acute bacterial skin and skin structure infections HIV Infection and AIDS on page 1477
(ABSSSI) caused by susceptible isolates of Staphylo- Brand Names: US Rescriptor
coccus aureus (including methicillin-resistant [MRSA] Brand Names: Canada Rescriptor
and methicillin-susceptible [MSSA] isolates), Staphylo- Pharmacologic Category Antiretroviral, Reverse
coccus haemolyticus, Staphylococcus lugdunensis, Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)
Streptococcus agalactiae, Streptococcus anginosus Use Treatment of HIV-1 infection in combination with at
group (including Streptococcus anginosus, Streptococ- least two additional antiretroviral agents
cus intermedius, and Streptococcus constellatus), Local Anesthetic/Vasoconstrictor Precautions
Streptococcus pyogenes, Enterococcus faecalis, No information available to require special precautions
Escherichia coli, Enterobacter cloacae, Klebsiella pneu- Effects on Dental Treatment No significant effects or
moniae, and Pseudomonas aeruginosa. complications reported
Local Anesthetic/Vasoconstrictor Precautions Effects on Bleeding No reports of bleeding or throm-
No information available to require special precautions bocytopenia.
Effects on Dental Treatment Key adverse event(s) Adverse Reactions Frequency not always defined.
related to dental treatment: Oral candidiasis has been Frequency of adverse reactions reported from occur-
reported, particularly with prolonged use of delafloxacin rence in clinical trials with delavirdine when used as part
Effects on Bleeding No information available to of combination antiretroviral therapy.
require special precautions Cardiovascular: Cardiac arrhythmia, cardiac insuffi-
Adverse Reactions ciency, cardiac rate disturbance, cardiomyopathy,
1% to 10%: hypersensitivity angiitis, hypertension, orthostatic
Cardiovascular: Bradycardia (<2%), edema (<2%), hypotension, peripheral vascular disease
flushing (<2%), hypertension (<2%), hypotension Central nervous system: Headache (19% to 20%),
(<2%), localized phlebitis (<2%), palpitations (<2%), depression (10% to 15%), anxiety (6% to 8%), cogni-
phlebitis (<2%), presyncope (<2%), sinus tachycar- tive dysfunction, confusion, emotional lability, halluci-
dia (<2%), syncope (<2%), thrombosis (<2%) nation, paralysis, vertigo
Central nervous system: Headache (3%), abnormal Dermatologic: Skin rash (16% to 32%), desquamation,
erythema multiforme, fungal dermatitis, Stevens-John-
dreams (<2%), anxiety (<2%), dizziness (<2%),
son syndrome
hypoesthesia (<2%), insomnia (<2%), local discom-
Endocrine & metabolic: Increased serum transami-
fort (<2%), paresthesia (<2%), vertigo (<2%)
nases (2% to 5%), increased amylase (3%), increased
Dermatologic: Dermatitis (<2%), localized erythema
serum bilirubin (2%), hyperglycemia, hyperkalemia,
(<2%; infusion site), extravasation reactions (<2%), hypertriglyceridemia, hyperuricemia, hypocalcemia,
pruritus (<2%), skin rash (<2%), urticaria (<2%) hyponatremia, hypophosphatemia, increased
Endocrine & metabolic: Hyperglycemia (<2%), hypo- gamma-glutamyl transferase, menstrual disease,
glycemia (<2%) redistribution of body fat
Gastrointestinal: Diarrhea (8%), nausea (8%), Gastrointestinal: Nausea (20% to 25%), vomiting (3% to
abdominal pain (<2%), Clostridioides (formerly Clos- 11%), abdominal pain (4% to 6%), anorexia, bloody
tridium) difficile (<2%), dysgeusia (<2%), dyspepsia stools, colitis, diarrhea, diverticulitis, fecal inconti-
(<2%), oral candidiasis (<2%), vomiting (2%) nence, gastroenteritis, gastrointestinal hemorrhage,
Genitourinary: Vulvovaginal candidiasis (<2%) gingival hemorrhage, increased serum lipase, pan-
Hepatic: Increased serum transaminases (3%), creatitis, vomiting
increased serum alkaline phosphatase (<2%) Genitourinary: Hematuria, urinary tract infection
Hypersensitivity: Hypersensitivity reaction (<2%) Hematologic & oncologic: Decreased hemoglobin (1%
Infection: Fungal infection (<2%) to 3%), prolonged prothrombin time (2%), adenopathy,
396
DENOSUMAB
bruise, eosinophilia, granulocytosis, leukopenia, pan- Effects on Dental Treatment No significant effects or
cytopenia, purpura, spleen disease, thrombocytopenia complications reported
Hepatic: Hepatomegaly, increased serum alkaline Mechanism of Action Reduces adhesion of plaque-
phosphatase, jaundice causing bacteria, reducing the formation of new plaque
Hypersensitivity: Angioedema, hypersensitivity reaction and promoting the removal of deposits with normal
Infection: Abscess, candidiasis (oral/vaginal), infection mechanical disruption (brushing and flossing). Ulti-
Neuromuscular & skeletal: Ostealgia, tetany mately causes a reduction in both plaque and gingivitis.
Ophthalmic: Conjunctivitis Decapinol® is regulated as a medical device because
Renal: Increased serum creatinine, nephrolithiasis, the primary mode of action is to serve as a physical
renal pain barrier without chemical activity.
Respiratory: Bronchitis (6% to 8%), chest congestion, Pregnancy Risk Factor The manufacturer does not
dyspnea, pneumonia recommend use in pregnant women.
Miscellaneous: Fever (4% to 12%)
<1%, postmarketing and/or case reports: Acute renal
failure, hemolytic anemia, hepatic failure, immune Denosumab (den OH sue mab)
reconstitution syndrome, rhabdomyolysis
Related Information
Mechanism of Action Delavirdine binds directly to
Osteonecrosis of the Jaw on page 1486
reverse transcriptase, blocking RNA-dependent and
DNA-dependent DNA polymerase activities Brand Names: US Prolia; Xgeva
Pharmacodynamics/Kinetics Brand Names: Canada Prolia; Xgeva
Half-life Elimination 5.8 hours (range: 2-11 hours) Generic Availability (US) No
Time to Peak Plasma: 1 hour Pharmacologic Category Bone-Modifying Agent;
Pregnancy Considerations Monoclonal Antibody
Maternal antiretroviral therapy (ART) may increase the Use
risk of preterm delivery, although available information Bone metastases from solid tumors (Xgeva): Pre-
is conflicting possibly due to variability of maternal vention of skeletal-related events in patients with bone
factors (disease severity; gestational age at initiation metastases from solid tumors.
of therapy). An increased risk of stillbirth, low birth Giant cell tumor of bone (Xgeva): Treatment of giant
weight, and small for gestational age infants has been cell tumor of bone (in adults and skeletally mature
observed in some but not all studies. Because there is adolescents) that is unresectable or where surgical
clear benefit to appropriate treatment, maternal ART resection is likely to result in severe morbidity.
should not be withheld due to concerns for adverse Glucocorticoid- induced osteoporosis (Prolia):
neonatal outcomes. Long-term follow-up is recom- Treatment of glucocorticoid-induced osteoporosis in
mended for all infants exposed to antiretroviral medi- patients at high risk of fracture who are initiating or
cations; children who develop significant organ system continuing systemic glucocorticoids at a daily dose
abnormalities of unknown etiology (particularly of the equivalent to ≥7.5 mg of prednisone for an anticipated
CNS or heart) should be evaluated for potential mito- duration of at least 6 months (high risk defined as
chondrial dysfunction. Hypersensitivity reactions osteoporotic fracture history, multiple risk factors for
(including hepatic toxicity and rash) are more common fracture, or failure of or intolerance to other available
in women on NNRTI therapy; it is not known if preg- osteoporosis therapy).
nancy increases this risk. Hypercalcemia of malignancy (Xgeva): Treatment of
hypercalcemia of malignancy refractory to bisphosph-
The Health and Human Services (HHS) Perinatal HIV onate therapy
Guidelines do not have recommendations specific to Multiple myeloma (Xgeva): Prevention of skeletal-
the use of delavirdine in pregnancy and females who related events in patients with multiple myeloma.
become pregnant on delavirdine should be switched to Osteoporosis/bone loss (Prolia): Treatment of osteo-
a recommended regimen. porosis in postmenopausal women at high risk of
In general, ART is recommended for all pregnant fracture; treatment of osteoporosis (to increase bone
females with HIV to keep the viral load below the limit mass) in men at high risk of fracture; treatment of bone
of detection and reduce the risk of perinatal trans- loss (to increase bone mass) in men receiving andro-
mission. Monitoring during pregnancy is more frequent gen-deprivation therapy for nonmetastatic prostate
than in non-pregnant adults. ART should be continued cancer; treatment of bone loss (to increase bone
postpartum for all females living with HIV and can be mass) in women receiving aromatase inhibitor therapy
modified after delivery. for breast cancer.
Health care providers are encouraged to enroll preg- No information available to require special precautions
nant females exposed to antiretroviral medications as Effects on Dental Treatment Cases of osteonecrosis
early in pregnancy as possible in the Antiretroviral of the jaw bone (ONJ) have been associated with
Pregnancy Registry (1-800-258-4263 or http://www.- denosumab exposure. ONJ presents clinically as
APRegistry.com). Health care providers caring for exposed necrotic bone of at least 8 weeks duration with
HIV-infected females and their infants may contact the or without the presence of pain, infection, or previous
National Perinatal HIV Hotline (888-448-8765) for clin- trauma in a patient who has not received radiation to the
ical consultation (HHS [perinatal] 2018). jaws. Since ONJ is also associated with bisphospho-
nate exposure, and osteoclasts are the common targets
Delmopinol (del MOE pi nol) of bisphosphonates and denosumab, osteoclastic inhib-
ition may play a central role in ONJ associated with
Brand Names: US Decapinol these two classes of drugs. Patients developing ONJ
Pharmacologic Category Antibacterial, Oral Rinse while on denosumab therapy should receive care by an
Local Anesthetic/Vasoconstrictor Precautions oral surgeon. See Warnings/Precautions and Dental
No information available to require special precautions Health Professional Considerations.
397
DENOSUMAB
Effects on Bleeding No information available to 2017). Denosumab has a reversible mechanism of

require special precautions action and therefore should not be discontinued
Adverse Reactions Percentages noted with Prolia abruptly (ASCO [Anderson 2018]).
(60 mg every 6 months) or Xgeva (120 mg every 4 Osteoporosis/bone loss (Prolia):
weeks). Treatment of androgen deprivation-induced bone
>10%: loss in men with prostate cancer: SubQ: 60 mg
Cardiovascular: Peripheral edema (Xgeva: 17% to as a single dose, once every 6 months
24%; Prolia: 5%), hypertension (Prolia: 4%) (Smith 2009)
Central nervous system: Fatigue (Xgeva: ≤45%), Treatment of aromatase inhibitor-induced bone
headache (Xgeva: 11% to 24%; Prolia: 4%) loss in women with breast cancer: SubQ: 60 mg
Dermatologic: Skin rash (≤14%), dermatitis (Prolia: as a single dose, once every 6 months (Ellis 2008)
≤11%), eczema (Prolia: ≤11%) Treatment of glucocorticoid-induced osteoporo-
Endocrine & metabolic: Hypophosphatemia (Xgeva: sis: SubQ: 60 mg as a single dose, once every 6
32%; severe: 10% to 21%), hypocalcemia (Xgeva: months (Saag 2018)
3% to 18%; Prolia: 2%) Treatment of osteoporosis in men or in postme-
Gastrointestinal: Diarrhea (Xgeva: 20% to 34%), nau- nopausal women: SubQ: 60 mg as a single dose,
sea (Xgeva: 30% to 32%), decreased appetite once every 6 months
(Xgeva: 24%), vomiting (Xgeva: 24%; Prolia 2%), Discontinuation/interruption of therapy: BMD returns
constipation (Xgeva: 21%; Prolia: 3%) to baseline within a relatively short timeframe fol-
Hematologic & oncologic: Anemia (Xgeva: 21% to lowing discontinuation of denosumab; therefore, a
22%), thrombocytopenia (Xgeva: 19%) drug holiday is not recommended (AACE/ACE
Neuromuscular & skeletal: Asthenia (Xgeva: ≤45%), [Camacho 2016]). Consider initiating alternative
back pain (5% to 21%), arthralgia (Prolia: 7% to osteoporosis therapy if denosumab is discontinued.
14%), limb pain (Prolia: 10% to 12%) Bone destruction caused by rheumatoid arthritis
Respiratory: Dyspnea (Xgeva: 21% to 27%), cough (off-label use): SubQ: 60 mg or 180 mg as a single
(Xgeva: 15%), upper respiratory tract infection one time dose and repeated at 6 months (in combi-
(Xgeva: 15%; Prolia: 5%) nation with continued methotrexate); a total of 2
1% to 10%: doses was administered in the study (Cohen 2008).
Cardiovascular: Angina pectoris (Prolia: 3%) Renal Impairment: Adult Monitor patients with
Central nervous system: Sciatica (Prolia: 5%) severe impairment (CrCl <30 mL/minute or on dialy-
Endocrine & metabolic: Hypercholesterolemia (Prolia: sis) closely due to increased risk of hypocalcemia.
7%), hypokalemia (Xgeva: grade 3: 3%); hypomag- Prolia: No dosage adjustment necessary. Denosumab
nesemia (Xgeva: grade 3: 3%), severe hypocalcemia may be a preferred agent for osteoporosis treatment
(symptomatic; Xgeva: 2% to 3%; Prolia: <1%) in patients with renal impairment, although evidence
Gastrointestinal: Upper abdominal pain (Prolia: 3%), in stage 4 CKD (eGFR <30 mL/minute) is limited
flatulence (Prolia: 2%) (AACE/ACE [Camacho 2016]; Jamal 2011). Use is
Genitourinary: Urinary tract infection (Prolia: 3%) not generally recommended in patients on dialysis or
Hematologic & oncologic: Malignant neoplasm (Prolia: with stage 5 CKD (eGFR <15 mL/minute) (AACE/
new; 3% to 5%) ACE [Camacho 2016]).
Infection: Serious infection (Prolia: 4%) Xgeva: There are no dosage adjustments provided in
Neuromuscular & skeletal: Musculoskeletal pain (Pro- the manufacturer's labeling. Guidelines suggest dos-
lia: 6%), ostealgia (Prolia: 4%), myalgia (Prolia: 3%), age adjustment is not necessary; close monitoring
osteonecrosis of the jaw (Xgeva ≤4%; Prolia: <1%), for hypocalcemia is recommended (ASCO [Ander-
polymyalgia rheumatic (Prolia: 2%)
son 2018]; ASCO/CCO [Van Poznak 2017]; Grava-
Ophthalmic: Cataract (Prolia: 5%)
los 2016).
Respiratory: Pneumonia (Xgeva: 8%), nasopharyngi-
tis (Prolia: 7%), bronchitis (Prolia: 4%)
adjustments provided in the manufacturer's labeling
(has not been studied).
antibody development, endocarditis, erythema, facial
swelling, femur fracture (diaphyseal, subtrochanteric), Pediatric
hypercalcemia (Xgeva, following discontinuation), Note: Administer calcium and vitamin D as necessary
hypersensitivity reaction, osteomyelitis, pancreatitis, to prevent or treat hypocalcemia.
increased parathyroid hormone, urticaria Giant cell tumor of the bone, treatment: Xgeva:
Dosing Adolescents (skeletally mature) weighing ≥45 kg:
Adult & Geriatric Note: Administer calcium and SubQ: 120 mg once every 4 weeks; during the first
vitamin D as necessary to prevent or treat hypocalce- month, give an additional dose of 120 mg on days 8
mia and 15
Bone metastases from solid tumors (prevention of Renal Impairment: Pediatric
skeletal-related events; Xgeva): SubQ: 120 mg Monitor patients with severe impairment (CrCl <30
every 4 weeks (Fizazi 2011; Henry 2011; Sto- mL/minute or on dialysis) due to increased risk of
peck 2010) hypocalcemia.
Giant cell tumor of bone (Xgeva): SubQ: 120 mg Xgeva: There are no dosage adjustments provided in
once every 4 weeks; during the first month, give an the manufacturer's labeling; however, in studies of
additional 120 mg on days 8 and 15 (Blay 2011; patients with varying degrees of renal impairment,
Thomas 2010) the degree of renal impairment had no effect on
Hypercalcemia of malignancy (Xgeva): SubQ: denosumab pharmacokinetics or pharmacody-
120 mg every 4 weeks; during the first month, give namics.
an additional 120 mg on days 8 and 15 (Hu 2014) Hepatic Impairment: Pediatric There are no dos-
Multiple myeloma (prevention of skeletal-related age adjustments provided in manufacturer's labeling
events; Xgeva): SubQ: 120 mg every 4 weeks (Raje (has not been studied).
398
DENOSUMAB
Mechanism of Action Denosumab is a monoclonal advised to contact their healthcare provider if signs or
antibody with affinity for nuclear factor-kappa ligand symptoms of severe infection or cellulitis develop. Use
(RANKL). Osteoblasts secrete RANKL; RANKL acti- with caution in patients with impaired immune systems
vates osteoclast precursors and subsequent osteolysis or using concomitant immunosuppressive therapy; may
which promotes release of bone-derived growth factors, be at increased risk for serious infections. Evaluate the
such as insulin-like growth factor-1 (IGF1) and trans- need for continued treatment with serious infection.
forming growth factor-beta (TGF-beta), and increases
Atypical femur fractures have been reported in patients
serum calcium levels. Denosumab binds to RANKL,
receiving denosumab. The fractures may occur any-
blocks the interaction between RANKL and RANK (a
where along the femoral shaft (may be bilateral) and
receptor located on osteoclast surfaces), and prevents
commonly occur with minimal to no trauma to the area.
osteoclast formation, leading to decreased bone resorp-
Some patients experience prodromal pain weeks or
tion and increased bone mass in osteoporosis. In solid
months before the fracture occurs. Because these
tumors with bony metastases, RANKL inhibition
fractures also occur in osteoporosis patients not treated
decreases osteoclastic activity leading to decreased
with denosumab, it is unclear if denosumab therapy is
skeletal related events and tumor-induced bone
the cause for the fractures; concomitant glucocorticoids
destruction. In giant cell tumors of the bone (which
may contribute to fracture risk. Advise patients to report
express RANK and RANKL), denosumab inhibits tumor
new/unusual hip, thigh, or groin pain; and if so, evaluate
growth by preventing RANKL from activating its recep-
for atypical/incomplete fracture. Contralateral limb
tor (RANK) on the osteoclast surface, osteoclast pre-
should be assessed if atypical fracture occurs. Consider
cursors, and osteoclast-like giant cells.
interrupting therapy in patients who develop an atypical
Contraindications femoral fracture. Following treatment discontinuation,
Prolia: Hypersensitivity (systemic) to denosumab or any the fracture risk increases, including risk of multiple
component of the formulation; preexisting hypocalce- vertebral fractures; patients with a history of prior
mia; pregnancy fractures or osteoporosis are at higher risk. Vertebral
Xgeva: Known clinically significant hypersensitivity to fractures occurred as early as 7 months (average: 19
denosumab or any component of the formulation;
months) after the last dose of denosumab. Evaluate
preexisting hypocalcemia
benefit/risk before initiating denosumab treatment for
Warnings/Precautions Clinically significant hypersen- osteoporosis, especially in patients with prior vertebral
sitivity (including anaphylaxis) has been reported. May fracture. If denosumab is discontinued, evaluate risk for
include throat tightness, facial edema, upper airway vertebral fracture and consider transitioning to an alter-
edema, lip swelling, dyspnea, pruritus, rash, urticaria, native osteoporosis therapy. Because denosumab is
and hypotension. If anaphylaxis or clinically significant associated with a severe bone turnover rebound follow-
hypersensitivity occurs, initiate appropriate manage- ing discontinuation, post-denosumab bisphosphonate
ment and permanently discontinue. Denosumab may therapy (IV or oral; dependent on the patient’s under-
cause or exacerbate hypocalcemia; severe sympto- lying indication for bone modifying therapy) is sug-
matic cases (including fatalities) have been reported. gested to mitigate decline in bone mineral density
An increased risk has been observed with increasing (Tsourdi 2017). Bisphosphonate therapy following
renal dysfunction, most commonly severe dysfunction denosumab discontinuation may reduce/prevent bone
(creatinine clearance <30 mL/minute and/or on dialy- turnover rebound (Lamy 2017).
sis), and with inadequate/no calcium supplementation.
Monitor calcium levels; correct preexisting hypocalce- Osteonecrosis of the jaw (ONJ), also referred to as
mia prior to therapy. Monitor levels more frequently medication-related osteonecrosis of the jaw (MRONJ),
when denosumab is administered with other drugs that has been reported in patients receiving denosumab.
can also lower calcium levels. Use caution in patients ONJ may manifest as jaw pain, osteomyelitis, osteitis,
with a history of hypoparathyroidism, thyroid surgery, bone erosion, tooth/periodontal infection, toothache,
parathyroid surgery, malabsorption syndromes, exci- gingival ulceration/erosion. Risk factors include invasive
sion of small intestine, severe renal impairment/dialysis, dental procedures (eg, tooth extraction, dental implants,
or other conditions which would predispose the patient oral surgery), cancer diagnosis, immunosuppressive
to hypocalcemia; monitor calcium, phosphorus, and therapy, angiogenesis inhibitor therapy, chemotherapy,
magnesium closely during therapy (the manufacturer systemic corticosteroids, poor oral hygiene, use of a
recommends monitoring within 14 days of injection dental appliance, ill-fitting dentures, periodontal and/or
[Prolia] or during the first weeks of therapy initiation other preexisting dental disease, diabetes and gingival
[Xgeva]). Hypocalcemia lasting weeks to months (and infections, local infection with delayed healing, anemia,
requiring frequent monitoring) has been reported in and/or coagulopathy. In studies of patients with cancer,
postmarketing analyses. Administer calcium, vitamin a longer duration of denosumab exposure was associ-
D, and magnesium as necessary. Patients with severe ated with a higher incidence of ONJ, although a majority
renal impairment (CrCl <30 mL/minute) or those on of patients had predisposing factors, including a history
dialysis may also develop marked elevations of serum of poor oral hygiene, tooth extraction, or the use of a
parathyroid hormone (PTH). Hypercalcemia (clinically dental appliance. Patients should maintain good oral
significant requiring hospitalization and complicated by hygiene during treatment. A dental exam and appropri-
acute renal injury) may occur in patients with giant cell ate preventive dentistry should be performed prior to
tumor of bone and patients with growing skeletons therapy. The manufacturer's labeling recommends
weeks to months following discontinuation of denosu- avoiding invasive dental procedures in patients with
mab therapy. Monitor for signs/symptoms of hypercal- bone metastases receiving denosumab for prevention
cemia (eg, nausea, vomiting, headache, decreased of skeletal-related events and to consider temporary
alertness), assess serum calcium periodically, and treat discontinuation of therapy in these patients if invasive
accordingly. Incidence of infections may be increased, dental procedure is required. According to a position
including serious skin infections, abdominal, urinary, paper by the American Association of Maxillofacial
ear, or periodontal infections. Endocarditis has also Surgeons (AAOMS), MRONJ has been associated with
been reported following use. Patients should be bisphosphonates and other antiresorptive agents
399
DENOSUMAB
(denosumab), and antiangiogenic agents (eg, bevaci- dialysis; risk of hypocalcemia is increased. Dose adjust-
zumab, sunitinib) used for the treatment of osteoporosis ment is not needed when administered at 60 mg every
or malignancy; risk is significantly higher in cancer 6 months (Prolia); once-monthly dosing has not been
patients receiving antiresorptive therapy compared to evaluated in patients with renal impairment (Xgeva).
patients receiving osteoporosis treatment (regardless of Dermatitis, eczema, and rash (which are not necessa-
medication used or dosing schedule). MRONJ risk is rily specific to the injection site) have been reported;
increased with intravenous antiresorptive therapy com- consider discontinuing if severe symptoms occur. Pack-
pared to the minimal risk associated with oral aging may contain natural latex rubber. May impair
bisphosphonate use, although risk appears to increase bone growth in children with open growth plates or
with oral bisphosphonates when duration of therapy inhibit eruption of dentition. In pediatrics, indicated only
exceeds 4 years. The AAOMS suggests that if medi- for the treatment of giant cell tumor of bone in adoles-
cally permissible, initiation of denosumab for cancer cents who are skeletally mature. Do not administer
therapy should be delayed until optimal dental health Prolia and Xgeva to the same patient for different
is attained (if extractions are required, antiresorptive indications. Potentially significant interactions may
therapy should delayed until the extraction site has exist, requiring dose or frequency adjustment, addi-
mucosalized or until after adequate osseous healing). tional monitoring, and/or selection of alternative
Once denosumab is initiated for oncologic disease, therapy.
procedures that involve direct osseous injury and place- Drug Interactions
ment of dental implants should be avoided. Patients Metabolism/Transport Effects None known.
developing ONJ during therapy should receive care by Avoid Concomitant Use
an oral surgeon (AAOMS [Ruggiero 2014]). According Avoid concomitant use of Denosumab with any of the
to the manufacturer, discontinuation of denosumab following: Belimumab
should be considered (based on risk/benefit evaluation) Increased Effect/Toxicity
in patients who develop ONJ. Denosumab may increase the levels/effects of: Beli-
mumab; Etelcalcetide; Immunosuppressants
Postmenopausal osteoporosis: For use in women at
high risk for fracture which is defined as a history of
Decreased Effect There are no known significant
interactions involving a decrease in effect.
osteoporotic fracture or multiple risk factors for fracture.
May also be used in women who failed or did not Dietary Considerations Ensure adequate calcium
tolerate other therapies. and vitamin D intake to prevent or treat hypocalcemia.
Calcium 1000 mg/day and vitamin D ≥400 units/day is
The American Society of Clinical Oncology (ASCO) has recommended in product labeling (Prolia). If dietary
updated guidelines on the role of bone-modifying intake is inadequate, dietary supplementation is recom-
agents (BMAs) in multiple myeloma (ASCO [Anderson mended. Women and men should consume:
2018]). The update now includes denosumab as an Calcium: 1000 mg/day (men: 50 to 70 years) or
alternate to zoledronic acid or pamidronate in patients 1200 mg/day (women ≥51 years and men ≥71 years)
with lytic disease, and as an additional option in adjunc- (IOM 2011; NOF 2014)
tive pain control in patients with pain due to osteolytic Vitamin D: 800 to 1000 units/day (men and women ≥50
disease and patients receiving other interventions for years) (NOF 2014). Recommended Dietary Allowance
fractures or impending fractures. Denosumab may also (RDA): 600 units/day (men and women ≤70 years) or
be preferred (to zoledronic acid) in patients with renal 800 units/day (men and women ≥71 years)
impairment. The ASCO guidelines recommend continu- (IOM 2011).
ing the BMA for up to 2 years in multiple myeloma Pharmacodynamics/Kinetics
patients; BMAs may then be resumed upon relapse Onset of Action Decreases markers of bone resorp-
with new onset skeletal-related events. Denosumab tion by ~85% within 3 days; maximal reductions
has a reversible mechanism of action and therefore observed within 1 month
should not be discontinued abruptly (refer to Bone Hypercalcemia of malignancy: Time to response
fractures [above] for further information). (median): 9 days; Time to complete response
(median): 23 days (Hu 2014)
Breast cancer: The American Society of Clinical Oncol-
Duration of Action Markers of bone resorption return
ogy (ASCO) /Cancer Care Ontario (CCO) updated
to baseline within 12 months of discontinuing therapy
guidelines on the role of bone-modifying agents (BMAs)
Hypercalcemia of malignancy: Duration of response
for metastatic breast cancer patients (ASCO/CCO [Van
(median): 104 days; Duration of complete response
Poznak 2017]).). The guidelines recommend initiating a (median): 34 days (Hu 2014)
BMA (denosumab, pamidronate, zoledronic acid) in
Half-life Elimination ~25 to 28 days
patients with metastatic breast cancer to the bone.
One BMA is not recommended over another (evidence
Time to Peak Serum: 10 days (range: 3 to 21 days)
supporting one BMA over another is insufficient). The Pregnancy Considerations Use of Prolia is contra-
optimal duration of BMA therapy is not defined; how- indicated in pregnant women. Based on data from
ever, the guidelines recommend continuing BMA ther- animal reproduction studies and the mechanism of
apy indefinitely. The analgesic effect of BMAs are action, denosumab may cause fetal harm if adminis-
modest and BMAs should not be used alone for pain tered to a pregnant woman. In females of reproductive
management; supportive care, analgesics, adjunctive potential, pregnancy status should be verified prior to
therapies, radiation therapy, surgery, and/or systemic treatment initiation. Denosumab is a human IgG mono-
anticancer therapy should be utilized. clonal antibody; fetal exposure to monoclonal antibod-
ies is expected to increase as pregnancy progresses.
Denosumab therapy results in significant suppression Women of reproductive potential should be advised to
of bone turnover; the long term effects of treatment are use effective contraception during denosumab treat-
not known but may contribute to adverse outcomes ment and for at least 5 months following the last dose.
such as ONJ, atypical fractures, or delayed fracture Studies of denosumab when used for osteoporosis/
healing; monitor. Use with caution in patients with renal bone loss in men demonstrated that denosumab is
impairment (CrCl <30 mL/minute) or patients on present in the semen in low concentrations (~2% of
400
DESIPRAMINE
serum exposure) and therefore unlikely that a female Local Anesthetic/Vasoconstrictor Precautions
partner or fetus would be exposed during unprotected Use with caution; epinephrine and levonordefrin have
sex to pharmacologically relevant denosumab concen- been shown to have an increased pressor response in
trations via seminal fluid; however, exposure from semi- combination with TCAs. Desipramine is one of the
nal fluid of men receiving denosumab for other drugs confirmed to prolong the QT interval and is
indications and higher doses is unknown and; therefore, accepted as having a risk of causing torsade de
their pregnant partners should be counseled regarding pointes. The risk of drug-induced torsade de pointes
this potential risk. is extremely low when a single QT interval prolonging
drug is prescribed. In terms of epinephrine, it is not
Women exposed to denosumab during pregnancy known what effect vasoconstrictors in the local anes-
should contact the Amgen Pregnancy Surveillance Pro- thetic regimen will have in patients with a known history
gram (800-772-6436). of congenital prolonged QT interval or in patients taking
Breastfeeding Considerations It is not known if any medication that prolongs the QT interval. Until more
denosumab is present in breast milk. According to the information is obtained, it is suggested that the clinician
manufacturer, the decision to discontinue denosumab consult with the physician prior to the use of a vaso-
or discontinue breastfeeding should take into account constrictor in suspected patients, and that the vaso-
the benefits of treatment to the mother as well as the constrictor (epinephrine, mepivacaine and
potential adverse effects on the breastfed infant. In levonordefrin [Carbocaine® 2% with Neo-Cobefrin®])
some animal studies, mammary gland development be used with caution.
was impaired following exposure to denosumab during Effects on Dental Treatment Key adverse event(s)
pregnancy, resulting in impaired lactation postpartum; related to dental treatment: Xerostomia and changes in
although development and lactation effects were not salivation (normal salivary flow resumes upon discon-
fully studied, mammary gland histopathology in female tinuation), unpleasant taste, stomatitis, and black
offspring exposed to denosumab in utero was normal at tongue. Long-term treatment with TCAs increases the
6 months. risk of caries by reducing salivation and salivary buffer
Dosage Forms: US capacity.
Solution, Subcutaneous [preservative free]: Effects on Bleeding Thrombocytopenia has been
Prolia: 60 mg/mL (1 mL) reported.
Xgeva: 120 mg/1.7 mL (1.7 mL) Adverse Reactions Frequency not defined. Some
Dental Health Professional Considerations In reactions listed are based on reports for other agents
head-to-head comparison trials of denosumab and in this same pharmacologic class, and may not be
zoledronate (a bisphosphonate) for the treatment of specifically reported for desipramine.
bone metastasis in patients with cancer, 20 cases of Cardiovascular: Cardiac arrhythmia, cerebrovascular
ONJ were detected out of a total of 1026 subjects accident, edema, flushing, heart block, hypertension,
(2.0%) exposed to denosumab. There were 14 cases hypotension, myocardial infarction, palpitations, pre-
of ONJ observed out of a total of 1020 subjects (1.4%) mature ventricular contractions, tachycardia, ventricu-
exposed to zoledronate (Kyrgidis, 2010). The case of a lar fibrillation, ventricular tachycardia
60-year old male cancer patient who developed ONJ Central nervous system: Agitation, anxiety, ataxia, con-
after treatment with denosumab has been published fusion, delusions, disorientation, dizziness, drowsi-
(Taylor, 2010). In that report, the patient participated in n e s s , d r u g f e v e r, E E G p a t t e r n c h a n g e s ,
a trial for a phase 3 study of denosumab. The patient extrapyramidal reaction, falling, fatigue, hallucination,
had never been prescribed a bisphosphonate medica- headache, hypomania, insomnia, neuroleptic malig-
tion before treatment with denosumab. Clinical and nant syndrome, nightmares, numbness, peripheral
radiological features of the lesion were diagnostic of neuropathy, psychosis (exacerbation), restlessness,
probable ONJ. After discontinuation of the denosumab, seizure, tingling of extremities, tingling sensation, with-
the patient was treated with antibiotics and chlorhex- drawal syndrome
idine rinses for a week. The necrotic bone sequestered Dermatologic: Alopecia, diaphoresis (excessive), pruri-
12 months later, and 15 months after initial presenta- tus, skin photosensitivity, skin rash, urticaria
tion, the mucosa had healed with no further symptoms. Endocrine & metabolic: Decreased libido, decreased
Another case reported the development of ONJ in a 65- serum glucose, galactorrhea, gynecomastia,
year old women being treated for giant cell tumor with increased libido, increased serum glucose, SIADH,
denosumab. Although the patient was medically com- weight gain, weight loss
promised and on multiple medications, the authors Gastrointestinal: Abdominal cramps, anorexia, consti-
proposed that a common thread in ONJ development pation, diarrhea, epigastric distress, increased pancre-
is inhibition of osteoclastic activity, mediated in this case atic enzymes, melanoglossia, nausea, paralytic ileus,
by denosumab. parotid gland enlargement, stomatitis, sublingual
adenitis, unpleasant taste, vomiting, xerostomia
Genitourinary: Breast hypertrophy, impotence, nocturia,
Desipramine (des IP ra meen) painful ejaculation, testicular swelling, urinary hesi-
tancy, urinary retention, urinary tract dilation
Related Information Hematologic & oncologic: Agranulocytosis, eosino-
Dentin Hypersensitivity, Acid Erosion, High Caries philia, petechia, purpura, thrombocytopenia
Index, Management of Alveolar Osteitis, and Xerosto- Hepatic: Abnormal hepatic function tests, cholestatic
mia on page 1548 jaundice, hepatitis, increased liver enzymes,
Vasoconstrictor Interactions With Antidepressants on increased serum alkaline phosphatase
page 1606 Neuromuscular & skeletal: Tremor, weakness
Brand Names: US Norpramin Ophthalmic: Accommodation disturbance, blurred
Pharmacologic Category Antidepressant, Tricyclic vision, increased intraocular pressure, mydriasis
(Secondary Amine) Otic: Tinnitus
Use Depression: Treatment of depression Renal: Polyuria
401
DESIPRAMINE
Miscellaneous: Fever that ambulatory patients presenting for dental treatment

Postmarketing and/or case reports: Angle-closure glau- will be taking intravenous anticoagulant therapy such as
coma, serotonin syndrome, suicidal ideation, suicidal desirudin.
tendencies Adverse Reactions As with all anticoagulants, bleed-
Mechanism of Action Traditionally believed to ing is the major adverse effect. Hemorrhage may occur
increase the synaptic concentration of norepinephrine at any site.
(and to a lesser extent, serotonin) in the central nervous 2% to 10%:
system by inhibition of its reuptake by the presynaptic Cardiovascular: Deep vein thrombophlebitis (2%)
neuronal membrane. However, additional receptor Dermatologic: Wound secretion (4%)
effects have been found including desensitization of Gastrointestinal: Nausea (2%)
adenyl cyclase, down regulation of beta-adrenergic Hematologic & oncologic: Hematoma (6%), anemia
receptors, and down regulation of serotonin receptors. (3%), major hemorrhage (≤3%; may include
Pharmacodynamics/Kinetics hemophthalmos, intracranial hemorrhage, intraspinal
Onset of Action Depression: Individual responses hemorrhage, prosthetic joint hemorrhage, or retro-
vary; however, 4 to 8 weeks of treatment is needed peritoneal hemorrhage)
before determining if a patient is partially or nonres- Local: Residual mass at injection site (4%)
ponsive (APA, 2010). <2%, postmarketing, and/or case reports: Anaphylac-
Half-life Elimination Adults: 15 to 24 hours (Weiner, toid reaction, anaphylaxis, cerebrovascular disease,
1981) decreased hemoglobin, dizziness, epistaxis, fever,
Time to Peak Plasma: ~6 hours (Weiner, 1981) hematemesis, hematuria, hemorrhage (fatal), hyper-
Pregnancy Considerations Animal reproduction sensitivity reaction, hypotension, leg pain, lower
studies are inconclusive. Tricyclic antidepressants extremity edema, thrombosis, vomiting, wound heal-
may be associated with irritability, jitteriness, and con- ing impairment
vulsions (rare) in the neonate (Yonkers 2009). Mechanism of Action Desirudin is a direct, highly
selective thrombin inhibitor. Reversibly binds to the
The ACOG recommends that therapy for depression active thrombin site of free and clot-associated throm-
during pregnancy be individualized; treatment should bin. Inhibits fibrin formation, activation of coagulation
incorporate the clinical expertise of the mental health factors V, VII, and XIII, and thrombin-induced platelet
clinician, obstetrician, primary health care provider, and aggregation resulting in a dose-dependent prolongation
pediatrician (ACOG 2008). According to the American of the activated partial thromboplastin time (aPTT).
Psychiatric Association (APA), the risks of medication Pharmacodynamics/Kinetics
treatment should be weighed against other treatment Half-life Elimination ~2 hours; Prolonged with renal
options and untreated depression. For women who impairment (CrCl <31 mL/minute/1.73 m2: Up to 12
discontinue antidepressant medications during preg- hours)
nancy and who may be at high risk for postpartum Time to Peak Plasma: 1 to 3 hours
depression, the medications can be restarted following
delivery (APA 2010). Treatment algorithms have been
developed by the ACOG and the APA for the manage- Pregnancy Considerations Adverse events have
ment of depression in women prior to conception and been observed in animal reproduction studies. Data
during pregnancy (Yonkers 2009). are insufficient to evaluate the safety of thrombin inhib-
itors during pregnancy (Guyatt, 2012).
Pregnancy Registry for Antidepressants (NPRAD).
Desloratadine (des lor AT a deen)
Women 18 to 45 years of age or their health care Brand Names: US Clarinex
providers may contact the registry by calling Brand Names: Canada Aerius; Aerius Kids; Deslor-
844-405-6185. Enrollment should be done as early in atadine Allergy Control
pregnancy as possible.
Pharmacologic Category Histamine H1 Antagonist;
Dental Health Professional Considerations See Histamine H1 Antagonist, Second Generation; Piperi-
Local Anesthetic/Vasoconstrictor Precautions dine Derivative
Use
Desirudin (des i ROO din) Allergic rhinitis: Relief of nasal and non-nasal symp-
toms of seasonal (SAR) and perennial (PAR) allergic
Related Information rhinitis
Cardiovascular Diseases on page 1442 Urticaria: Symptomatic relief of pruritus, reduction in
Brand Names: US Iprivask [DSC] number of hives, and reduction in size of hives asso-
Pharmacologic Category Anticoagulant; Anticoagu- ciated with chronic idiopathic urticaria (CIU)
lant, Direct Thrombin Inhibitor Local Anesthetic/Vasoconstrictor Precautions
Use Deep vein thrombosis, prophylaxis: Prophylaxis No information available to require special precautions
of deep vein thrombosis (DVT) in patients undergoing Effects on Dental Treatment Key adverse event(s)
hip-replacement surgery related to dental treatment: Xerostomia (normal salivary
Local Anesthetic/Vasoconstrictor Precautions flow resumes upon discontinuation)
No information available to require special precautions Effects on Bleeding No information available to
Effects on Dental Treatment No significant effects or require special precautions
complications reported Adverse Reactions Note: Frequency reported in chil-
Effects on Bleeding As with all anticoagulants, bleed- dren, unless otherwise noted.
ing is a potential adverse effect of desirudin during >10%:
dental surgery; risk is dependent on multiple variables, Central nervous system: Headache (adults 14%), irri-
including the intensity of anticoagulation and patient tability (12%)
susceptibility. Medical consult is suggested. It is unlikely Gastrointestinal: Diarrhea (15% to 20%)
402
DESMOPRESSIN
Respiratory: Upper respiratory tract infection (11% to prior to the scheduled procedure and to also stop
21%), cough (11%) bleeding due to spontaneous or trauma-induced
Miscellaneous: Fever (12% to 17%) injuries, such as hemarthroses, intramuscular hem-
1% to 10%: atomas, or mucosal bleeding.
Central nervous system: Drowsiness (children 9%; Limitations of use: Not indicated for the treatment of
adults 2%), insomnia (5%), fatigue (adults 2% to hemophilia A with factor VIII coagulant activity
5%), dizziness (adults 4%), emotional lability (3%) levels ≤5%, for the treatment of hemophilia B, or
Dermatologic: Erythema (3%), maculopapular in patients who have factor VIII antibodies. In
rash (3%) certain clinical situations, it may be justified to try
Gastrointestinal: Vomiting (6%), anorexia (5%), nau- desmopressin with careful monitoring in patients
sea (children 3%; adults 5%), dyspepsia (adults 3%), with factor VIII levels between 2% and 5%.
increased appetite (3%), xerostomia (adults 3%) Von Willebrand disease (type 1): For use in patients
Genitourinary: Urinary tract infection (4%), dysmenor- with mild to moderate classic von Willebrand disease
rhea (adults 2%) (type 1) with factor VIII coagulant activity levels >5%
Infection: Varicella (4%), parasitic infection (3%) to maintain hemostasis during surgical procedures
Neuromuscular & skeletal: Myalgia (adults 2% to 3%) and postoperatively when administered 30 minutes
Otic: Otitis media (children 6%) prior to the scheduled procedure and to stop bleed-
Respiratory: Bronchitis (6%), rhinorrhea (5%), phar- ing due to spontaneous or trauma-induced injuries,
yngitis (children 3% to 5%; adults 3% to 4%), epis- such as hemarthroses, intramuscular hematomas, or
taxis (3%) mucosal bleeding.
Postmarketing and/or case reports: Hepatitis (rare), Limitations of use: Patients with von Willebrand
hyperbilirubinemia, hypersensitivity reactions (includ- disease who are least likely to respond are those
ing anaphylaxis, dyspnea, edema, pruritus, rash, urti- with severe homozygous von Willebrand disease
caria), increased liver enzymes, movement disorder with factor VIII coagulant activity and factor VIII von
(including dystonia, tics, and extrapyramidal symp- Willebrand factor antigen levels <1%; other patients
toms), palpitations, psychomotor agitation, seizure, may respond (variable) depending on the type of
tachycardia molecular defect they have. Check bleeding time
Mechanism of Action Desloratadine, a major active and factor VIII coagulant activity, ristocetin cofactor
metabolite of loratadine, is a long-acting tricyclic anti- activity, and von Willebrand factor antigen during
histamine with selective peripheral histamine H1 recep- administration of desmopressin to ensure that
tor antagonistic activity. adequate levels are being achieved. Not indicated
Pharmacodynamics/Kinetics for the treatment of severe classic von Willebrand
Onset of Action Within 1 hour disease (type I) or when there is evidence of an
Duration of Action 24 hours abnormal molecular form of factor VIII antigen.
Half-life Elimination 27 hours Uremic bleeding (Octostim [Canadian product]):
Time to Peak 3 hours Prevention or treatment of bleeding in patients with
Pregnancy Risk Factor C uremia.
Pregnancy Considerations Intranasal:
Guidelines for the use of antihistamines in the treatment Diabetes insipidus:
of allergic rhinitis or urticaria in pregnancy are generally DDAVP Nasal Spray: Antidiuretic replacement ther-
the same as in nonpregnant females. Second gener- apy in the management of central diabetes insip-
ation antihistamines may be used for the treatment of idus in adults and children ≥4 years.
allergic rhinitis and urticaria during pregnancy; however, DDAVP Rhinal tube: Antidiuretic replacement ther-
information related to the use of desloratadine in preg- apy in the management of central diabetes insip-
nancy is limited and other medications may be pre- idus; management of the temporary polyuria and
ferred (Wallace 2008; Zuberbier 2018). polydipsia following head trauma or surgery in the
pituitary region.
Desmopressin (des moe PRES in) Limitation of use: Treatment of nephrogenic diabetes
insipidus or primary nocturnal enuresis.
Brand Names: US DDAVP; DDAVP Rhinal Tube; Hemophilia A (Stimate; Octostim [Canadian prod-
Nocdurna; Noctiva; Stimate uct]): For use in patients with hemophilia A with
Brand Names: Canada DDAVP; DDAVP Melt; DDAVP factor VIII coagulant activity levels >5% and to stop
Rhinyle; DDAVP Spray; Nocdurna; Octostim bleeding due to spontaneous or trauma-induced
Pharmacologic Category Antihemophilic Agent; injuries, such as hemarthroses, intramuscular hem-
Hemostatic Agent; Hormone, Posterior Pituitary; Vaso- atomas, or mucosal bleeding.
pressin Analog, Synthetic Limitations of use: Not indicated for the treatment of
Use hemophilia A with factor VIII coagulant activity
Injection: levels ≤5%, for the treatment of hemophilia B, or
Diabetes insipidus: Antidiuretic replacement therapy in patients who have factor VIII antibodies.
in the management of central (cranial) diabetes Nocturia (Noctiva): Treatment of nocturia due to
insipidus; management of the temporary polyuria nocturnal polyuria in adults who awaken at least 2
and polydipsia following head trauma or surgery in times per night to void.
the pituitary region. Limitations of use: Has not been studied in patients
Limitations of use: Desmopressin is ineffective for <50 years of age.
the treatment of nephrogenic diabetes insipidus. von Willebrand disease (type 1) (Stimate; Octostim
Hemophilia A: For use in patients with hemophilia A [Canadian product]): For use in patients with mild
with factor VIII coagulant activity levels >5% to to moderate classic von Willebrand disease (type 1)
maintain hemostasis during surgical procedures with factor VIII coagulant activity levels >5% and to
and postoperatively when administered 30 minutes stop bleeding due to spontaneous or trauma-induced
403
DESMOPRESSIN
injuries, such as hemarthroses, intramuscular hem- Local: Burning sensation at injection site, erythema at
atomas, mucosal bleeding, or menorrhagia. injection site, swelling at injection site
Limitations of use: Not indicated for the treatment of Ophthalmic: Eye pruritus (intranasal), photophobia
severe classic von Willebrand disease (type 1) or (intranasal)
when there is evidence of an abnormal molecular Respiratory: Cough (intranasal), upper respiratory
form of factor VIII antigen. tract infection
Oral: atrial fibrillation, dysuria, serum hyposmolality, severe
Diabetes insipidus: Antidiuretic replacement therapy hypersensitivity, water intoxication
in the management of central diabetes insipidus; Mechanism of Action Synthetic analogue of the anti-
management of the temporary polyuria and polydip- diuretic hormone arginine vasopressin. In a dose
sia following head trauma or surgery in the pituitary dependent manner, desmopressin increases cyclic
region. adenosine monophosphate (cAMP) in renal tubular
Limitation of use: Desmopressin is ineffective for the cells which increases water permeability resulting in
treatment of nephrogenic diabetes insipidus. decreased urine volume and increased urine osmolality;
Nocturia (Nocdurna): Treatment of nocturia due to increases plasma levels of von Willebrand factor, factor
nocturnal polyuria in adults who awaken at least 2 VIII, and t-PA contributing to a shortened activated
times per night to void. partial thromboplastin time (aPTT) and bleeding time.
Primary nocturnal enuresis: Management of pri- Pharmacodynamics/Kinetics
mary nocturnal enuresis, either alone or as an Onset of Action
adjunct to behavioral conditioning or other nonphar- Intranasal: Antidiuretic: 15 to 30 minutes; Increased
macologic intervention. factor VIII and von Willebrand factor (vWF) activity
Local Anesthetic/Vasoconstrictor Precautions (dose related): 30 minutes
No information available to require special precautions Peak effect: Antidiuretic: 1 hour; Increased factor VIII
Effects on Dental Treatment No significant effects or and vWF activity: 1.5 hours; Nocturia: 0.25 to
complications reported 0.75 hour
Effects on Bleeding Rare reports of thrombotic events IV infusion: Increased factor VIII and vWF activity: 30
including thromboembolism have been associated with minutes (dose related)
desmopressin, although no causality has been deter- Peak effect: 1.5 to 2 hours
mined. Oral tablet: Antidiuretic: ~1 hour
Adverse Reactions Peak effect: 4 to 7 hours
>10%: Sublingual: Antidiuretic: ~30 minutes
Endocrine & metabolic: Hyponatremia (<1%; intra- Duration of Action Intranasal, Injection, Oral tablet,
nasal: 2% to 12%; sublingual: 3% to 4%) Sublingual: ~6 to 14 hours
Gastrointestinal: Xerostomia (sublingual: ≤14%) Half-life Elimination 2 to 4 hours; Severe renal
1% to 10%: impairment: ~9 hours
Cardiovascular: Hypertension (intranasal: 2% to 3%) Pregnancy Considerations
Central nervous system: Headache (2% to 5%), dizzi- In vitro studies demonstrate poor placental transfer of
ness (intranasal, sublingual: 2% to 3%), chills (intra- desmopressin.
nasal: 2%), nostril pain (intranasal: 2%) Desmopressin may be used throughout pregnancy for
Gastrointestinal: Abdominal pain (intranasal: 2%), the treatment of diabetes insipidus (Aleksandrov 2010;
gastrointestinal disease (intranasal: 2%), nausea Ananthakrishnan 2016; Brewster 2005; Schrier 2010).
(intranasal: 2%) Information related to desmopressin for the treatment of
Neuromuscular & skeletal: Asthenia (intranasal: 2%), von Willebrand disease in pregnancy is limited (NHLBI
back pain (intranasal: 1% to 2%) 2007); however, use is recommended for bleeding
Ophthalmic: Abnormal lacrimation (intranasal: 2%), prophylaxis when otherwise indicated (Demers 2018;
conjunctivitis (intranasal: 2%), ocular edema (intra- Pacheco 2010; Trigg 2012). Desmopressin is not rec-
nasal: 2%) ommended for nocturia caused by normal physiologic
Respiratory: Rhinitis (intranasal: 3% to 8%), nasal changes which occur during pregnancy.
discomfort (intranasal: 6%), nasopharyngitis (intra-
nasal: 4%), nasal congestion (intranasal: ≤3%), epis- Desonide (DES oh nide)
taxis (intranasal: 2% to 3%), sneezing (intranasal:
2% to 3%), bronchitis (intranasal: 2%) Brand Names: US Desonate; DesOwen; LoKara
Frequency not defined: [DSC]; Tridesilon; Verdeso
Cardiovascular: Altered blood pressure, chest pain Brand Names: Canada Desocort; PDP-Desonide;
(intranasal), edema, facial flushing, flushing (intra- Tridesilon; Verdeso
nasal), palpitations (intranasal), tachycardia (intra- Pharmacologic Category Corticosteroid, Topical
nasal) Use
Central nervous system: Abnormality in thinking, agi- Atopic dermatitis (foam and gel): Treatment of mild to
tation (intranasal), drowsiness (intranasal), insomnia moderate atopic dermatitis in patients 3 months and
(intranasal), localized warm feeling (intranasal), pain older
(intranasal) Corticosteroid-responsive dermatoses (cream,
Endocrine & metabolic: Weight gain ointment, and lotion): Relief of inflammatory and
Gastrointestinal: Abdominal cramps, diarrhea, dys- pruritic manifestations of corticosteroid-responsive
pepsia (intranasal), sore throat (intranasal), vomiting dermatoses.
(intranasal) Local Anesthetic/Vasoconstrictor Precautions
Genitourinary: Balanitis (intranasal), vulvar pain No information available to require special precautions
Hepatic: Increased serum aspartate aminotransferase Effects on Dental Treatment No significant effects or
(oral; transient) complications reported
404
DESVENLAFAXINE
Effects on Bleeding No information available to Adverse Reactions

require special precautions >10%:
Adverse Reactions Frequency not defined. Central nervous system: Dizziness (10% to 13%),
Cardiovascular: Hypertension insomnia (9% to 12%)
Central nervous system: Headache, irritability Dermatologic: Hyperhidrosis (10% to 11%)
Dermatologic: Erythema (transient, intense), exfoliation Gastrointestinal: Nausea (22% to 26%), xerostomia
of skin, pruritus, skin rash, telangiectasia, xeroderma (11% to 17%)
1% to 10%:
Endocrine & metabolic: HPA-axis suppression, hyper-
Cardiovascular: Orthostatic hypotension (elderly 8%),
glycemia
syncope (<2%), tachycardia (<2%), hypertension
Infection: Increased susceptibility to infection (dose related; ≤1% of patients taking 50 to 100 mg
Local: Application site: Atrophic striae, dermatitis, dys- daily had sustained diastolic BP ≥90 mm Hg)
chromia, local irritation, local pruritus, localized burn- Central nervous system: Drowsiness (≤9%), fatigue
ing, skin atrophy, stinging of the skin (7%), anxiety (3% to 5%), delayed ejaculation (1%
Respiratory: Asthma, cough, pharyngitis, upper respi- to 5%), abnormal dreams (2% to 3%), anorgasmia
ratory tract infection (males ≤3%; females 1%), jitteriness (2%), vertigo
Postmarketing and/or case reports: Localized eryth- (≤2%), depersonalization (<2%), dystonia (<2%),
ema, dermatological reaction, facial swelling seizure (<2%), disturbance in attention (1%), yawn-
Mechanism of Action Topical corticosteroids have ing (1%), male sexual disorder (≤1%)
anti-inflammatory, antipruritic, and vasoconstrictive Dermatologic: Alopecia (<2%), skin photosensitivity
properties. May depress the formation, release, and (<2%), skin rash (<2%)
activity of endogenous chemical mediators of inflam- Endocrine & metabolic: Decreased libido (males 4% to
mation (kinins, histamine, liposomal enzymes, prosta- 5%), increased serum cholesterol (increased by
glandins) through the induction of phospholipase A2 ≥50 mg/dL and ≥261 mg/dL: 3% to 4%), increased
inhibitory proteins (lipocortins) and sequential inhibition serum prolactin (<2%), weight gain (<2%), hot flash
(1%), increased LDL cholesterol (increased by
of the release of arachidonic acid. Desonide has low
≥50 mg/dL and ≥190 mg/dL: ≤1%)
range potency.
Gastrointestinal: Constipation (9%), decreased appe-
Pregnancy Risk Factor C tite (5% to 8%), vomiting (≤4%), bruxism (<2%)
Pregnancy Considerations Adverse events have Genitourinary: Proteinuria (5% to 8%), erectile dys-
been observed in animal reproduction studies. function (3% to 6%), urinary retention (<2%), ejacu-
lation failure (≤1%), urinary hesitancy (≤1%)
Desvenlafaxine (des ven la FAX een)
Hepatic: Abnormal hepatic function tests (<2%)
Hypersensitivity: Angioedema (<2%)
Related Information Neuromuscular & skeletal: Tremor (≤3%), stiffness
Dentin Hypersensitivity, Acid Erosion, High Caries (<2%), weakness (<2%)
Index, Management of Alveolar Osteitis, and Xerosto- Ophthalmic: Blurred vision (3% to 4%), mydriasis (2%)
Otic: Tinnitus (≤2%)
mia on page 1548
Frequency not defined: Cardiovascular: Coronary
Vasoconstrictor Interactions With Antidepressants on occlusion, ischemic heart disease, myocardial
page 1606 infarction
Brand Names: US Khedezla; Pristiq <1%, postmarketing, and/or case reports: Acute pan-
Brand Names: Canada Pristiq creatitis, angle-closure glaucoma, cardiomyopathy
Pharmacologic Category Antidepressant, Serotonin/ (takotsubo), Stevens-Johnson syndrome
Norepinephrine Reuptake Inhibitor Mechanism of Action Desvenlafaxine is a potent and
Use Major depressive disorder: Treatment of major selective serotonin and norepinephrine reuptake inhib-
depressive disorder (MDD) itor.
Part of the mechanism of desvenlafaxine is to block Half-life Elimination ~10 to 11 hours; prolonged in
reuptake of norepinephrine along with dopamine. renal failure and hepatic failure
Because of the potential for norepinephrine elevation Pregnancy Considerations
Nonteratogenic effects in the newborn following SSRI/
within CNS synapses, it is suggested that vasoconstric-
SNRI exposure late in the third trimester include respi-
tor be administered with caution and to monitor vital
ratory distress, cyanosis, apnea, seizures, temperature
signs in dental patients taking antidepressants that
instability, feeding difficulty, vomiting, hypoglycemia,
affect norepinephrine in this way. This is particularly hyper- or hypotonia, hyper-reflexia, jitteriness, irritabil-
important in patients taking desvenlafaxine, which has ity, constant crying, and tremor. Symptoms may be due
been noted to cause a sustained increase in blood to the toxicity of the SNRIs/SSRIs or a discontinuation
pressure or heart rate. Dose-related increase in systolic syndrome and may be consistent with serotonin syn-
and diastolic blood pressure have also been reported. drome associated with treatment. The long-term effects
Effects on Dental Treatment Key adverse event(s) of in utero SNRI/SSRI exposure on infant development
related to dental treatment: Significant xerostomia (nor- and behavior are not known.
mal salivary flow resumes upon discontinuation). See
The ACOG recommends that therapy with SSRIs or
Effects on Bleeding. SNRIs during pregnancy be individualized; treatment of
Effects on Bleeding Platelet dysfunction (ie, impaired depression during pregnancy should incorporate the
platelet aggregation) may occur during treatment with clinical expertise of the mental health clinician, obste-
serotonin norepinephrine reuptake inhibitors (SNRIs), trician, primary health care provider, and pediatrician.
such as desvenlafaxine, due to platelet serotonin deple- According to the American Psychiatric Association
tion, possibly increasing the risk of a bleeding compli- (APA), the risks of medication treatment should be
cation. NSAIDs may increase this risk. weighed against other treatment options and untreated
405
DESVENLAFAXINE
depression. For women who discontinue antidepres- (hydrocortisone or cortisone is the first choice); pre-
sant medications during pregnancy and who may be operatively, and in the event of serious trauma or
at high risk for postpartum depression, the medications illness, in adrenal insufficiency or when adrenocort-
can be restarted following delivery. Treatment algo- ical reserve is doubtful (injection only); septic shock
rithms have been developed by the ACOG and the unresponsive to conventional therapy if adrenocort-
APA for the management of depression in women prior ical insufficiency exists or is suspected (injection
to conception and during pregnancy. only); congenital adrenal hyperplasia; nonsuppura-
tive thyroiditis; hypercalcemia associated with
Desvenlafaxine is the major active metabolite of ven-
cancer.
lafaxine; also refer to the Venlafaxine monograph. GI diseases: To tide the patient over a critical period
Pregnant women exposed to antidepressants during of the disease in ulcerative colitis or regional
pregnancy are encouraged to enroll in the National enteritis.
Pregnancy Registry for Antidepressants (NPRAD). Hematologic disorders: Immune thrombocytopenia
Women 18 to 45 years of age or their health care (formerly known as idiopathic thrombocytopenic pur-
providers may contact the registry by calling pura) in adults (not IM); secondary thrombocytopenia
844-405-6185. Enrollment should be done as early in in adults (select cases); acquired (autoimmune)
pregnancy as possible. hemolytic anemia; pure red cell aplasia; congenital
(erythroid) hypoplastic anemia (Diamond Blackfan
anemia).
Dexamethasone (Systemic) Neoplastic diseases: Palliative management of leu-
(deks a METH a sone)
kemias and lymphomas in adults and acute leukemia
Related Information of childhood.
Respiratory Diseases on page 1467 Nervous system: Cerebral edema associated with
Ulcerative, Erosive, and Painful Oral Mucosal Disorders primary or metastatic brain tumor or craniotomy;
on page 1544 multiple sclerosis (acute exacerbations). Note:
Related Sample Prescriptions Treatment guidelines recommend the use of high
dose IV or oral methylprednisolone for acute exac-
Ulcerative and Erosive Disorders - Sample Prescrip-
erbations of multiple sclerosis (AAN [Scott 2011];
tions on page 47
NICE 2014).
Brand Names: US Active Injection D; Decadron; Dex-
Ophthalmic diseases: Severe acute and chronic
amethasone Intensol; DexPak 10 Day; DexPak 13 Day;
allergic and inflammatory processes involving the
DexPak 6 Day; DoubleDex; Dxevo 11-Day; HiDex 6-
eye and its adnexa such as allergic conjunctivitis;
Day; LoCort 11-Day [DSC]; LoCort 7-Day [DSC]; MAS
keratitis; allergic corneal marginal ulcers; herpes
Care-Pak; ReadySharp Dexamethasone; TaperDex 12-
zoster ophthalmicus; iritis and iridocyclitis; choriore-
Day; TaperDex 6-Day; TaperDex 7-Day; TopiDex;
tinitis; anterior segment inflammation; diffuse poste-
Zodex 12-Day [DSC]; Zodex 6-Day [DSC]; ZonaCort
rior uveitis and choroiditis; optic neuritis; sympathetic
11 Day [DSC]; ZonaCort 7 Day [DSC]
ophthalmia; temporal arteritis; uveitis; ocular inflam-
Brand Names: Canada Dexasone matory conditions unresponsive to topical cortico-
Generic Availability (US) May be product dependent steroids.
Pharmacologic Category Anti-inflammatory Agent; Respiratory diseases: Symptomatic sarcoidosis;
Antiemetic; Corticosteroid, Systemic Loeffler syndrome not manageable by other means;
Dental Use Treatment of a variety of oral diseases of berylliosis; fulminating or disseminated pulmonary
allergic, inflammatory or autoimmune origin; aphthous tuberculosis when used concurrently with appropri-
stomatitis (systemic dexamethasone used topically); ate antituberculous chemotherapy; aspiration pneu-
lichen planus (erosive) and other oral vesiculoerosive monitis; idiopathic eosinophilic pneumonias.
diseases Rheumatic disorders: As adjunctive therapy for
Use short-term administration in psoriatic arthritis, rheu-
Oral, IV or IM injection: matoid arthritis (RA), juvenile RA, ankylosing spon-
Allergic states: Control of severe or incapacitating dylitis, acute and subacute bursitis, acute nonspecific
allergic conditions intractable to adequate trials of tenosynovitis, acute gouty arthritis, posttraumatic
conventional treatment: seasonal or perennial aller- osteoarthritis, synovitis of osteoarthritis, epicondyli-
gic rhinitis, bronchial asthma, contact dermatitis, tis; treatment of dermatomyositis, polymyositis, and
atopic dermatitis, serum sickness, drug hypersensi- systemic lupus erythematosus.
tivity reactions; acute noninfectious laryngeal edema, Miscellaneous: Tuberculous meningitis with subar-
urticarial transfusion reactions (injection only). achnoid block or impending block when used with
Collagen diseases: During an exacerbation or as appropriate antituberculous chemotherapy; trichino-
maintenance therapy in selected cases of systemic sis with neurologic or myocardial involvement.
lupus erythematosus or acute rheumatic carditis.
Intraarticular or soft tissue injection: As adjunctive
Dermatologic diseases: Pemphigus; bullous derma-
therapy for short-term administration in synovitis of
titis herpetiformis; severe erythema multiforme (Ste-
osteoarthritis, RA, acute and subacute bursitis, acute
vens-Johnson syndrome); exfoliative dermatitis;
gouty arthritis, epicondylitis, acute nonspecific tenosy-
exfoliative erythroderma; mycosis fungoides; severe
novitis, posttraumatic osteoarthritis
psoriasis; severe seborrheic dermatitis.
Diagnostic testing: Diagnostic testing of adrenocort- Intralesional injection: Keloids; localized hypertro-
ical hyperfunction. phic, infiltrated, inflammatory lesions of lichen planus,
Edematous states: To induce a diuresis or remission psoriatic plaques, granuloma annulare, and lichen
of proteinuria in idiopathic nephrotic syndrome or simplex chronicus (neurodermatitis); discoid lupus
that because of systemic lupus erythematosus. erythematosus; necrobiosis lipoidica diabeticorum;
Endocrine disorders: Primary, secondary, or acute alopecia areata; cystic tumors of an aponeurosis or
(injection only) adrenocortical insufficiency tendon (ganglia)
406
DEXAMETHASONE (SYSTEMIC)
Local Anesthetic/Vasoconstrictor Precautions rinse with 5 mL 4 times/day and swallow; then for 3
No information available to require special precautions days, rinse with 5 mL 4 times/day and swallow every
Effects on Dental Treatment No significant effects or other time. Then for 3 days rinse with 5 mL 4 times/day
complications reported and expectorate. Continue the rinse and expectorate
Effects on Bleeding No information available to mode for 2 minutes, but discontinue medication when
require special precautions mouth becomes completely comfortable.
Adverse Reactions Some reactions listed are based Recurrent aphthous stomatitis: Rinse with 5 mL dex-
on reports for other agents in this same pharmacologic amethasone (0.5 mg/5 mL) oral elixir for 2 minutes 4
class and may not be specifically reported for dexame- times/day and expectorate
thasone. Dosing
Adult
Cardiovascular: Bradycardia, cardiac arrhythmia, car-
diac failure, cardiomegaly, circulatory shock, edema, Adrenal crisis (shock due to adrenal insufficiency
embolism (fat), hypertension, hypertrophic cardiomy- and unresponsive to conventional therapy) (off-
opathy (premature infants), myocardial rupture (post- label dose): IV: 4 to 10 mg as a single dose, which
MI), syncope, tachycardia, thromboembolism, throm- may be repeated if necessary. Note: Hydrocortisone
bophlebitis, vasculitis is the preferred agent in this setting (ES [Bornstein
Central nervous system: Depression, emotional labil- 2016]; SCCM/ESICM [Annane 2017]).
ity, euphoria, headache, increased intracranial pres- Anti-inflammatory/immunosuppressive/endocrine
sure, insomnia, malaise, myasthenia, neuritis, disorders:
neuropathy, paresthesia, personality changes, pseu- Oral, IM, IV: 0.5 to 9 mg/day in divided doses every 6
dotumor cerebri (usually following discontinuation), to 12 hours; dose depends upon condition being
psychic disorder, seizure, vertigo treated and response of patient.
Dermatologic: Acne vulgaris, allergic dermatitis, alo- Intra-articular, intralesional, or soft tissue injection:
pecia, atrophic striae, diaphoresis, ecchymoses, Dosage and frequency depend on the condition
erythema, facial erythema, fragile skin, hyperpig- and the site of injection; frequency range: once
mentation, hypertrichosis, hypopigmentation, peria- every 3 to 5 days to once every 2 to 3 weeks
nal skin irritation (itching, burning, tingling; following Large joints (eg, knee): Single dose: 2 to 4 mg
IV injection), petechiae, skin atrophy, skin rash, sub- Small joints (eg, interphalangeal, temporomandib-
cutaneous atrophy, suppression of skin test reaction, ular): Single dose: 0.8 to 1 mg
urticaria, xeroderma Bursae: Single dose: 2 to 4 mg
Endocrine & metabolic: Adrenal suppression, carbo- Tendon Sheaths: Single dose: 0.4 to 1 mg
hydrate intolerance, Cushing syndrome, decreased Soft tissue infiltration: Single dose: 2 to 6 mg
glucose tolerance, decreased serum potassium, dia- Ganglia: 1 to 2 mg
betes mellitus, fluid retention, glycosuria, growth Brain tumor (palliative management of cerebral
suppression (children), hirsutism, HPA-axis suppres- edema or neurological deficits associated with
sion, hyperglycemia, hypokalemic alkalosis, men- recurrent or inoperable brain tumors): Oral, IV:
strual disease, moon face, negative nitrogen 2 mg 2 to 3 times daily may be effective; individualize
balance, protein catabolism, redistribution of body dose based on disease response and patient tol-
fat, sodium retention, weight gain erance.
Gastrointestinal: Abdominal distention, gastrointesti- Cerebral edema (associated with brain tumor or
nal hemorrhage, gastrointestinal perforation, hic- craniotomy): IM, IV: 10 mg IV immediately, followed
cups, increased appetite, nausea, pancreatitis, by 4 mg IM every 6 hours until cerebral edema
peptic ulcer, pruritus ani (following IV injection), subsides, then switch to oral regimen; dosage may
ulcerative esophagitis be reduced after 2 to 4 days and gradually discon-
Genitourinary: Defective (increased or decreased) tinued over 5 to 7 days
spermatogenesis
Congenital adrenal hyperplasia, classic (alterna-
Hematologic & oncologic: Kaposi sarcoma, petechial,
tive agent): Oral: 0.25 to 0.5 mg once daily; use of
tumor lysis syndrome
a liquid dosage form may be preferable to allow for
Hepatic: Hepatomegaly, increased serum transami-
better dose titration (Endocrine Society [Spe-
nases
iser 2018])
Hypersensitivity: Anaphylactoid reaction, anaphylaxis,
angioedema, hypersensitivity Cushing syndrome, diagnostic (low dose): Oral:
Infection: Infection, sterile abscess 1 mg at 11 PM, draw blood at 8 AM; greater accuracy
Local: Postinjection flare (intra-articular use) for Cushing syndrome may be achieved with 0.5 mg
Neuromuscular & skeletal: Amyotrophy, aseptic every 6 hours for 48 hours (with 24-hour urine
necrosis of bones (femoral and humoral heads), collection for 17-hydroxycorticosteroid excretion)
bone fractures, Charcot-like arthropathy, myasthe- Differentiation of Cushing syndrome due to ACTH
nia, myopathy (particularly in conjunction with neuro- excess from Cushing due to other causes: Oral:
muscular disease or neuromuscular-blocking 2 mg every 6 hours for 48 hours (with 24-hour urine
agents), osteoporosis, rupture of tendon, steroid collection for 17-hydroxycorticosteroid excretion)
myopathy, vertebral compression fracture Immune thrombocytopenia (primary), initial ther-
Ophthalmic: Exophthalmos, glaucoma, increased apy: Oral: 40 mg once daily for 4 consecutive days;
intraocular pressure, subcapsular posterior cataract if platelet count continues to remain <30,000/mm3 or
Respiratory: Pulmonary edema bleeding symptoms occur by day 10, may administer
Miscellaneous: Wound healing impairment an additional 4-day course of 40 mg once daily (Wei
Dental Usual Dosage 2016) or 40 mg once daily for 4 consecutive days, if
Erosive lichen planus and major aphthae: Oral: For 3 platelets fall below 30,000/mm3 within 6 months a
days, rinse with 15 mL dexamethasone (0.5 mg/5 mL) second course may be administered, followed by a
oral elixir 4 times/day and swallow; then for 3 days,
407
prednisone taper (Cheng 2003). Pulsed dexametha- Moderate emetic potential chemotherapy: Oral, IV:
sone dosing of 40 mg once daily for 4 days every 14 8 mg on day 1 prior to chemotherapy (in combina-
or 28 days for 4 to 6 cycles has also been used tion with a 5HT3 antagonist on day 1) and 8 mg on
(Mazzucconi 2007; Provan 2010). days 2 and 3; may be administered as 4 mg twice
Multiple sclerosis (acute exacerbation): daily (Hesketh 2017; Roila 2016)
Note: Treatment guidelines recommend the use of Low emetic potential chemotherapy: Oral, IV: 4 to
high dose IV or oral methylprednisolone for acute 8 mg prior to chemotherapy (Hesketh 2017;
exacerbations of multiple sclerosis (AAN [Scott Roila 2016)
2011], NICE 2014). Dosing when used in combination with extended-
Oral: 30 mg/day for 1 week, followed by 4 to 12 mg release granisetron (Raftopoulos 2015):
every other day for 1 month Day 1: IV: 20 mg (for highly emetic chemotherapy)
Acute mountain sickness (AMS)/high altitude cer- or 8 mg (for moderately emetic chemotherapy)
ebral edema (HACE) (off-label use): Days 2, 3, and 4: Oral: 8 mg twice daily (for highly
Prevention: Oral: 2 mg every 6 hours or 4 mg every emetic chemotherapy)
12 hours starting on the day of ascent; may be Dosing when used in combination with IV aprepitant
discontinued after staying at the same elevation (and a 5HT3 antagonist):
for 2 to 3 days or if descent is initiated; do not Highly emetic chemotherapy: Oral: 12 mg on day 1,
exceed a 10 day duration (Luks 2010). Note: In followed by 8 mg on day 2 and then 8 mg twice
situations of rapid ascent to altitudes >3500 meters daily on days 3 and 4
(such as rescue or military operations), 4 mg every Moderately emetic chemotherapy: Oral: 12 mg on
6 hours may be considered (Luks 2010). day 1 only
Treatment: Oral, IM, IV: Dexamethasone suppression test (depression/sui-
AMS: 4 mg every 6 hours (Luks 2010) cide indicator) (off-label use): Oral: 1 mg at 11 PM,
HACE: Initial: 8 mg as a single dose; Maintenance: draw blood at 8 AM the following day for plasma
4 mg every 6 hours until symptoms resolve cortisol determination
(Luks 2010) Glucocorticoid remediable aldosteronism, treat-
Accelerated fetal lung maturation (off-label use): ment (off-label use): Oral: Initial: 0.125 to 0.25 mg
IM: 6 mg every 12 hours for a total of 4 doses (ACOG once daily, preferably at bedtime to suppress early
171 2016). A single course is recommended for morning ACTH surge (Funder 2016)
women between 24 and 34 weeks of gestation, Multiple myeloma (off-label use): Note: Multiple
including those with ruptured membranes or multiple
dexamethasone-containing regimens are available
gestations, who are at risk of delivering within 7 days.
for the treatment of multiple myeloma. Refer to
A single course may be appropriate in some women
appropriate literature/guidelines for additional
beginning at 23 weeks gestation or late preterm
details.
(between 34 0/7 weeks and 36 6/7 weeks gestation).
Oral: 40 mg once daily on days 1 to 4, 9 to 12, and
A single repeat course may be considered in some
17 to 20 (as induction therapy) in combination with
women with pregnancies less than 34 weeks ges-
bortezomib and doxorubicin for 3 cycles (Sonne-
tation at risk for delivery within 7 days and who had a
veld 2012) or 40 mg once weekly on days 1, 8, 15,
course of antenatal corticosteroids >14 days prior
and 22 every 28 days (in combination with lenali-
(ACO G 171 20 16; ACOG 713 201 7; ACOG
188 2018). domide) until disease progression (Rajkumar 2010)
Airway edema or extubation (off-label use): IV: or 40 mg once weekly on days 1, 8, 15, and 22
0.5 mg/kg/dose (maximum dose: 10 mg/dose) 6 to every 28 days (in combination with pomalidomide)
12 hours prior to extubation then every 6 hours for 5 until disease progression or unacceptable toxicity
doses (Khemani 2009) or 5 mg every 6 hours for 4 (San Miguel 2013) or 40 mg once weekly on days
doses with extubation performed 24 hours after last 1, 8, 15, and 22 every 28 days (in combination with
injection (Lee 2007). ixazomib and lenalidomide) until disease progres-
Chemotherapy-associated nausea and vomiting, sion or unacceptable toxicity (Moreau 2015) or
prevention (off-label use): 28 mg orally plus 8 mg IV (prior to elotuzumab)
Highly emetic chemotherapy (in combination with an on days 1, 8, 15, and 22 every 28 days for 2 cycles,
NK1 receptor antagonist, a 5-HT3 antagonist, and followed by 28 mg orally plus 8 mg IV (prior to
olanzapine; dexamethasone dose depends on spe- elotuzumab) on days 1 and 15 and 40 mg orally
cific NK1 receptor antagonist [Hesketh 2017; Roila on days 8 and 22 every 28 days thereafter until
2016]): Oral or IV: disease progression or unacceptable toxicity (in
In combination with oral aprepitant, or netupitant- combination with elotuzumab and lenalidomide)
palonosetron: 12 mg on day 1, followed by 8 mg (Lonial 2015) or 40 mg weekly (20 mg weekly in
once daily on days 2 to 4 patients >75 years), except on days elotuzumab is
In combination with IV fosaprepitant: 12 mg on day administered (administer dexamethasone 28 mg
1, followed by 8 mg on day 2, and 8 mg twice daily orally [8 mg orally in patients >75 years] plus
on days 3 and 4 8 mg IV prior to elotuzumab) (in combination with
In combination with rolapitant: 20 mg on day 1, elotuzumab and pomalidomide) until disease pro-
followed by 8 mg twice daily on days 2 to 4 gression or unacceptable toxicity (Dimopoulos
If NK1 receptor antagonist not used: 20 mg day 1, 2018) or 40 mg once weekly on days 1, 8, 15,
followed by 8 mg twice daily on days 2 to 4 and 22 every 28 days in cycles 1 to 9, and then
High emetic potential anthracycline/cyclophospha- 40 mg once weekly on days 1, 8, and 15 every 28
mide chemotherapy: Oral, IV: 12 mg with aprepi- days beginning at cycle 10 and continuing until
tant, fosaprepitant, or netupitant/palonosetron or disease progression or unacceptable toxicity (in
20 mg with rolapitant; in combination with a 5HT3 combination with carfilzomib) (Moreau 2018) or
antagonist on day 1 and olanzapine on days 1 to 4 40 mg once weekly on days 1, 8, 15, and 22 every
(Hesketh 2017) 28 days until disease progression or unacceptable
408
toxicity (in combination with carfilzomib [through on disease severity and patient response; usual
cycle 18] and lenalidomide) (Stewart 2015). adult daily dose range: 0.75 to 9 mg/day
Oral or IV: 20 mg once daily days 1, 2, 4, 5, 8, 9, 11, Asthma exacerbation: Limited data available:
and 12 every 21 days (in combination with daratu- Infants, Children, and Adolescents: Oral, IM, IV:
mumab and bortezomib) for 8 cycles (Palumbo 0.6 mg/kg once daily as a single dose or once daily
2016) or 40 mg weekly (20 mg weekly in patients for 2 days; maximum dose: 16 mg/dose (AAP
>75 years or BMI <18.5) (in combination with [Hegenbarth 2008]; Keeney 2014; Qureshi 2001);
daratumumab and pomalidomide), except on days single dose regimens as low as 0.3 mg/kg/dose
daratumumab is administered (administer dexame- and as high as 1.7 mg/kg/dose have also been
thasone 20 mg before and the day after daratumu- reported (Keeney 2014; Qureshi 2001; Shefrin
mab infusion [20 mg prior to daratumumab infusion 2009). Note: Duration >2 days is not recommended
only in patients >75 years or BMI <18.5]); continue due to increased risk of metabolic effects
until disease progression (Chari 2017) or 20 mg on (GINA 2014).
days 1, 2, 8, 9, 15, 16, 22, and 23 every 28 days Bacterial meningitis (H. influenzae type b): Lim-
until disease progression or unacceptable toxicity ited data available: Infants >6 weeks and Children:
(in combination with carfilzomib) (Dimopoulos IV: 0.15 mg/kg/dose every 6 hours for the first 2 to 4
2016a) or 20 mg on days 1 (prior to daratumumab days of antibiotic treatment; start dexamethasone
infusion) and 2 each week (in combination with 10 to 20 minutes before or with the first dose of
daratumumab and lenalidomide) until disease pro- antibiotic; if antibiotics have already been adminis-
gression or unacceptable toxicity (Dimopoulos tered, dexamethasone use has not been shown to
2016b); for patients >75 years of age, BMI <18.5, improve patient outcome and is not recommended
poorly controlled diabetes, or corticosteroid intoler- (IDSA [Tunkel 2004]). Note: For pneumococcal
ance, a reduced dexamethasone dose of 20 mg meningitis, data has not shown clear benefit from
once a week was used (Dimopoulos 2016b; Pal- dexamethasone administration; risk and benefits
umbo 2016). should be considered prior to use (Red Book
Geriatric Refer to adult dosing. Use cautiously in the [AAP 2012]).
elderly in the smallest possible dose. Cerebral edema: Infants, Children, and Adoles-
Renal Impairment: Adult There are no dosage cents: Oral, IM, IV: Loading dose: 1 to 2 mg/kg/
adjustments provided in the manufacturer’s labeling; dose as a single dose; maintenance: 1 to
1.5 mg/kg/day in divided doses every 4 to 6 hours;
use with caution.
maximum daily dose: 16 mg/day (Kliegman 2007)
Hemodialysis: Supplemental dose is not necessary
Chemotherapy-induced nausea and vomiting,
(Aronoff 2007).
prevention: Refer to individual protocols and
Peritoneal dialysis: Supplemental dose is not neces-
emetogenic potential: Infants, Children, and Ado-
sary (Aronoff 2007).
lescents:
International Myeloma Working Group (IMWG) Rec-
POGO recommendations (Dupuis 2013): Note:
ommendations: The International Myeloma Working
Reduce dose by 50% if administered concomi-
Group (IMWG) recommendations suggest that dex-
tantly with aprepitant:
amethasone may be administered without dosage
Highly/severely emetogenic chemotherapy: Oral,
adjustment in multiple myeloma patients with renal
IV: 6 mg/m2/dose every 6 hours
impairment, including those on dialysis. The IMWG
Moderately emetogenic chemotherapy: Oral, IV:
recommends the use of the Chronic Kidney Disease
BSA ≤0.6 m2: 2 mg every 12 hours
Epidemiology Collaboration (CKD-EPI) equation
BSA >0.6 m2: 4 mg every 12 hours
(preferred) or the Modification of Diet in Renal Dis- Alternate dosing: Highly/severely emetogenic che-
ease (MDRD) formula to evaluate renal function motherapy: IV: Usual: 10 mg/m2/dose once daily
estimation in multiple myeloma patients with a stable on days of chemotherapy; some patients may
serum creatinine (Dimopoulos 2016c). require every 12-hour dosing; usual range: 8 to
Hepatic Impairment: Adult There are no dosage 14 mg/m2/dose (Holdsworth 2006; Jordan 2010;
adjustments provided in the manufacturer’s labeling. Phillips 2010); others have used: Initial: 10 mg/
Pediatric m2/dose prior to chemotherapy (maximum dose:
Acute mountain sickness (AMS) (moderate)/high 20 mg) then 5 mg/m2/dose every 6 hours (Klieg-
altitude cerebral edema (HACE); treatment: Lim- man 2007)
ited data available: Infants, Children, and Adoles- Congenital adrenal hyperplasia: Adolescents (fully
cents: Oral, IM, IV: 0.15 mg/kg/dose every 6 hours; grown): Oral: 0.25 to 0.5 mg once daily; use of a
maximum dose: 4 mg/dose; consider using for high liquid dosage form may be preferable to allow for
altitude pulmonary edema because of associated better dose titration (AAP 2010; Speiser 2010).
HACE with this condition (Luks 2010; Pollard 2001) Note: For younger patients who are still growing,
Airway edema or extubation: Limited data avail- hydrocortisone or fludrocortisone are preferred.
able: Infants, Children, and Adolescents: Oral, IM, Croup (laryngotracheobronchitis): Limited data
IV: 0.5 mg/kg/dose (maximum dose: 10 mg/dose) available; dosing regimens variable: Infants and
administered 6 to 12 hours prior to extubation then Children: Oral, IM, IV: 0.6 mg/kg once; reported
every 6 hours for 6 doses (total dexamethasone maximum dose highly variable; usual maximum
dose: 3 mg/kg) (Anene 1996; Khemani 2009; dose: 16 mg/dose (AAP [Hegenbarth 2008]); in
Tellez 1991) trials, maximum doses of 10 to 20 mg/dose have
Anti-inflammatory: Infants, Children, and Adoles- been reported with similar efficacy findings for mild
cents: Oral, IM, IV: Initial dose range: 0.02 to to moderate croup. The majority of reported expe-
0.3 mg/kg/day or 0.6 to 9 mg/m2/day in divided rience in infants are those ≥3 months of age; data
doses every 6 to 12 hours; dose depends upon available in <3 months of age is very limited (AAP
condition being treated and response of patient; [Hegenbarth 2008]; Bjornson 2004; Cruz 1995;
dosage for infants and children should be based Petrocheilou 2014; Russell 2011). In one evaluation
409
of 22 children >2 years of age, a maximum dose of pediatric patients. Withdraw therapy with gradual taper-
12 mg/dose (at 0.6 mg/kg/dose) did not decrease ing of dose.
endogenous glucocorticoid levels (Gill 2017). A
May cause hypercortisolism or suppression of hypo-
single oral dose of 0.15 mg/kg has also been
thalamic-pituitary-adrenal (HPA) axis, particularly in
shown effective in infants ≥3 months and children younger children or in patients receiving high doses
with mild to moderate croup (Russell 2004; Spar- for prolonged periods. HPA axis suppression may lead
row 2006). to adrenal crisis. Withdrawal and discontinuation of a
Physiologic replacement: Infants, Children, and corticosteroid should be done slowly and carefully.
Adolescents: Oral, IM, IV: 0.03 to 0.15 mg/kg/day Particular care is required when patients are transferred
in divided doses every 6 to 12 hours (Kliegman from systemic corticosteroids to inhaled products due to
2007) or Initial: 0.2 to 0.25 mg/m2/day adminis- possible adrenal insufficiency or withdrawal from ste-
tered once daily; some patients may require roids, including an increase in allergic symptoms. Adult
0.3 mg/m2/day (Gupta 2008) patients receiving >20 mg per day of prednisone (or
Renal Impairment: Pediatric Infants, Children, and equivalent) may be most susceptible. Fatalities have
Adolescents: There are no dosage adjustments pro- occurred due to adrenal insufficiency in asthmatic
vided in the manufacturer's labeling; use with caution. patients during and after transfer from systemic cortico-
Hemodialysis or peritoneal dialysis: Supplemental steroids to aerosol steroids; aerosol steroids do not
dose is not necessary. provide the systemic steroid needed to treat patients
Hepatic Impairment: Pediatric Infants, Children, having trauma, surgery, or infections. Dexamethasone
and Adolescents: There are no dosage adjustments does not provide adequate mineralocorticoid activity in
provided in the manufacturer's labeling. adrenal insufficiency (may be employed as a single
Mechanism of Action Dexamethasone is a long act- dose while cortisol assays are performed). In the man-
ing corticosteroid with minimal sodium-retaining poten- agement/prevention of adrenal crisis in patients with
tial. It decreases inflammation by suppression of known primary adrenal insufficiency, the Endocrine
neutrophil migration, decreased production of inflam- Society practice guidelines state dexamethasone (intra-
matory mediators, and reversal of increased capillary venous) is the least preferred alternative agent and
permeability; suppresses normal immune response. should be used only if no other glucocorticoid is avail-
Dexamethasone's mechanism of antiemetic activity is able. For the treatment of chronic primary adrenal
unknown. insufficiency (ie, physiologic replacement), dexametha-
sone (oral) is not recommended due to the risk of
Contraindications
Cushingoid side effects (ES [Bornstein 2016]). Rare
Hypersensitivity to dexamethasone or any component
cases of anaphylactoid reactions have been observed
of the formulation; systemic fungal infections
in patients receiving corticosteroids. Patients may
Documentation of allergenic cross-reactivity for cortico-
require higher doses when subject to stress (ie, trauma,
steroids is limited. However, because of similarities in surgery, severe infection).
chemical structure and/or pharmacologic actions, the
possibility of cross-sensitivity cannot be ruled out with Acute myopathy has been reported with high dose
certainty. corticosteroids, usually in patients with neuromuscular
Warnings/Precautions Corticosteroids are not transmission disorders; may involve ocular and/or res-
approved for epidural injection. Serious neurologic piratory muscles; monitor creatine kinase; recovery may
events (eg, spinal cord infarction, paraplegia, quadri- be delayed. Perineal burning, tingling, pain and pruritus
plegia, cortical blindness, stroke), some resulting in have been reported with IV administration. May occur
death, have been reported with epidural injection of more commonly in females, with higher doses, and with
corticosteroids, with and without use of fluoroscopy. rapid administration. Symptom onset is sudden and
Intra-articular injection may produce systemic as well usually resolves in <1 minute (Allan 1986; Neff 2002;
as local effects. Appropriate examination of any joint Perron 2003; Singh 2011). Corticosteroid use may
fluid present is necessary to exclude a septic process. cause psychiatric disturbances, including depression,
euphoria, insomnia, mood swings, severe depression to
Avoid injection into an infected site. Do not inject into
psychotic manifestations. Preexisting psychiatric con-
unstable joints. Patients should not overuse joints in
ditions may be exacerbated by corticosteroid use. Pro-
which symptomatic benefit has been obtained as long
longed use of corticosteroids may increase the
as the inflammatory process remains active. Frequent
incidence of secondary infection, cause activation of
intra-articular injection may result in damage to joint
latent infections, mask acute infection (including fungal
tissues. infections), prolong or exacerbate viral infections, or
Use with caution in patients with thyroid disease, hep- limit response to killed or inactivated vaccines. Expo-
atic impairment, renal impairment, cardiovascular dis- sure to chickenpox or measles should be avoided;
ease, diabetes, glaucoma, cataracts, myasthenia corticosteroids should not be used to treat ocular her-
gravis, osteoporosis, seizures, or GI diseases (divertic- pes simplex. Corticosteroids should not be used for
ulitis, fresh intestinal anastomoses, active or latent cerebral malaria, fungal infections, or viral hepatitis.
peptic ulcer, ulcerative colitis, abscess or other pyo- Close observation is required in patients with latent
genic infection) due to perforation risk. Use caution tuberculosis and/or TB reactivity; restrict use in active
following acute MI (corticosteroids have been associ- TB (only fulminating or disseminated TB in conjunction
ated with myocardial rupture). Use with caution in with antituberculosis treatment). Amebiasis should be
patients with a history of ocular herpes simplex; corneal ruled out in any patient with recent travel to tropic
perforation has occurred; do not use in active ocular climates or unexplained diarrhea prior to initiation of
herpes simplex. Not recommended for the treatment of corticosteroids. Use with extreme caution in patients
with Strongyloides infections; hyperinfection, dissemi-
optic neuritis; may increase frequency of new episodes.
nation and fatalities have occurred.
Use with caution in the elderly with the smallest possi-
ble effective dose for the shortest duration. May affect Prolonged treatment with corticosteroids has been
growth velocity; growth should be routinely monitored in associated with the development of Kaposi sarcoma
410
(case reports); if noted, discontinuation of therapy Fusidic Acid (Systemic); Idelalisib; Indium 111 Capro-
should be considered (Goedert 2002). High-dose corti- mab Pendetide; Lapatinib; Macimorelin; Mifamurtide;
costeroids should not be used to manage acute head MiFEPRIStone; Natalizumab; Pimecrolimus; Rilpivir-
injury (BTF [Carney 2016]). Some products may contain ine; Simeprevir; Tacrolimus (Topical)
sodium sulfite, a sulfite that may cause allergic-type Increased Effect/Toxicity
reactions including anaphylaxis and life-threatening or Dexamethasone (Systemic) may increase the levels/
less severe asthmatic episodes in susceptible patients. effects of: Acetylcholinesterase Inhibitors; Amphoter-
Potentially significant drug-drug interactions may exist, icin B; Androgens; Baricitinib; CycloSPORINE (Sys-
requiring dose or frequency adjustment, additional mon- temic); Deferasirox; Desirudin; Desmopressin;
itoring, and/or selection of alternative therapy. Some Fingolimod; Fosphenytoin; Leflunomide; Lenalido-
dosage forms may contain propylene glycol; large mide; Loop Diuretics; Natalizumab; Nicorandil; Non-
amounts are potentially toxic and have been associated steroidal Anti-Inflammatory Agents (COX-2 Selective);
hyperosmolality, lactic acidosis, seizures, and respira- Nonsteroidal Anti-Inflammatory Agents (Nonselec-
tory depression; use caution (AAP ["Inactive" 1997]; tive); Phenytoin; Quinolones; Ritodrine; Sargramos-
Zar 2007). tim; Siponimod; Thalidomide; Thiazide and Thiazide-
Benzyl alcohol and derivatives: Some dosage forms Like Diuretics; Tofacitinib; Vaccines (Live); Warfarin
may contain sodium benzoate/benzoic acid; benzoic The levels/effects of Dexamethasone (Systemic) may
acid (benzoate) is a metabolite of benzyl alcohol; large be increased by: Aprepitant; Asparaginase (E. coli);
amounts of benzyl alcohol (≥99 mg/kg/day) have been Asparaginase (Erwinia); Cladribine; Clofazimine; Con-
associated with a potentially fatal toxicity ("gasping ivaptan; CycloSPORINE (Systemic); CYP3A4 Inhibi-
syndrome") in neonates; the "gasping syndrome" con- tors (Moderate); CYP3A4 Inhibitors (Strong);
sists of metabolic acidosis, respiratory distress, gasping Denosumab; DilTIAZem; Duvelisib; Estrogen Deriva-
respirations, CNS dysfunction (including convulsions, tives; Fosamprenavir; Fosaprepitant; Fosnetupitant;
intracranial hemorrhage), hypotension, and cardiovas- Fusidic Acid (Systemic); Idelalisib; Indacaterol; Laro-
cular collapse (AAP ["Inactive" 1997]; CDC 1982); some trectinib; MiFEPRIStone; Netupitant; Neuromuscular-
data suggests that benzoate displaces bilirubin from Blocking Agents (Nondepolarizing); Ocrelizumab; Pal-
protein binding sites (Ahlfors 2001); avoid or use dos- bociclib; P-glycoprotein/ABCB1 Inhibitors; Pimecroli-
age forms containing benzyl alcohol derivative with mus; Ranolazine; Roflumilast; Salicylates; Stiripentol;
caution in neonates. See manufacturer's labeling. Tacrolimus (Topical); Trastuzumab
Warnings: Additional Pediatric Considerations Decreased Effect
May cause osteoporosis (at any age) or inhibition of
Dexamethasone (Systemic) may decrease the levels/
bone growth in pediatric patients. Use with caution in
effects of: Aldesleukin; Antidiabetic Agents; Axicabta-
patients with osteoporosis. In a population-based study
gene Ciloleucel; BCG (Intravesical); Calcitriol (Sys-
of children, risk of fracture was shown to be increased
temic); Caspofungin; CloZAPine; Cobicistat;
with >4 courses of corticosteroids; underlying clinical
Coccidioides immitis Skin Test; Corticorelin; Cosyntro-
condition may also impact bone health and osteoporotic
pin; CycloSPORINE (Systemic); Daclatasvir; Dasati-
effect of corticosteroids (Leonard, 2007). In premature
nib; Elvitegravir; Fosamprenavir; Fosphenytoin;
neonates, the use of high-dose dexamethasone
Hyaluronidase; Imatinib; Indium 111 Capromab Pen-
(approximately >0.5 mg/kg/day) for the prevention or
detide; Isoniazid; Ixabepilone; Lapatinib; Macimorelin;
treatment of BPD has been associated with adverse
Mifamurtide; Nalmefene; NiMODipine; Nivolumab;
neurodevelopmental outcomes, including higher rates
Phenytoin; Pidotimod; Rilpivirine; Salicylates; Sime-
of cerebral palsy without additional clinical benefit over
previr; Sipuleucel-T; Somatropin; SUNItinib; Tacroli-
lower doses; current data does not support use of high
doses, further studies are needed (Watterberg, 2010). mus (Systemic); Temsirolimus; Tertomotide;
Increased IOP may occur especially with prolonged Tisagenlecleucel; Triazolam; Urea Cycle Disorder
use; in children, increased IOP has also been shown Agents; Vaccines (Inactivated); Vaccines (Live); Vor-
to be dose-dependent with a greater IOP observed in iconazole
children <6 years than older children after ophthalmic The levels/effects of Dexamethasone (Systemic) may
dexamethasone application; monitor closely (Lam be decreased by: Antacids; Bile Acid Sequestrants;
2005). Bosentan; CYP3A4 Inducers (Moderate); CYP3A4
Some dosage forms may contain propylene glycol; in Inducers (Strong); Dabrafenib; Deferasirox; Echina-
neonates large amounts of propylene glycol delivered cea; Enzalutamide; Fosphenytoin; Ivosidenib; Lorlati-
orally, intravenously (eg, >3,000 mg/day), or topically nib; MiFEPRIStone; Mitotane; Phenytoin; Pitolisant;
have been associated with potentially fatal toxicities Sarilumab; Siltuximab; St John's Wort; Tocilizumab
which can include metabolic acidosis, seizures, renal Dietary Considerations May be taken with meals to
failure, and CNS depression; toxicities have also been decrease GI upset. May need diet with increased
reported in children and adults including hyperosmolal- potassium, pyridoxine, vitamin C, vitamin D, folate,
ity, lactic acidosis, seizures and respiratory depression; calcium, and phosphorus.
use caution (AAP 1997; Shehab 2009). Pharmacodynamics/Kinetics
Drug Interactions Onset of Action
Metabolism/Transport Effects Substrate of Acetate: IV: Rapid
CYP3A4 (major), P-glycoprotein/ABCB1; Note: Immune thrombocytopenia: Oral: Initial response: 2 to
Assignment of Major/Minor substrate status based 14 days; Peak response: 4 to 28 days (Neu-
on clinically relevant drug interaction potential; Indu- nert 2011)
ces CYP3A4 (weak) Duration of Action IV: Short
Avoid Concomitant Use Half-life Elimination
Avoid concomitant use of Dexamethasone (Systemic) Extremely low birth-weight infants with BPD: 9.26 ±
with any of the following: Aldesleukin; BCG (Intra- 3.34 hours (range: 5.85 to 16.1 hours) (Charles
vesical); Cladribine; Conivaptan; Desmopressin; 1993)
411
Children 4 months to 16 years: 4.34 ± 4.14 hours cause adverse events in a breastfeeding infant (eg,
(range: 2.33 to 9.54 hours) (Richter 1983) growth suppression, interfere with endogenous cortico-
Adults: Oral: 4 ± 0.9 hours (Czock 2005); IV: ~1 to 5 steroid production). Due to the potential for serious
hours (Hochhaus 2001; Miyabo 1981; Rohdewald adverse reactions in the breastfeeding infant, the man-
1987; Tóth 1999) ufacturer recommends a decision be made whether to
Time to Peak Serum: Oral: 1 to 2 hours (Czock 2005); discontinue breastfeeding or to discontinue the drug,
IM: ~30 to 120 minutes (Egerman 1997; Hochhaus taking into account the importance of treatment to the
2001); IV: 5 to 10 minutes (free dexamethasone) mother. Single doses of dexamethasone are consid-
(Miyabo 1981; Rohdewald 1987) ered compatible with breastfeeding; information related
Pregnancy Risk Factor C to prolonged use is not available (WHO 2002). If there is
Pregnancy Considerations Adverse events have concern about exposure to the infant, some guidelines
been observed with corticosteroids in animal reproduc- recommend waiting 4 hours after the maternal dose of
tion studies. Dexamethasone crosses the placenta an oral systemic corticosteroid before breastfeeding in
(Brownfoot 2013); and is partially metabolized by pla- order to decrease potential exposure to the breastfed
cental enzymes to an inactive metabolite (Murphy infant (based on a study using prednisolone) (Bae
2007). Some studies have shown an association 2012; Leachman 2006; Makol 2011; Ost 1985).
between first trimester systemic corticosteroid use and Dosage Forms: US
oral clefts or decreased birth weight; however, informa- Concentrate, Oral:
tion is conflicting and may be influenced by maternal Dexamethasone Intensol: 1 mg/mL (30 mL)
dose/indication for use (Lunghi 2010; Park-Wyllie 2000; Elixir, Oral:
Pradat 2003). Hypoadrenalism may occur in newborns Decadron: 0.5 mg/5 mL (237 mL)
following maternal use of corticosteroids during preg- Generic: 0.5 mg/5 mL (237 mL)
nancy; monitor. Kit, Injection:
ReadySharp Dexamethasone: 10 mg/mL
Because antenatal corticosteroid administration may TopiDex: 10 mg/mL
reduce the incidence of intraventricular hemorrhage, Kit, Injection [preservative free]:
necrotizing enterocolitis, neonatal mortality, and respi- Active Injection D: 10 mg/mL
ratory distress syndrome, the injection is often used for DoubleDex: 10 mg/mL
antenatal fetal lung maturation in patients with preterm MAS Care-Pak: 10 mg/mL
premature rupture of membranes or preterm labor who Solution, Injection:
are at risk of preterm delivery (most data is available for Generic: 4 mg/mL (1 mL); 20 mg/5 mL (5 mL);
betamethasone). A single course of corticosteroids is 120 mg/30 mL (30 mL); 10 mg/mL (1 mL); 100 mg/
recommended for women between 24 and 34 weeks' 10 mL (10 mL)
gestation who are at risk of delivering within 7 days, Solution, Injection [preservative free]:
including those with ruptured membranes or multiple Generic: 4 mg/mL (1 mL); 10 mg/mL (1 mL)
gestations. A single course of corticosteroids may be Solution, Oral:
considered for women beginning at 23 weeks' gesta- Generic: 0.5 mg/5 mL (240 mL, 500 mL)
tion, who are at risk of delivering within 7 days, in Tablet, Oral:
consultation with the family. In addition, a single course Decadron: 0.5 mg, 0.75 mg, 4 mg, 6 mg
of corticosteroids may be given to women between Generic: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg,
34 0/7 weeks and 36 6/7 weeks who are at risk of 4 mg, 6 mg
preterm delivery within 7 days and who have not Tablet Therapy Pack, Oral:
previously received corticosteroids; use of concomitant DexPak 10 Day: 1.5 mg (35 ea)
tocolytics is not currently recommended and adminis- DexPak 13 Day: 1.5 mg (51 ea)
tration of late preterm corticosteroids has not been DexPak 6 Day: 1.5 mg (21 ea)
evaluated in women with intrauterine infection, multiple Dxevo 11-Day: 1.5 mg (39 ea)
gestations, pregestational diabetes, or women who HiDex 6-Day: 1.5 mg (21 ea)
delivered previously by cesarean section at term. Multi- TaperDex 12-Day: 1.5 mg (49 ea)
ple repeat courses are not recommended. However, in TaperDex 6-Day: 1.5 mg (21 ea)
women with pregnancies less than 34 weeks' gestation TaperDex 7-Day: 1.5 mg (27 ea)
at risk for delivery within 7 days and who had a course Generic: 1.5 mg (21 ea)
of antenatal corticosteroids >14 days prior, a single
repeat course may be considered; use of a repeat Dexchlorpheniramine (deks klor fen EER a meen)
course in women with premature rupture of membranes
is controversial (ACOG 171 2016; ACOG 713 2017; Brand Names: US RyClora
ACOG 188 2018). Pharmacologic Category Alkylamine Derivative; His-
tamine H1 Antagonist; Histamine H1 Antagonist, First
When systemic corticosteroids are needed in preg-
Generation
nancy, it is generally recommended to use the lowest
effective dose for the shortest duration of time, avoiding Use Hypersensitivity reactions: For the treatment of
high doses during the first trimester (Leachman 2006; perennial and seasonal allergic rhinitis; vasomotor rhi-
Lunghi 2010; Makol 2011; Østensen 2009). Dexame- nitis; allergic conjunctivitis; mild, uncomplicated allergic
skin manifestations of urticaria and angioedema; ameli-
thasone should not be used to treat primary adrenal
oration of allergic reactions to blood or plasma; derma-
insufficiency or congenital adrenal hyperplasia in preg-
tographism; adjunctive therapy for the management of
nant women (ES [Bornstein 2016]; ES [Speiser 2018]).
anaphylactic reactions.
Breastfeeding Considerations Corticosteroids are
present in breast milk; information specific to dexame-
thasone has not been located.
The manufacturer notes that when used systemically, related to dental treatment: Significant xerostomia (nor-
maternal use of corticosteroids have the potential to mal salivary flow resumes upon discontinuation)
412
DEXLANSOPRAZOLE
Effects on Bleeding No information available to flow resumes upon discontinuation) and taste alteration
require special precautions has been reported in <2% of patients.
Adverse Reactions Frequency not defined. Effects on Bleeding No information available to
Cardiovascular: Chest tightness require special precautions
Central nervous system: Ataxia, chills, confusion, con- Adverse Reactions Incidence reported for adults
vulsions, dizziness, drowsiness (slight to moderate), unless otherwise specified.
euphoria, excitement, fatigue, hysteria, insomnia, irri- 1% to 10%:
tability, nervousness, neuritis, paresthesia, restless- Cardiovascular: Angina pectoris (<2%), bradycardia
ness, sedation, vertigo (<2%), cardiac arrhythmia (<2%), chest pain (<2%),
Dermatologic: Diaphoresis, skin photosensitivity, skin deep vein thrombosis (<2%), edema (<2%; including
rash (due to drug), urticaria oral, facial, and pharyngeal), hypertension (<2%),
Gastrointestinal: Anorexia, constipation, diarrhea, epi- palpitations (<2%), tachycardia (<2%)
gastric distress, nausea, vomiting, xerostomia Central nervous system: Headache (adolescents:
Genitourinary: Difficulty in micturition, early menses, ≥5%; adults: <2%), abnormal dreams (<2%), anxiety
urinary frequency, urinary retention (<2%), chills (<2%), depression (<2%), dizziness
Hematologic & oncologic: Agranulocytosis, hemolytic (<2%), falling (<2%), feeling abnormal (<2%), insom-
anemia, thrombocytopenia nia (<2%), memory impairment (<2%), migraine
Hypersensitivity: Anaphylactic shock (<2%), myocardial infarction (<2%), pain (<2%),
Neuromuscular & skeletal: Tremor painful defecation (<2%), procedural pain (<2%),
Ophthalmic: Blurred vision, diplopia psychomotor agitation (<2%), seizure (<2%), trige-
Otic: Acute labyrinthitis, tinnitus minal neuralgia (<2%), vertigo (<2%)
Respiratory: Dry nose, dry throat, nasal congestion, Dermatologic: Acne vulgaris (<2%), dermatitis (<2%),
thickening of bronchial secretions, wheezing erythema (<2%), pruritus (<2%), skin lesion (<2%),
Mechanism of Action Dexchlorpheniramine com- skin rash (<2%), sunburn (<2%), urticaria (<2%)
petes with histamine for H1-receptor sites on effector Endocrine & metabolic: Change in libido (<2%), goiter
cells in the gastrointestinal tract, blood vessels, and (<2%), heavy menstrual bleeding (<2%), hot flash
respiratory tract. Dexchlorpheniramine is the predom- (<2%), hypercalcemia (<2%), hypokalemia (<2%),
inant active isomer of chlorpheniramine and is approx- increased gastrin (<2%), increased serum glucose
imately twice as active as the racemic compound (<2%), increased serum potassium (<2%), increased
(Moreno 2010). serum total protein (<2%), menstrual disease (<2%),
Pharmacodynamics/Kinetics weight gain (<2%)
Half-life Elimination 20 to 30 hours (Moreno 2010) Gastrointestinal: Abdominal pain (adolescents: ≥5%),
Time to Peak ~3 hours (Moreno 2010) diarrhea (adolescents and adults: ≥5%), flatulence
Pregnancy Considerations Maternal antihistamine (1% to 3%), abdominal distress (<2%), abdominal
use has generally not resulted in an increased risk of tenderness (<2%), abnormal bowel sounds (<2%),
birth defects; however, information specific to dexchlor- abnormal stools (<2%), anorectal pain (<2%), Barrett
pheniramine is limited (Källén 2002). Dexchlorphenir- esophagus (<2%), bezoar formation (<2%), biliary
amine is the dextro-isomer of chlorpheniramine. colic (<2%), change in appetite (<2%), cholelithiasis
Antihistamines may be used for the treatment of rhinitis, (<2%), colitis (microscopic; <2%), colonic polyps
urticaria, and pruritus with rash in pregnant women (<2%), constipation (<2%), delayed gastric emptying
(although second generation antihistamines may be (<2%), duodenitis (<2%), dysgeusia (<2%), dyspep-
preferred) (Murase 2014; Wallace 2008; Zuberbier sia (<2%), dysphagia (<2%), enteritis (<2%), eructa-
2014). Antihistamines are not recommended for treat- tion (<2%), esophagitis (<2%), gastric polyp (<2%),
ment of pruritus associated with intrahepatic cholestasis gastritis (<2%), gastroenteritis (<2%), gastroesopha-
in pregnancy (Ambros-Rudolph 2011; Kremer 2011). geal reflux disease (<2%), gastrointestinal disease
(<2%), gastrointestinal hypermotility (<2%), gastro-
intestinal perforation (<2%), gastrointestinal ulcer
Dexlansoprazole (deks lan SOE pra zole) (<2%), halitosis (<2%), hematemesis (<2%), hema-
tochezia (<2%), hemorrhoids (<2%), hiccups (<2%),
Related Information
irritable bowel syndrome (<2%), mucosal inflamma-
Gastrointestinal Disorders on page 1465 tion (<2%), mucus stools (<2%), oral bullae (<2%),
Brand Names: US Dexilant oral herpes simplex infection (<2%), oral paresthesia
Brand Names: Canada Dexilant (<2%), proctitis (<2%), retching (<2%), sore throat
Pharmacologic Category Proton Pump Inhibitor; (<2%), vomiting (2%), xerostomia (<2%)
Substituted Benzimidazole Genitourinary: Dysmenorrhea (<2%), dyspareunia
Use (<2%), dysuria (<2%), urinary urgency (<2%), vulvo-
Erosive esophagitis: Healing of all grades of erosive vaginal infection (<2%)
esophagitis in patients ≥12 years of age for up to 8 Hematologic & oncologic: Anemia (<2%), decreased
weeks; to maintain healing of erosive esophagitis and platelet count (<2%), lymphadenopathy (<2%), rectal
relief of heartburn for up to 6 months in adults and 16 hemorrhage (<2%)
weeks in patients 12 to 17 years of age. Hepatic: Abnormal hepatic function tests (<2%),
Gastroesophageal reflux disease: Treatment of decreased serum bilirubin (<2%), hepatomegaly
heartburn associated with symptomatic nonerosive (<2%), increased serum alkaline phosphatase
gastroesophageal reflux disease (GERD) in patients (<2%), increased serum alanine aminotransferase
≥12 years of age for 4 weeks. (<2%), increased serum aspartate aminotransferase
Local Anesthetic/Vasoconstrictor Precautions (<2%), increased serum bilirubin (<2%)
No information available to require special precautions Hypersensitivity: Hypersensitivity reaction (<2%)
Effects on Dental Treatment Key adverse event(s) Infection: Candidiasis (<2%), influenza (<2%), viral
related to dental treatment: Xerostomia (normal salivary infection (<2%)
413
DEXLANSOPRAZOLE
Neuromuscular & skeletal: Arthralgia (<2%), arthritis salivation (normal salivary flow resumes upon discon-
(<2%), asthenia (<2%), bone fracture (<2%), joint tinuation)
sprain (<2%), muscle cramps (<2%), musculoskele- Effects on Bleeding No information available to
tal pain (<2%), myalgia (<2%), tremor (<2%) require special precautions
Ophthalmic: Eye irritation (<2%), swelling of Adverse Reactions Frequency dependent upon dose,
eye (<2%) duration, and indication.
Otic: Otalgia (<2%), tinnitus (<2%) >10%:
Renal: Increased serum creatinine (<2%) Cardiovascular: Hypotension (24% to 56%), bradycar-
Respiratory: Nasopharyngitis (adolescents: ≥5%; dia (5% to 42%), systolic hypertension (28%), tachy-
adults: <2%), oropharyngeal pain (adolescents: cardia (25%), hypertension (diastolic; 12%),
≥5%), upper respiratory tract infection (2% to 3%), hypertension (11%)
asthma (<2%), bronchitis (<2%), cough (<2%), dysp- Central nervous system: Agitation (5% to 14%)
nea (<2%), hyperventilation (<2%), pharyngitis Gastrointestinal: Constipation (6% to 14%), nausea
(<2%), pulmonary aspiration (<2%), respiratory con- (3% to 11%)
gestion (<2%), sinusitis (<2%) Respiratory: Respiratory depression (37%; pla-
Miscellaneous: Fever (<2%), inflammation (<2%), cebo 32%)
nodule (<2%) 1% to 10%:
<1%, postmarketing, and/or case reports: Acute renal Cardiovascular: Atrial fibrillation (2% to 9%), periph-
failure, anaphylactic shock, autoimmune hemolytic eral edema (3% to 7%), hypovolemia (3%),
anemia, blurred vision, cerebrovascular accident, edema (2%)
chronic renal failure (Lazarus 2016), Clostridioides Central nervous system: Anxiety (5% to 9%)
(formerly Clostridium) difficile-associated diarrhea, Endocrine & metabolic: Hypokalemia (9%), hypergly-
constriction of the pharynx, deafness, exfoliative der- cemia (7%), hypoglycemia (5%), increased thirst
matitis, hepatitis, hepatotoxicity (idiosyncratic) (Chala- (2%), hypocalcemia (1%), hypomagnesemia (1%)
sani 2014), hypersensitivity angiitis, Gastrointestinal: Xerostomia (3% to 4%)
hypomagnesemia, hyponatremia, immune thrombocy- Genitourinary: Oliguria (2%)
topenia, pancreatitis, polyp (fundic gland), Stevens- Hematologic & oncologic: Anemia (3%)
Johnson syndrome, toxic epidermal necrolysis, tran- Renal: Acute renal failure (2% to 3%), decreased urine
sient ischemic attacks output (1%)
Mechanism of Action Proton pump inhibitor; Respiratory: Respiratory failure (2% to 10%), adult
decreases acid secretion in gastric parietal cells respiratory distress syndrome (1% to 9%), pleural
through inhibition of (H+, K+)-ATPase enzyme system, effusion (2%), wheezing (≤1%)
blocking the final step in gastric acid production Miscellaneous: Fever (5% to 7%), withdrawal syn-
Pharmacodynamics/Kinetics drome (ICU sedation; 3% to 5%)
Half-life Elimination ~1 to 2 hours Postmarketing and/or case reports: Abdominal pain,
Time to Peak Serum: Two distinct peaks secondary to acidosis, apnea, atrioventricular block, broncho-
dual release formulation: Initial peak between 1 and 2 spasm, cardiac arrhythmia, cardiac disease, chills,
hours and a second higher peak between 4 and 5 confusion, convulsions, decreased visual acuity, delir-
hours. ium, diaphoresis, diarrhea, dizziness, drug tolerance
Pregnancy Considerations Adverse events have not (use >24 hours), dyspnea, extrasystoles, hallucina-
been observed in animal reproduction studies. tion, headache, heart block, hemorrhage, hepatic
insufficiency, hyperbilirubinemia, hypercapnia, hyper-
Recommendations for the treatment of GERD in preg-
kalemia, hypernatremia, hyperpyrexia, hypoventila-
nancy are available. As in nonpregnant patients, life-
tion, hypoxia, illusion, increased blood urea nitrogen,
style modifications followed by other medications are
increased gamma-glutamyl transferase, increased
the initial treatments (Body 2016; Huerta-Iga 2016; Katz
serum alkaline phosphatase, increased serum ALT,
2013; van der Woude 2014). Based on available data,
increased serum AST, inversion T-wave on ECG,
PPIs may be used when clinically indicated (use of
myocardial infarction, neuralgia, neuritis, pain, photop-
agents with more available data may be preferred)
sia, polyuria, prolonged Q-T interval on ECG, pulmo-
(Body 2016; Matok 2012; Pasternak 2010; van der
nary congestion, respiratory acidosis, rigors, seizure,
Woude 2014).
sinoatrial arrest, speech disturbance, supraventricular
tachycardia, tachyphylaxis (use >24 hours), variable
Dexmedetomidine (deks MED e toe mi deen) blood pressure, ventricular arrhythmia, ventricular
tachycardia, visual disturbance, vomiting
Brand Names: US Precedex Mechanism of Action Selective alpha2-adrenoceptor
Brand Names: Canada Precedex agonist with anesthetic and sedative properties thought
Pharmacologic Category Alpha2-Adrenergic Agonist; to be due to activation of G-proteins by alpha2a-adre-
Sedative noceptors in the brainstem resulting in inhibition of
Use norepinephrine release; peripheral alpha2b-adrenocep-
Intensive care unit sedation: Sedation of initially- tors are activated at high doses or with rapid IV admin-
intubated and mechanically-ventilated patients during istration resulting in vasoconstriction.
treatment in an intensive care setting Pharmacodynamics/Kinetics
Procedural sedation: Procedural sedation prior to and/ Onset of Action
or during awake fiberoptic intubation; sedation prior to IV loading dose: 5 to 10 minutes
and/or during surgical or other procedures of non- Intranasal: 45 to 60 minutes (Yuen 2007), may be
intubated patients faster in pediatric patients when administered via
Local Anesthetic/Vasoconstrictor Precautions an atomizing device (Talon 2009)
No information available to require special precautions Peak effect:
Effects on Dental Treatment Key adverse event(s) IV loading dose: 15 to 30 minutes
related to dental treatment: Xerostomia and changes in Intranasal: 90 to 105 minutes (Yuen 2007)
414
DEXTROAMPHETAMINE
Duration of Action Dose dependent: 60 to 120 Miscellaneous: Fever (children and adolescents: 5%)
minutes Frequency not defined:
Half-life Elimination C e n t r a l n e r v o u s s y s t em : D r u g a b u s e, d r u g
Preterm Neonates (28 to <36 weeks GA): Terminal: dependence
7.6 hours (range: 3 to 9.1 hours) (Chrysostomou Endocrine & metabolic: Growth suppression,
2014) weight loss
Term Neonates (36 to ≤44 weeks GA): Terminal: <1%, postmarketing, and/or case reports: Anaphylaxis,
Median: 3.2 hours (range: 1 to 9.4 hours) (Chrys- angioedema, hypersensitivity reactions, peripheral
ostomou 2014) vascular disease, Raynaud disease, rhabdomyolysis
Infants and Children <2 years: Terminal: Median: 2.3 Mechanism of Action Dexmethylphenidate is the
hours (range: 1.5 to 3.3 hours) (Vilo 2008) more active, d-threo-enantiomer, of racemic methylphe-
Children 2 to 11 years: Terminal: Median: 1.6 hours nidate. It is a CNS stimulant; blocks the reuptake of
(range: 1.2 to 2.3 hours) (Vilo 2008) norepinephrine and dopamine, and increases their
Adults: Distribution: ~6 minutes; Terminal: ~up to 3 release into the extraneuronal space.
hours (Venn 2002); significantly prolonged in Pharmacodynamics/Kinetics
patients with severe hepatic impairment (Cunning- Onset of Action Rapid, within 1 to 2 hours of an
ham 1999) effective dose
Time to Peak Serum: Intranasal: Median: 38 minutes Duration of Action Immediate release: 3 to 5 hours;
(range: 15 to 60 minutes) (Iirola 2011) extended release: 9 to 12 hours (Dopheide 2009)
Pregnancy Risk Factor C Half-life Elimination Immediate release: Children: 2
Pregnancy Considerations Adverse effects have to 3 hours; Adults: 3 hours
been observed in some animal reproduction studies. Time to Peak Fasting:
Dexmedetomidine is expected to cross the placenta. Immediate release: 1 to 1.5 hours; after a high-fat
Information related to use during pregnancy is limited meal: 2.9 hours
(El-Tahan 2012). Extended release: First peak: 1.5 hours (range: 1 to 4
hours); Second peak: 6.5 hours (range: 4.5 to 7
hours)
Dexmethylphenidate (dex meth il FEN i date)
Brand Names: US Focalin; Focalin XR Pregnancy Considerations Adverse events have
Pharmacologic Category Central Nervous System been observed in animal reproduction studies. Dexme-
Stimulant thylphenidate is the more active d-threo enantiomer of
racemic methylphenidate; refer to Methylphenidate
Use ADHD: Treatment of ADHD
monograph for additional information
Controlled Substance C-II
related to dental treatment: Dexmethylphenidate Dextroamphetamine (deks troe am FET a meen)
causes tachycardia, increases in blood pressure, and
palpitations. Consider monitoring blood pressure prior Brand Names: US Dexedrine; ProCentra; Zenzedi
to using local anesthetic with a vasoconstrictor. Symp- Brand Names: Canada Dexedrine
toms associated with bruxism have been observed in Pharmacologic Category Central Nervous System
some patients. Stimulant
Effects on Bleeding No information available to Use
require special precautions Attention-deficit/hyperactivity disorder: Treatment
Adverse Reactions Actual frequency may be depend- of attention-deficit/hyperactivity disorder (ADHD) as
ent upon dose and/or formulation. Also refer to Methyl- part of a total treatment program that typically includes
phenidate for adverse effects seen with other other remedial measures (psychological, educational,
methylphenidate products. social) for a stabilizing effect in children 3 to 16 years
>10%: of age.
Central nervous system: Headache (adults: 26% to Narcolepsy: Treatment of narcolepsy.
39%; children and adolescents: 25%), insomnia (chil- Local Anesthetic/Vasoconstrictor Precautions
dren and adolescents: 5% to 17%), jitteriness Use vasoconstrictor with caution in patients taking
(adults: 12%), anxiety (5% to 11%) dextroamphetamine. Amphetamines enhance the sym-
Gastrointestinal: Decreased appetite (children and pathomimetic response of epinephrine and norepi-
adolescents: 30%), xerostomia (adults: 7% to nephrine leading to potential hypertension and
20%), abdominal pain (children and adoles- cardiotoxicity.
cents: 15%) Effects on Dental Treatment Key adverse event(s)
1% to 10%: related to dental treatment: Dextroamphetamine causes
Central nervous system: Dizziness (adults: 6%), irrita- tachycardia, increases in blood pressure, and palpita-
bility (children and adolescents: 2% to 5%), depres- tions. Consider monitoring blood pressure prior to using
sion (children and adolescents: 3%), emotional local anesthetic with a vasoconstrictor. Symptoms asso-
lability (children and adolescents: 3%) ciated with bruxism have been observed in some
Dermatologic: Pruritus (children and adolescents: 3%) patients.
Gastrointestinal: Nausea (children and adolescents: Effects on Bleeding No information available to
9%), dyspepsia (5% to 9%), vomiting (children and require special precautions
adolescents: 2% to 9%), anorexia (children and Adverse Reactions Frequency not defined.
adolescents: 5% to 7%) Cardiovascular: Cardiomyopathy, hypertension, palpita-
Respiratory: Pharyngolaryngeal pain (adults: 4% to tions, tachycardia
7%), nasal congestion (children and adoles- Central nervous system: Aggressive behavior, dizzi-
cents: 5%) ness, dysphoria, euphoria, exacerbation of tics, Gilles
415
DEXTROAMPHETAMINE
de la Tourette syndrome, headache, insomnia, mania, Effects on Bleeding No information available to

overstimulation, psychosis, restlessness require special precautions
Dermatologic: Alopecia, urticaria Adverse Reactions Frequency not always defined.
Endocrine & metabolic: Change in libido, weight loss Cardiovascular: Systolic hypertension (extended
Gastrointestinal: Anorexia, constipation, diarrhea, release; adolescents: 12% to 35%; dose related; tran-
unpleasant taste, xerostomia sient), tachycardia (extended release; adults: ≤6%),
Genitourinary: Frequent erections, impotence, pro- palpitations (extended release: 2% to 4%), increased
longed erection blood pressure, myocardial infarction, Raynaud's phe-
Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis, nomenon
tremor Central nervous system: Insomnia (extended release:
Ophthalmic: Accommodation disturbances, blurred 8% to 31%), headache (extended release; adults:
vision ≤26%), emotional lability (extended release: 2% to
Mechanism of Action Amphetamines are noncate- 9%), anxiety (extended release; adults: 7% to 8%),
cholamine, sympathomimetic amines that promote agitation (extended release; adults: 2% to ≤8%), dizzi-
release of catecholamines (primarily dopamine and ness (extended release: 2% to 7%), irritability (6%),
norepinephrine) from their storage sites in the presy- fatigue (extended release: 2% to 6%), drowsiness
naptic nerve terminals. A less significant mechanism (extended release: 2% to 4%), speech disturbance
may include their ability to block the reuptake of cat- (extended release: 2% to 4%), twitching (extended
echolamines by competitive inhibition. release: 2% to 4%), depression (3%), jitteriness
Pharmacodynamics/Kinetics (2%), aggressive behavior, dysphoria, euphoria, exac-
Duration of Action Immediate release: 4 to 6 hours; erbation of vocal tics, formication, outbursts of anger,
extended release: 8 hours (Dopheide 2009) overstimulation, paresthesia, psychosis, restlessness,
Half-life Elimination Adults: 10 to 12 hours talkativeness
Time to Peak Serum: Immediate release: ~3 hours; Dermatologic: Diaphoresis (extended release: 2% to
Sustained release: ~8 hours 4%), skin photosensitivity (extended release: 2% to
Pregnancy Considerations Adverse effects have 4%), alopecia, dermatillomania, skin rash, urticaria
been observed in animal reproduction studies. The Endocrine & metabolic: Weight loss (extended release:
majority of human data is based on illicit amphet- 4% to 10%), decreased libido (extended release: 2%
amine/methamphetamine exposure and not from ther- to 4%), dysmenorrhea (extended release: 2% to 4%)
apeutic maternal use (Golub 2005). Use of Gastrointestinal: Decreased appetite (extended
amphetamines during pregnancy may lead to an release: 22% to 36%), xerostomia (extended release:
increased risk of premature birth and low birth weight; 2% to 35%), abdominal pain (extended release: 11%
newborns may experience symptoms of withdrawal. to 14%), nausea (extended release: 2% to 8%), vomit-
Behavioral problems may also occur later in childhood ing (extended release: 2% to 7%), diarrhea (extended
(LaGasse 2012). release: 2% to 6%), constipation (extended release:
Controlled Substance C-II 2% to 4%), dyspepsia (extended release: 2% to 4%),
teeth clenching (extended release: ≤4%), tooth infec-
Dextroamphetamine and tion (extended release: ≤4%), anorexia (extended
release: 2%), bruxism (2%), unpleasant taste
Amphetamine Genitourinary: Urinary tract infection (extended release:
(deks troe am FET a meen & am FET a meen)
5%), upper abdominal pain (adolescents: 4%), impo-
Related Information tence (extended release: 2% to 4%), erectile dysfunc-
Dextroamphetamine on page 415 tion (2%), frequent erections, prolonged erections
Brand Names: US Adderall; Adderall XR; Mydayis Hypersensitivity: Anaphylaxis, angioedema, hypersen-
Brand Names: Canada Adderall XR sitivity reaction
Pharmacologic Category Central Nervous System Infection: Infection (extended release: 2% to 4%)
Stimulant Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis,
Use tremor
Attention-deficit/hyperactivity disorder: Treatment Ophthalmic: Blurred vision, mydriasis
of attention-deficit/hyperactivity disorder (ADHD) as Respiratory: Dyspnea (extended release: 2% to 4%)
part of a total treatment program that typically includes Miscellaneous: Fever (extended release: 5%), acciden-
other remedial measures (psychological, educational, tal injury (children and adolescents: 4%)
social) for a stabilizing effect. <1%, postmarketing, and/or case reports: Cardiomyop-
Narcolepsy (immediate release only): Treatment of athy, cerebrovascular accident, exacerbation of Gilles
narcolepsy. de la Tourette's syndrome, exacerbation of vocal tics,
Local Anesthetic/Vasoconstrictor Precautions peripheral vascular disease, seizure, Stevens-John-
Use vasoconstrictor with caution in patients taking son syndrome, toxic epidermal necrolysis
dextroamphetamine. Amphetamines enhance the sym- Mechanism of Action Amphetamines are noncate-
pathomimetic response of epinephrine and norepi- cholamine, sympathomimetic amines that promote
nephrine leading to potential hypertension and release of catecholamines (primarily dopamine and
cardiotoxicity. norepinephrine) from their storage sites in the presy-
Effects on Dental Treatment Key adverse event(s) naptic nerve terminals. A less significant mechanism
related to dental treatment: Dextroamphetamine and may include their ability to block the reuptake of cat-
amphetamine causes tachycardia, increases in blood echolamines by competitive inhibition.
pressure, and palpitations. Consider monitoring blood Pharmacodynamics/Kinetics
pressure prior to using local anesthetic with a vaso- Duration of Action Immediate-release tablet: 4 to 6
constrictor. Symptoms associated with bruxism have hours (Dopheide 2009); Adderall XR: 8 to 12 hours
been observed in some patients. (Jain 2017); Mydayis: ≤16 hours
416
DIAZEPAM
Half-life Elimination When an antitussive is needed during pregnancy, dex-

Children 6 to 12 years: d-amphetamine: 9 hours; l- tromethorphan at standard OTC doses is generally
amphetamine: 11 hours considered acceptable. Some sources recommend
Adolescents 13 to 17 years: d-amphetamine: 11 use be reserved for significant maternal need; products
hours; l-amphetamine: 13 to 14 hours containing alcohol should be avoided (Chasnoff 1981;
Adults: d-amphetamine: 10 hours; l-amphetamine: 13 Conover 2003; Koren 1998; Ward 2005).
hours
Time to Peak Immediate release: 3 hours; Adderall DiazePAM (dye AZ e pam)
XR: 7 hours; Mydayis: 7 to 10 hours (children and
adolescents 6 to 17 years), 8 hours (adults) Related Information
Pregnancy Risk Factor C Dentin Hypersensitivity, Acid Erosion, High Caries
Pregnancy Considerations Adverse events have Index, Management of Alveolar Osteitis, and Xerosto-
been observed in animal reproduction studies. Refer mia on page 1548
to individual monographs. Management of the Patient With Anxiety or Depression
Controlled Substance C-II on page 1564
Temporomandibular Dysfunction (TMD), Chronic Pain,
Dextromethorphan (deks troe meth OR fan) and Fibromyalgia on page 1559
Brand Names: US Buckleys Cough [OTC]; Cough DM Sedation (Prior to Dental Treatment) - Sample Prescrip-
[OTC]; Creomulsion Adult [OTC] [DSC]; Creomulsion tions on page 46
for Children [OTC] [DSC]; Delsym Cough Childrens Brand Names: US Diastat AcuDial; Diastat Pediatric;
[OTC]; Delsym [OTC]; ElixSure Cough [OTC]; Good- diazePAM Intensol; Valium
Sense Cough DM Childrens [OTC]; GoodSense Cough Brand Names: Canada Diastat; Diazemuls; Diazepam
DM [OTC]; Hold [OTC]; Little Colds Cough Formula Auto Injector; Diazepam Injection SDZ; Diazepam Injec-
[OTC]; PediaCare Childrens Long-Act [OTC]; Robafen tion USP; Novo-Dipam; Valium
Cough [OTC]; Robitussin 12 Hour Cough Child [OTC]; Generic Availability (US) Yes
Robitussin 12 Hour Cough [OTC]; Robitussin Childrens Pharmacologic Category Anticonvulsant, Benzodia-
Cough LA [OTC]; Robitussin Lingering CoughGels zepine; Benzodiazepine
[OTC]; Robitussin Lingering LA Cough [OTC] [DSC]; Dental Use Oral medication for preoperative dental
Scot-Tussin Diabetes CF [OTC] [DSC]; Silphen DM anxiety; sedative component in IV conscious sedation
Cough [OTC]; Triaminic Long Acting Cough [OTC]; in oral surgery patients; skeletal muscle relaxant
Trocal Cough Suppressant [OTC] [DSC]
Use
Pharmacologic Category Antitussive; N-Methyl-D- Acute ethanol withdrawal (oral and injection): May
Aspartate (NMDA) Receptor Antagonist be useful in symptomatic relief of acute agitation,
Use Cough (suppressant): Temporary control of cough tremor, impending or acute delirium, delirium tremens,
due to minor throat and bronchial irritation associated and hallucinosis.
with the common cold or inhaled irritants; temporary Anxiety (oral and injection): Management of anxiety
relief of cough impulse to improve sleep (extended disorders; short-term relief of the symptoms of anxiety.
release formulations) Muscle spasm (oral and injection): As an adjunct for
Local Anesthetic/Vasoconstrictor Precautions the relief of skeletal muscle spasm due to reflex
No information available to require special precautions spasm caused by local pathology (eg, inflammation
Effects on Dental Treatment No significant effects or of muscles or joints, secondary to trauma); spasticity
complications reported caused by upper motor neuron disorders (eg, cerebral
Effects on Bleeding No information available to palsy, paraplegia); athetosis; stiff-man syndrome;
require special precautions tetanus.
Adverse Reactions Preoperative (injection): Relief of anxiety and tension
Frequency not defined. in patients undergoing surgical procedures; prior to
Central nervous system: Dizziness, drowsiness, nerv- cardioversion for the relief of anxiety and tension and
ousness, restlessness to diminish patient's recall (IV only); as an adjunct prior
Gastrointestinal: Gastrointestinal distress, nausea, to endoscopic procedures for apprehension, anxiety,
stomach pain, vomiting or acute stress reactions and to diminish patient's
Mechanism of Action Decreases the sensitivity of recall.
cough receptors and interrupts cough impulse trans- Note: Use of diazepam in patients undergoing cardi-
mission by depressing the medullary cough center oversion or endoscopic procedures has been super-
through sigma receptor stimulation; structurally related seded by agents with a more pharmacokinetically
to codeine favorable profile (eg, midazolam) (Thomas 2014;
Pharmacodynamics/Kinetics Triantafillidis 2013)
Onset of Action Antitussive: 15-30 minutes Seizures: Adjunct in convulsive disorders (oral); man-
Duration of Action ≤6 hours agement of select, refractory epilepsy patients on
Half-life Elimination Dextromethorphan: Extensive stable regimens of antiepileptic drugs requiring inter-
metabolizers: 2-4 hours; poor metabolizers: 24 hours mittent use of diazepam to control episodes of
Time to Peak 2-3 hours increased seizure activity (rectal); adjunct in severe
Pregnancy Considerations Dextromethorphan is recurrent convulsive seizures (injection).
metabolized in the liver via CYP2D6 and CYP3A Status epilepticus (injection): Adjunct in status epi-
enzymes. The activity of both enzymes is increased in lepticus.
the mother during pregnancy (Tracy 2005; Wadelius Local Anesthetic/Vasoconstrictor Precautions
1997). In the fetus, CYP2D6 activity is low in the fetal No information available to require special precautions
liver and CYP3A4 activity is present by ~17 weeks' Effects on Dental Treatment Key adverse event(s)
gestation (Jacqz-Aigrain 1992). related to dental treatment: Xerostomia and changes in
417
DIAZEPAM
salivation (normal salivary flow resumes upon discon- IV, IM: Initial: 5 to 10 mg; then 5 to 10 mg in 3 to 4
tinuation) (see Dental Health Professional Considera- hours, if necessary. Larger doses may be required if
tions) associated with tetanus.
Effects on Bleeding No information available to Preoperative: Anxiety: IM: 10 mg prior to surgery
require special precautions Sedation in the ICU patient: IV: Loading dose: 5 to
Adverse Reactions Adverse reactions may vary by 10 mg; Maintenance dose: 0.03 to 0.1 mg/kg every
route of administration. 30 minutes to 6 hours (Barr 2013)
>10%: Central nervous system: Drowsiness (23%) Seizures:
1% to 10%: Adjunctive maintenance therapy: Oral: 2 to 10 mg 2
Cardiovascular: Hypotension (1% to 2%), vasodilation to 4 times daily.
(1% to 2%) Intermittent management of seizures: Rectal gel
Central nervous system: Headache (5%), ataxia (3%), (Diastat): 0.2 mg/kg; may be repeated in 4 to 12
dizziness (3%), euphoria (3%), abnormality in think- hours if needed; do not use for more than 5 epi-
ing (1% to 2%), agitation (≥1%), confusion (≥1%), sodes per month or more than one episode every 5
emotional lability (≥1%), nervousness (≥1%), pain days. Note: Round dose to the nearest 2.5 mg
(≥1%), speech disturbance (≥1%) increment.
Dermatologic: Skin rash (3%) Status epilepticus:
Gastrointestinal: Diarrhea (4%), abdominal pain (≥1%) IV:
Neuromuscular & skeletal: Asthenia (1% to 2%) American Epilepsy Society recommendations: 0.15
Respiratory: Asthma (2%), rhinitis (≥1%) to 0.2 mg/kg (maximum dose: 10 mg); may repeat
Frequency not defined: once (AES [Glauser 2016])
Neurocritical Care Society recommendations:
Cardiovascular: ECG changes, localized phlebitis,
0.15 mg/kg (maximum dose: 10 mg) given at a
venous thrombosis
rate of ≤5 mg/minute; may repeat in 5 minutes
Central nervous system: Anterograde amnesia, cen-
(NCS [Brophy 2012]).
tral nervous system depression, depression, drug
Rectal (formulation not specified) (off-label use):
dependence, drug withdrawal, dysarthria, fatigue,
Note: The parenteral formulation of diazepam
hypoactivity, myasthenia, paradoxical central nerv-
may be given rectally if rectal gel (Diastat) is not
ous system stimulation, psychiatric signs and symp-
available (Arif 2008).
toms, slurred speech, vertigo
American Epilepsy Society recommendations: 0.2
Endocrine & metabolic: Change in libido to 0.5 mg/kg (maximum dose: 20 mg) (AES
Gastrointestinal: Altered salivation, constipation, gas- [Glauser 2016])
trointestinal distress, hiccups, nausea Premonitory/Out-of-hospital treatment: 10 mg
Genitourinary: Urinary incontinence, urinary retention once; may repeat once if necessary (Kälviäi-
Hematologic & oncologic: Neutropenia nen 2007)
Hepatic: Increased serum alkaline phosphatase, Skeletal muscle relaxant (adjunct therapy): Oral: 2
increased serum transaminases, jaundice to 10 mg 3 to 4 times daily
Neuromuscular & skeletal: Tremor Geriatric Oral absorption is more reliable than IM
Ophthalmic: Blurred vision, diplopia Elderly and/or debilitated patients:
<1%, postmarketing, and/or case reports: Anemia, ano- Oral: 2 to 2.5 mg 1 to 2 times daily initially; increase
rexia, bradycardia, circulatory shock, cough, diapho- gradually as needed and tolerated.
resis, hyperkinesia, infection, lymphadenopathy, Rectal gel: Due to the increased half-life in elderly and
mydriasis, neutropenia, nystagmus, pruritus, syncope, debilitated patients, consider reducing dose.
tonic clonic type of status epilepticus, urinary tract Renal Impairment: Adult There are no dosage
infection, urticaria, vomiting adjustments provided in the manufacturer’s labeling;
Dental Usual Dosage use with caution.
Anxiety/sedation/skeletal muscle relaxant: Adults: Hemodialysis: Not dialyzable (0% to 5%); supplemen-
Oral: 2 to 10 mg 2 to 4 times daily tal dose is not necessary.
IM, IV: 2 to 10 mg, may repeat in 3 to 4 hours if Hepatic Impairment: Adult There are no dosage
needed adjustments provided in the manufacturer’s labeling;
Anxiety: Elderly: Oral: Initial: 1 to 2 mg 1 to 2 times use with caution. The oral tablets are contraindicated
daily; increase gradually as needed, rarely need to in severe hepatic impairment.
use >10 mg daily (watch for hypotension and exces- Pediatric
sive sedation) Seizures, acute:
Skeletal muscle relaxant: Elderly: Oral: Initial: 2 to 5 mg Rectal gel formulation:
2 to 4 times daily Infants and Children 6 months to 2 years: Rectal:
Dosing Dose not established
Adult Note: Oral absorption is more reliable than IM Children 2 to 5 years: Rectal: 0.5 mg/kg
Acute ethanol withdrawal: Children 6 to 11 years: Rectal: 0.3 mg/kg
IV, IM: 10 mg initially; may administer 5 to 10 mg 3 to Children ≥12 years and Adolescents: Rectal:
4 hours later, if needed 0.2 mg/kg
Oral: 10 mg 3 to 4 times during first 24 hours, then Note: Round dose to the nearest 2.5 mg incre-
decrease to 5 mg 3 to 4 times daily as needed ment, not exceeding a 20 mg/dose; dose may
Anxiety (symptoms/disorders): be repeated in 4 to 12 hours if needed; do not
Oral: 2 to 10 mg 2 to 4 times daily if needed use more than 5 times per month or more than
IM, IV: 2 to 10 mg; may repeat in 3 to 4 hours, if once every 5 days
needed Rectal: Undiluted 5 mg/mL parenteral formulation
Muscle spasm: (filter if using ampul): Infants, Children, and Ado-
Oral: 2 to 10 mg 3 or 4 times daily lescents: 0.5 mg/kg/dose then 0.25 mg/kg/dose in
418
DIAZEPAM
10 minutes if needed. Maximum dose: 20 mg/dose is 5 mg/dose and in children ≥5 years and ado-
(Hegenbarth 2008; Kliegman 2007) lescents is 10 mg/dose (Kliegman 2016).
Status epilepticus: Sedation, anxiolysis, and amnesia prior to proce-
Weight-directed: Infants >30 days, Children, and dure: Limited data available:
Adolescents: IV: 0.1 to 0.3 mg/kg/dose given over Oral:
3 to 5 minutes, every 5 to 10 minutes; maximum Infants ≥6 months: 0.2 to 0.3 mg/kg 45 to 60
d o s e : 1 0 m g / d o s e (B r o p h y 2 0 1 2 ; H e g e n - minutes prior to procedure. Maximum dose:
barth 2008) 10 mg/dose (Zeltzer 1990)
Fixed dosing: Manufacturer's labeling: Children: 0.2 to 0.5 mg/kg 45 to 60 minutes prior to
Infants >30 days and Children <5 years: IV: 0.2 to procedure; maximum dose: 10 mg/dose (Everitt
0.5 mg slow IV every 2 to 5 minutes up to a 2002; Fell 1985; Tyagi 2012; Zeltzer 1990)
maximum total dose of 5 mg; repeat in 2 to 4 Adolescents: 0.2 to 0.3 mg/kg 45 to 60 minutes
hours if needed prior to procedure. Maximum dose: 10 mg/dose
Children ≥5 years and Adolescents: IV: 1 mg slow (Zeltzer 1990)
IV every 2 to 5 minutes up to a maximum of IV:
10 mg; repeat in 2 to 4 hours if needed Infants and Children: Initial: 0.05 to 0.1 mg/kg over
Febrile seizure, prophylaxis: Limited data available: 3 to 5 minutes, titrate slowly to effect (maximum
Children: Oral: 1 mg/kg/day divided every 8 hours; total dose: 0.25 mg/kg) (Krauss 2006)
initiate therapy at first sign of fever and continue for Adolescents: IV: 5 mg; may repeat with 2.5 mg if
24 hours after fever resolves (Rosman 1993; Steer- needed (Zeltzer 1990)
ing Committee 2008) Renal Impairment: Pediatric There are no dosage
Spasticity/muscle spasms: adjustments provided in the manufacturer’s labeling;
General dosing: Note: Initiate therapy with lowest use with caution.
dose; dose should be individualized and titrated to Hemodialysis: Not dialyzable (0% to 5%); supplemen-
effect and tolerability: tal dose is not necessary.
Manufacturer's labeling: Infants ≥6 months, Chil- Hepatic Impairment: Pediatric There are no dos-
dren, and Adolescents: Oral: Initial: 1 to 2.5 mg age adjustments provided in the manufacturer’s label-
3 to 4 times daily; increase gradually as needed ing ; use with c autio n. The oral ta blets a re
and tolerated contraindicated in severe hepatic impairment.
Alternate dosing (Kliegman 2016):
Mechanism of Action Binds to stereospecific benzo-
Oral:
diazepine receptors on the postsynaptic GABA neuron
Infants ≥6 months and Children <12 years: 0.12
at several sites within the central nervous system,
to 0.8 mg/kg/day in divided doses every 6 to 8
including the limbic system, reticular formation.
hours; maximum dose: 10 mg/dose
Enhancement of the inhibitory effect of GABA on neuro-
Children ≥12 years and Adolescents: 2 to 10 mg
nal excitability results by increased neuronal membrane
2 to 4 times daily
permeability to chloride ions. This shift in chloride ions
Cerebral palsy-associated spasticity: Limited data
results in hyperpolarization (a less excitable state) and
available. Note: Dose should be individualized
stabilization. Benzodiazepine receptors and effects
and titrated to effect and tolerability:
appear to be linked to the GABA-A receptors. Benzo-
Weight-based dosing: Children: Oral: 0.01 to
0.3 mg/kg/day divided 2 or 4 times daily (Klieg- diazepines do not bind to GABA-B receptors.
man 2016) Contraindications
Low-dose fixed dosing (Mathew 2005): Children Hypersensitivity to diazepam or any component of the
<12 years: Oral: formulation; acute narrow-angle glaucoma; untreated
<8.5 kg: 0.5 to 1 mg at bedtime open-angle glaucoma; infants <6 months of age (oral);
8.5 to 15 kg: 1 to 2 mg at bedtime myasthenia gravis, severe respiratory impairment,
Fixed dosing: Children ≥5 years and Adolescents: severe hepatic impairment, sleep apnea syndrome
Oral: Initial: 1.25 mg 3 times daily; may titrate to (oral tablet).
5 mg 4 times daily (Engle 1966) Documentation of allergenic cross-reactivity for benzo-
Tetanus-associated spasm: diazepines is limited. However, because of similarities
Manufacturer's labeling: in chemical structure and/or pharmacologic actions,
Infants >30 days and children <5 years: IV, IM: 1 the possibility of cross-sensitivity cannot be ruled out
to 2 mg every 3 to 4 hours as needed with certainty.
Children ≥5 years and Adolescents: IV, IM: 5 to Warnings/Precautions When used as an adjunct in
10 mg every 3 to 4 hours as needed treating convulsive disorders, an increase in frequency/
Alternate dosing (WHO 2010): severity of tonic-clonic seizures may occur and require
Infants and Children: IV: Initial: 0.1 to 0.2 mg/kg/ dose adjustment of anticonvulsant. Abrupt withdrawal
dose every 2 to 6 hours; titrate as needed may result in a temporary increase in the frequency
Adolescents: IV: Initial: 5 mg every 2 to 6 hours, and/or severity of seizures. Use with caution in debili-
titrate as needed. Large doses may be required. tated patients, elderly patients, obese patients, patients
Muscle spasm/spasticity associated with chronic/ter- with hepatic disease, or renal impairment. Active
minal illness (eg, palliative care settings): Limited metabolites with extended half-lives may lead to
data available: Infants, Children, and Adolescents: delayed accumulation and adverse effects; limit dose
Oral: 0.12 to 0.8 mg/kg/day divided every 6 to 12 to smallest effective amount and increase gradually and
hours; maximum dose: 10 mg/dose (Wust- as tolerated to avoid adverse reactions. Elderly patients
off 2007) may be at an increased risk of death with use; risk has
IM, IV: 0.05 to 0.2 mg/kg/dose every 6 to 12 hours; been found highest within the first 4 months of use in
maximum total dose: 0.6 mg/kg cumulative in 8 elderly dementia patients (Jennum 2015; Saarelainen
hours (Wustoff 2007); Note: In palliative situa- 2018). Oral tablet is contraindicated in patients with
tions, the usual initial dose for children <5 years severe hepatic impairment, severe respiratory
419
DIAZEPAM
impairment, or sleep apnea syndrome. Use with caution Rectal gel: Administration of rectal gel should only be
in patients with respiratory disease. performed by individuals trained to recognize character-
istic seizure activity and monitor response. Not recom-
Use caution in patients with depression or anxiety
mended for chronic, daily use. Use with caution in
associated with depression, particularly if suicidal risk
patients with neurologic damage.
may be present. Use with extreme caution in patients
with a history of drug abuse or acute alcoholism; Some dosage forms may contain benzyl alcohol and/or
potential for drug dependency exists. Tolerance and sodium benzoate/benzoic acid; benzoic acid (benzoate)
psychological and physical dependence may occur with is a metabolite of benzyl alcohol; large amounts of
prolonged use (generally >10 days). Use with extreme benzyl alcohol (≥99 mg/kg/day) have been associated
caution in patients who are at risk of falls; benzodiaze- with a potentially fatal toxicity ("gasping syndrome") in
pines have been associated with falls and traumatic neonates; the "gasping syndrome" consists of meta-
injury (Nelson 1999). Rebound or withdrawal symptoms bolic acidosis, respiratory distress, gasping respira-
may occur following abrupt discontinuation or large tions, CNS dysfunction (including convulsions,
decreases in dose. Use caution when reducing dose intracranial hemorrhage), hypotension, and cardiovas-
or withdrawing therapy; decrease slowly and monitor for cular collapse (AAP 1997; CDC 1982); some data
withdrawal symptoms. The benzodiazepine receptor suggest that benzoate displaces bilirubin from protein
antagonist flumazenil may cause withdrawal in patients binding sites (Ahlfors 2001); avoid or use dosage forms
receiving long-term benzodiazepine therapy. Diazepam containing benzyl alcohol and/or benzyl alcohol deriva-
is a long half-life benzodiazepine. Tolerance develops tive with caution in neonates. See manufacturer's
to the sedative, hypnotic, and anticonvulsant effects. It labeling.
does not develop to the anxiolytic or skeletal muscle
relaxing effects (Vinkers 2012). Chronic use of this Some dosage forms may contain propylene glycol;
agent may increase the perioperative benzodiazepine large amounts are potentially toxic and have been
dose needed to achieve desired effect. associated with hyperosmolality, lactic acidosis, seiz-
ures, and respiratory depression; use caution (AAP
Benzodiazepines have been associated with anterog- 1997; Wilson 2000; Wilson 2005; Zar 2007).
rade amnesia (Nelson 1999). Paradoxical reactions, Warnings: Additional Pediatric Considerations
including hyperactive or aggressive behavior, have Neonates and young infants have decreased metabo-
been reported with benzodiazepines; risk may be lism of diazepam and desmethyldiazepam (active
increased in adolescent/pediatric, geriatric patients, or metabolite), both can accumulate with repeated use
patients with a history of alcohol use disorder or psychi- and cause increased toxicity.
atric/personality disorders (Mancuso 2004). Does not Drug Interactions
have analgesic, antidepressant, or antipsychotic prop- Metabolism/Transport Effects Substrate of
erties. May be used in patients with open-angle glau- CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (major),
coma who are receiving appropriate therapy; CYP2C9 (minor), CYP3A4 (major); Note: Assignment
contraindicated in acute narrow-angle glaucoma and of Major/Minor substrate status based on clinically
untreated open-angle glaucoma. Potentially significant relevant drug interaction potential
interactions may exist, requiring dose or frequency Avoid Concomitant Use
adjustment, additional monitoring, and/or selection of Avoid concomitant use of DiazePAM with any of the
alternative therapy. [US Boxed Warning]: Concomi- following: Azelastine (Nasal); Benznidazole; Bromper-
tant use of benzodiazepines and opioids may result idol; Conivaptan; Fusidic Acid (Systemic); Idelalisib;
in profound sedation, respiratory depression, MetroNIDAZOLE (Systemic); OLANZapine; Orphena-
coma, and death; reserve concomitant prescribing drine; Oxomemazine; Paraldehyde; Sodium Oxybate;
of these drugs for use in patients for whom alter- Thalidomide
native treatment options are inadequate, and limit Increased Effect/Toxicity
dosages and durations to the minimum required. DiazePAM may increase the levels/effects of: Ajma-
Follow patients for signs and symptoms of respira- line; Alcohol (Ethyl); Alfentanil; Azelastine (Nasal);
tory depression and sedation. Blonanserin; Brexanolone; Buprenorphine; CloZA-
May cause CNS depression, which may impair physical Pine; CNS Depressants; Flunitrazepam; HYDROco-
or mental abilities; patients must be cautioned about done; Methadone; Methotrimeprazine; MetyroSINE;
performing tasks that require mental alertness (eg, Mirtazapine; Opioid Agonists; Orphenadrine; OxyCO-
operating machinery, driving). Hazardous sleep-related DONE; Paraldehyde; Piribedil; Pramipexole; ROPI-
activities such as sleep-driving, cooking and eating NIRole; Rotigotine; Selective Serotonin Reuptake
food, and making phone calls while asleep have been Inhibitors; Sodium Oxybate; Suvorexant; Thalidomide;
noted with benzodiazepines (Dolder 2008). Zolpidem
Parenteral: Vesicant; ensure proper needle or catheter The levels/effects of DiazePAM may be increased by:
placement prior to and during administration; avoid Alizapride; Aprepitant; Benznidazole; Brimonidine
extravasation. Acute hypotension, muscle weakness, (Topical); Bromopride; Bromperidol; Cannabidiol; Can-
apnea, and/or cardiac arrest have occurred with paren- nabis; Chlormethiazole; Chlorphenesin Carbamate;
teral administration. Acute effects may be more preva- Clofazimine; Conivaptan; Cosyntropin; CYP2C19
lent in patients receiving concurrent barbiturates, Inhibitors (Moderate); CYP2C19 Inhibitors (Strong);
opioids, or ethanol. Appropriate resuscitative equipment CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors
and qualified personnel should be available during (Strong); Dimethindene (Topical); Disulfiram; Doxyl-
administration and monitoring. Avoid use of the injection amine; Dronabinol; Droperidol; Duvelisib; Esketamine;
in patients in shock, coma, or in acute ethanol intox- Etravirine; Fosamprenavir; Fosaprepitant; Fosnetupi-
ication with depression of vital signs. Intra-arterial injec- tant; Fusidic Acid (Systemic); HydrOXYzine; Idelalisib;
tion should be avoided. Tonic status epilepticus has Kava Kava; Larotrectinib; Lofexidine; Magnesium Sul-
been precipitated in patients treated with diazepam IV fate; Melatonin; Methotrimeprazine; MetroNIDAZOLE
for absence status or absence variant status. (Systemic); MiFEPRIStone; Minocycline; Nabilone;
420
DIBUCAINE
Netupitant; OLANZapine; Oxomemazine; Palbociclib; Breastfeeding Considerations Diazepam and its

Perampanel; Ritonavir; Rufinamide; Saquinavir; Sime- metabolites are present in breast milk.
previr; Stiripentol; Tapentadol; Teduglutide; Tetrahy-
d r o c a n n a b i n o l ; Te t r a h y d r o c a n n a b i n o l a n d Using data from one study, the relative infant dose
Cannabidiol; Trimeprazine (RID) of diazepam is 8.9% when compared to a
weight-adjusted maternal dose of 10 mg/day.
Decreased Effect
The levels/effects of DiazePAM may be decreased by: In general, breastfeeding is considered acceptable
Bosentan; CYP2C19 Inducers (Moderate); CYP2C19 when the RID of a medication is <10% (Anderson
Inducers (Strong); CYP3A4 Inducers (Moderate); 2016; Ito 2000). However some sources note breast-
CYP3A4 Inducers (Strong); Dabrafenib; Deferasirox; feeding should only be considered if the RID is <5% for
Enzalutamide; Etravirine; Ivosidenib; Lorlatinib; Mito- psychotropic agents (Larsen 2015).
tane; Ombitasvir, Paritaprevir, and Ritonavir; Ombitas-
vir, Paritaprevir, Ritonavir, and Dasabuvir; Pitolisant; The RID of diazepam was calculated using a milk
Sarilumab; Siltuximab; St John's Wort; Theophylline concentration of 85 ng/mL, providing an estimated daily
Derivatives; Tocilizumab; Yohimbine infant dose via breast milk of 0.01275 mg/kg/day. This
Pharmacodynamics/Kinetics was the highest milk concentration obtained in one
Onset of Action study following maternal administration of diazepam
Sedation: Pediatric patients: IV: 4 to 5 minutes (Krauss 10 mg once daily at bedtime to four postpartum women
2006) (this sample was obtained after five maternal doses)
Status epilepticus: IV: 1 to 3 minutes; Rectal: 2 to 10 (Brandt 1976). Higher milk concentrations have been
minutes reported; however, milk concentration related to mater-
Duration of Action nal dose was not stated (Dusci 1990; Wesson 1985).
The active metabolites of diazepam (desmethyldiaze-
Sedation: Pediatric patients: 60 to 120 minutes
pam, oxazepam, and temazepam) have also been
(Krauss 2006)
detected in breast milk and the urine of exposed infants
Status epilepticus: 15 to 30 minutes
(Brandt 1976; Cole 1975; Dusci 1990; Erkkola 1972;
Half-life Elimination Note: Diazepam accumulates
Wesson 1985). Relative infant doses of up to 11% have
upon multiple dosing and the terminal elimination half-
been reported (McElhatton 1994).
life is slightly prolonged.
IM: Sedation and weight loss have been observed in some
Premature neonates (GA: 28 to 34 weeks): 54 hours infants exposed to diazepam via breast milk (Patrick
Infants: ~30 hours (Morselli 1973) 1972; Wesson 1985)
Children 3 to 8 years: 18 hours (Morselli 1973)
Adults: Parent: ~60 to 72 hours; Desmethyldiaze- Diazepam has a long half-life and may accumulate in
pam: ~152 to 174 hours (Lamson 2011) the breastfed infant, especially preterm infants or those
IV: Parent: 33 to 45 hours; Desmethyldiazepam: 87 exposed to chronic maternal doses (Davanzo 2013).
hours (Cloyd 1998; Greenblatt 1989a) Significant accumulation may occur even if the maternal
Oral: Parent: 44 to 48 hours; Desmethyldiazepam: dose is low (Wesson 1985). A single maternal dose
100 hours (Greenblatt 1989b) may be compatible with breastfeeding (WHO 2002). If
Rectal: Parent: 45 to 46 hours; Desmethyldiazepam: chronic use of a benzodiazepine is needed in breast-
71 to 99 hours (Cloyd 1998) feeding women, use of shorter acting agents is pre-
ferred (Davanzo 2013; WHO 2002). Infants should be
Time to Peak
monitored for drowsiness, decreased feeding, and poor
IM: Median: 1 hour (range: 0.25 to 2 hours) (Lamson
weight gain (Veiby 2015).
2011)
IV: ~1 minute (Cloyd 1998) Controlled Substance C-IV
Oral: 15 minutes to 2.5 hours (1.25 hours when Dosage Forms: US
fasting; 2.5 hours with food) (Greenblatt 1989b) Concentrate, Oral:
Rectal: 1.5 hours diazePAM Intensol: 5 mg/mL (30 mL)
Pregnancy Risk Factor D Generic: 5 mg/mL (30 mL)
Pregnancy Considerations Adverse events have Gel, Rectal:
been observed in animal reproduction studies. In Diastat AcuDial: 10 mg (1 ea); 20 mg (1 ea)
humans, diazepam and its metabolites (N-desmethyl- Diastat Pediatric: 2.5 mg (1 ea)
diazepam, temazepam, and oxazepam) cross the pla- Generic: 2.5 mg (1 ea); 10 mg (1 ea); 20 mg (1 ea)
centa. Teratogenic effects have been observed with Solution, Injection:
diazepam; however, additional studies are needed. Generic: 5 mg/mL (2 mL, 10 mL)
The incidence of premature birth and low birth weights Solution, Oral:
may be increased following maternal use of benzodia- Generic: 5 mg/5 mL (500 mL)
zepines; hypoglycemia and respiratory problems in the Solution Auto-injector, Intramuscular:
neonate may occur following exposure late in preg- Generic: 10 mg/2 mL (2 mL)
nancy. Neonatal withdrawal symptoms may occur within Tablet, Oral:
days to weeks after birth and "floppy infant syndrome" Valium: 2 mg, 5 mg, 10 mg
(which also includes withdrawal symptoms) has been Generic: 2 mg, 5 mg, 10 mg
reported with some benzodiazepines (including diaze- Dental Health Professional Considerations An
pam) (Bergman 1992; Iqbal 2002; Wikner 2007). A adult companion should accompany the patient to and
combination of factors influences the potential terato- from dental office.
genicity of anticonvulsant therapy. When treating
women with epilepsy, monotherapy with the lowest Dibucaine (DYE byoo kane)
effective dose and avoidance of medications known to
have a high incidence of teratogenic effects is recom- Brand Names: US Nupercainal [OTC]
mended (Harden 2009; Wlodarczyk 2012). Generic Availability (US) Yes
421
DIBUCAINE
Pharmacologic Category Antihemorrhoidal Agent; effects (eg, methemoglobinemia, irregular heart beats,
Local Anesthetic respiratory depression, seizures, death) have been
Dental Use Amide derivative local anesthetic for minor reported in patients who (without supervision of a
skin conditions trained professional) have applied topical anesthetics
Use in large amounts (or to large areas of the skin), left
Dermal pain/itching: Temporary relief of pain and these products on for prolonged periods of time, or have
itching caused by sunburn, minor burns, minor cuts, used wraps/dressings to cover the skin following appli-
scrapes, insect bites or minor skin irritation. cation.
Hemorrhoids/anorectal disorders; rectal pain/itch-
Self-medication (OTC use): For external use only.
ing: Temporary relief of pain and itching due to hem-
When used for self-medication, notify healthcare pro-
orrhoids and other anorectal disorders.
vider and discontinue use if condition worsens, does not
improve within 7 days, or if redness, irritation, swelling,
bleeding or other symptoms develop or increase. Do
not put this product into the rectum using fingers or any
mechanical device or applicator; do not exceed recom-
mended dose unless directed by a healthcare provider.
Do not use in large quantities, particularly over raw
Adverse Reactions Frequency not defined. surfaces or blistered areas.
1% to 10%: Drug Interactions
Central nervous system: Localized burning
Metabolism/Transport Effects None known.
Dermatologic: Contact dermatitis
Hypersensitivity: Angioedema
Avoid Concomitant Use There are no known inter-
actions where it is recommended to avoid concomitant
Dental Usual Dosage Local pain (local anesthetic):
use.
Children and Adults: Topical: Apply gently to the
affected areas; no more than 30 g for adults or 7.5 g Increased Effect/Toxicity
for children should be used in any 24-hour period The levels/effects of Dibucaine may be increased by:
Dosing Methemoglobinemia Associated Agents
Adult & Geriatric Decreased Effect There are no known significant
Dermal pain/itching: Topical: Apply to affected area interactions involving a decrease in effect.
up to 3 or 4 times daily. Maximum daily dose: 30 g/ Pharmacodynamics/Kinetics
day Onset of Action Within 15 minutes
Hemorrhoids/anorectal disorders; rectal pain/itch- Duration of Action 2 to 4 hours
ing: Topical: Apply to affected external anal area up Dosage Forms: US
to 3 or 4 times daily. Ointment, External:
Renal Impairment: Adult There are no dosage Nupercainal [OTC]: 1% (56.7 g)
adjustments provided in the manufacturer's labeling. Generic: 1% (28 g, 28.35 g)
Hepatic Impairment: Adult There are no dosage Ointment, Rectal:
adjustments provided in the manufacturer's labeling. Nupercainal [OTC]: 1% (28.4 g, 60 g)
Pediatric
Dermal pain/itching: Children ≥2 years weighing Diclofenac (Systemic) (dye KLOE fen ak)
≥16 kg and Adolescents: Topical: Apply to affected
area up to 3 or 4 times daily. Maximum daily dose: Related Information
7.5 g/day for children and 30 g/day for adults Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
Hemorrhoids/anorectal disorders; rectal pain/ on page 1484
itching: Children ≥12 years and Adolescents: Top- Temporomandibular Dysfunction (TMD), Chronic Pain,
ical: Apply to affected external anal area up to 3 or 4
times daily
Brand Names: US Cambia; Dyloject [DSC]; Voltaren-
XR [DSC]; Zipsor; Zorvolex
adjustments provided in the manufacturer’s labeling.
Brand Names: Canada Cambia; Diclofenac K; Volta-
ren; Voltaren Rapide; Voltaren SR
ing. Generic Availability (US) May be product dependent
Mechanism of Action Blocks both the initiation and Pharmacologic Category Analgesic, Nonopioid; Non-
conduction of nerve impulses by decreasing the neuro- steroidal Anti-inflammatory Drug (NSAID); Nonsteroidal
nal membrane's permeability to sodium ions, which Anti-inflammatory Drug (NSAID), Oral
results in inhibition of depolarization with resultant Dental Use Immediate-release tablets: Acute treatment
blockade of conduction. of mild-to-moderate pain
Contraindications OTC labeling: When used for self- Use
medication, do not use in or near the eyes or in children Ankylosing spondylitis (delayed-release tablets
<2 years or weight <16 kg. only): Acute or long-term use in the relief of signs
Documentation of allergenic cross-reactivity for amide and symptoms of ankylosing spondylitis.
local anesthetics limited. However, because of sim- Dysmenorrhea (immediate-release tablets only):
ilarities in chemical structure and/or pharmacologic Treatment of primary dysmenorrhea.
actions, the possibility of cross-sensitivity cannot be Migraine (powder for oral solution only): Acute treat-
ruled out with certainty. ment of migraine attacks with or without aura in adults.
Warnings/Precautions When topical anesthetics are Osteoarthritis (immediate-release, extended-
used prior to cosmetic or medical procedures, the low- release, and delayed-release tablets; capsules
est amount of anesthetic necessary for pain relief [Zorvolex]; and suppositories [Canadian product]
should be applied. High systemic levels and toxic only): Relief of signs and symptoms of osteoarthritis.
422
DICLOFENAC (SYSTEMIC)
Pain melena, meningitis, nervousness, oliguria, palpita-

Capsules/immediate-release tablets only: Relief of tions, pancreatitis, pancytopenia, paresthesia, pneu-
mild to moderate acute pain. monia, polyuria, proteinuria, purpura, rectal
Injection only: Management of mild to moderate pain hemorrhage, renal failure, respiratory depression,
and moderate to severe pain (alone or in combina- sepsis, skin photosensitivity, stomatitis, syncope,
tion with opioid analgesics) in adults. tachycardia, thrombocytopenia, toxic epidermal nec-
Rheumatoid arthritis (immediate-release, extended- rolysis, tremor, urticaria, vasculitis, vertigo, weakness,
release, and delayed-release tablets; and suppo- weight changes
sitories [Canadian product] only): Relief of signs Oral: Frequency not always defined.
and symptoms of rheumatoid arthritis. >10%:
Local Anesthetic/Vasoconstrictor Precautions Cardiovascular: Edema (33%)
No information available to require special precautions Hepatic: Increased serum transaminases (≤3 x
Effects on Dental Treatment The dentist should be ULN; 15%)
aware of the potential of abnormal coagulation. Caution 1% to 10%:
should also be exercised in the use of NSAIDs in Cardiovascular: Hypertension (2% to 3%)
patients already on anticoagulant therapy with drugs Central nervous system: Headache (4% to 8%), pro-
such as warfarin (Coumadin®). See Effects on Bleed- cedural pain (3%), dizziness (2%), falling (2%)
ing. Dermatologic: Pruritus (7%), skin rash
Effects on Bleeding Nonselective NSAIDs such as Gastrointestinal: Constipation (5% to 8%), nausea
diclofenac (systemic) inhibit platelet aggregation and (6% to 7%), diarrhea (6%), GI adverse effects (gas-
prolong bleeding time in some patients. Unlike aspirin, tric ulcer, hemorrhage, and perforation; ≤4%, risk
the NSAID effect on platelet function is quantitatively increases with therapy duration), abdominal pain
less, of shorter duration, and reversible. Normal platelet (2% to 3%), vomiting (3%), dyspepsia (2% to 3%),
function should occur in ~5 elimination half-lives or in flatulence (2% to 3%), heartburn, abdominal discom-
<10 hours after discontinuation of diclofenac (systemic). fort (2%), duodenal ulcer
Concomitant use of other NSAIDs should be avoided. Genitourinary: Urinary tract infection (7%)
Adverse Reactions Hematologic & oncologic: Bruise (3%), anemia, pro-
Injection: Frequency not always defined. longed bleeding time
Cardiovascular: Edema (≤10%), cerebrovascular acci- Hepatic: Increased serum ALT (>3 x ULN: ≤4%; >8 x
dent, hypertension, myocardial infarction, significant ULN: ≤1%), increased serum AST (>3 x ULN; ≤4%;
cardiovascular event >8 x ULN: ≤1%)
Central nervous system: Headache (≤10%), dizzi- Infection: Influenza (3%)
ness (8%) Neuromuscular & skeletal: Osteoarthritis (5%), arthral-
Dermatologic: Pruritus (≤10%), skin rash (≤10%), exfo- gia (3%), back pain (3%), limb pain (3%)
liative dermatitis, Stevens-Johnson syndrome, toxic Renal: Renal function abnormality
epidermal necrolysis Otic: Tinnitus
Endocrine & metabolic: Fluid retention Renal: Increased serum creatinine (2%), renal func-
Gastrointestinal: Constipation (13%), abdominal pain
tion abnormality
(≤10%), diarrhea (≤10%), dyspepsia (≤10%), esoph-
ageal perforation (≤10%), flatulence (≤10%), gastro-
nasopharyngitis (6%), sinusitis (3% to 5%), cough
intestinal ulcer (≤10%; including gastric/duodenal),
(4%), bronchitis (3%)
heartburn (≤10%), intestinal perforation (≤10%), nau-
sea (≤10%), vomiting (≤10%)
dreams, agranulocytosis, alopecia, anaphylactoid
Hematologic & oncologic: Anemia (≤10%), hemorrhage
reaction, anaphylaxis, angioedema, anxiety, aplastic
(≤10%), prolonged bleeding time (≤10%)
anemia, aseptic meningitis, asthma, auditory impair-
Hepatic: Increased liver enzymes (≤10%), increased
serum transaminases (15%), increased serum ALT ment, azotemia (Gurwitz, 1990), blurred vision, car-
(≤4%; >8X ULN: ≤1%), increased serum AST (2% to diac arrhythmia, cardiac failure, cerebrovascular
≤4%; >8X ULN: ≤1%) accident, change in appetite, chest pain, colitis, coma,
Hypersensitivity: Anaphylactoid reaction confusion, conjunctivitis, cystitis, decreased hemoglo-
Local: Infusion site reaction (10%), extravasation (3%) bin (Goldstein, 2011), depression, diaphoresis, diplo-
Otic: Tinnitus (≤10%) pia, disorientation, drowsiness, dyspnea, dysuria,
Renal: Renal insufficiency (≤10%) ecchymoses, eosinophilia, eructation, erythema multi-
Miscellaneous: Wound healing impairment (8%), gas- forme, esophageal ulcer, esophagitis, exfoliative der-
trointestinal inflammation matitis, fever, fluid retention, fulminant hepatitis,
<1%, postmarketing, and/or case reports: Abnormal gastritis, glossitis, hallucination, hearing loss, hema-
Dreams, agranulocytosis, alopecia, anaphylaxis, temesis, hematuria, hemolytic anemia, hepatic failure,
angioedema, anxiety, aplastic anemia, asthma, audi- hepatic necrosis, hepatitis, hepatotoxicity, hyperglyce-
tory impairment, blurred vision, cardiac arrhythmia, mia, hypotension, infection, insomnia, interstitial neph-
cardiac failure, change in appetite, colitis, coma, con- ritis, intestinal perforation, jaundice, leukopenia,
fusion, conjunctivitis, convulsions, cystitis, depression, lymphadenopathy, malaise, melena, memory impair-
diaphoresis, drowsiness, dyspnea, dysuria, ecchymo- ment, meningitis, myocardial infarction, nephrotic syn-
ses, eosinophilia, eructation, erythema multiforme, drome, nervousness, oliguria, palpitations,
esophagitis, exfoliative dermatitis, fever, fulminant pancreatitis, pancytopenia, paresthesia, peptic ulcer,
hepatitis, gastritis, gastrointestinal hemorrhage, glos- pneumonia, polyuria, proteinuria, psychotic reaction,
sitis, hallucination, hematemesis, hematuria, hemo- purpura, rectal hemorrhage, renal failure, renal papil-
lytic anemia, hepatic failure, hepatic necrosis, lary necrosis, respiratory depression, seizure, sepsis,
hepatitis, hepatotoxicity, hyperglycemia, hypertension, skin photosensitivity, Stevens-Johnson syndrome, sto-
hypotension, infection, insomnia, interstitial nephritis, matitis, syncope, tachycardia, taste disorder, thrombo-
jaundice, leukopenia, lymphadenopathy, malaise, cytopenia, toxic epidermal necrolysis, tremor, urticaria,
423
vasculitis, vertigo, weakness, weight changes, xero- Injection:

stomia Mild impairment: There are no dosage adjustments
provided in the manufacturer's labeling.
Rectal suppository [Canadian product]:
Moderate to severe impairment: Use is not recom-
Also refer to adverse reactions associated with oral
mended; contraindicated in patients in the perioper-
formulations.
ative period and who are at risk for volume
<1%, postmarketing, and/or case reports: Hemor-
depletion.
rhoids (exacerbation), local hemorrhage, proctitis,
KDIGO 2012 guidelines provide the following recom-
rectal irritation
mendations for NSAIDs:
Dental Usual Dosage Pain: Adults: Oral: Starting eGFR 30 to <60 mL/minute/1.73 m2: Temporarily
dose: 50 mg 3 times/day; maximum dose: 150 mg/day discontinue in patients with intercurrent disease
Dosing that increases risk of acute kidney injury.
Adult Note: Dyloject (diclofenac injection) has been eGFR <30 mL/minute/1.73 m2: Avoid use.
discontinued in the United States for more than 1 year.
Note: For all indications, it has been recommended to
adjustments provided in the manufacturer's labeling;
not exceed 100 mg/day based on increased risk of
however, may require dosage adjustment due to
vascular events (eg, stroke, nonfatal MI) (Bhala
extensive hepatic metabolism. Additional product-spe-
2013; Health Canada communication 2014)
cific recommendations:
Ankylosing spondylitis: Oral: Delayed-release tab-
Cambia: Use the lowest effective dose for the short-
let: 25 mg 4 times daily and 25 mg at bedtime as
est duration possible.
needed Zipsor/Zorvolex: Initial: Initiate treatment at the low-
Migraine: Oral: Powder for oral solution: 50 mg (one est dose; if efficacy is not achieved with the lowest
packet) as a single dose; safety and efficacy of a dose, discontinue use.
second dose have not been established. Injection:
Osteoarthritis: Mild impairment: No dosage adjustment necessary.
Oral: Moderate to severe impairment: Use is not recom-
Immediate-release tablet: 50 mg 2 to 3 times daily; mended (has not been studied).
Delayed-release tablet: 50 mg 2 to 3 times daily or
Pediatric Note: Different oral formulations are not
75 mg twice daily; Extended-release tablet:
bioequivalent; do not interchange products.
100 mg once daily
Juvenile idiopathic arthritis: Limited data avail-
Immediate-release capsule: Zorvolex (diclofenac
able: Children and Adolescents: Oral: Immediate
acid): 35 mg 3 times daily.
release tablet: 2 to 3 mg/kg/day in divided doses
Rectal suppository [Canadian product]: Insert 50 mg
2 to 4 times/day; maximum daily dose: 150 mg/day
or 100 mg rectally as single dose to substitute for
(Haapasaari 1983; Hashkes 2005; Leak 1996;
final oral daily dose (maximum combined dose
Petty 2016)
[rectal and oral]: 100 mg/day)
Migraine: Adolescents ≥18 years: Oral: Oral solu-
Pain:
tion: 50 mg (one packet) as a single dose at the
Oral:
time of migraine onset; safety and efficacy of a
Immediate-release tablet: 50 mg 3 times daily; may
second dose have not been established
administer 100 mg as an initial dose, followed by
Renal Impairment: Pediatric
50 mg 3 times daily
Children and Adolescents: There are no pediatric-
Immediate-release capsule:
specific dosage adjustments provided in the manu-
Zipsor (diclofenac potassium): 25 mg 4 times daily
facturer's labeling; some experts have suggested the
Zorvolex (diclofenac acid): 18 mg or 35 mg 3
following:
times daily
KDIGO 2012 guidelines provide the following recom-
IV: 37.5 mg every 6 hours as needed; adjust fre-
mendations for NSAIDs (KDIGO 2013):
quency according to patient response (maximum:
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily
150 mg/day).
discontinue in patients with intercurrent disease
Primary dysmenorrhea: Oral: Immediate-release
that increases risk of acute kidney injury
tablet: 50 mg 3 times daily; may administer 100 mg
eGFR <30 mL/minute/1.73 m2: Avoid use.
as an initial dose, followed by 50 mg 3 times daily
Rheumatoid arthritis:
Oral: Immediate-release tablet: 50 mg 3 to 4 times
ing; however, may require dosage adjustment due to
daily; Delayed-release tablet: 50 mg 3 to 4 times
extensive hepatic metabolism.
daily or 75 mg twice daily; Extended-release tablet:
100 mg once daily; may increase to 100 mg twice Mechanism of Action Reversibly inhibits cyclooxyge-
nase-1 and 2 (COX-1 and 2) enzymes, which results in
daily
decreased formation of prostaglandin precursors; has
Rectal suppository [Canadian product]: Insert 50 mg
antipyretic, analgesic, and anti-inflammatory properties
or 100 mg rectally as single dose to substitute for
final oral daily dose (maximum combined dose Other proposed mechanisms not fully elucidated (and
[rectal and oral]: 100 mg/day possibly contributing to the anti-inflammatory effect to
Geriatric Refer to adult dosing. Use with caution; varying degrees), include inhibiting chemotaxis, altering
initiate using lowest recommended dose and fre- lymphocyte activity, inhibiting neutrophil aggregation/
quency. activation, and decreasing proinflammatory cytokine
Renal Impairment: Adult levels.
Oral: Contraindications
Mild or moderate impairment: No dosage adjustment Hypersensitivity to diclofenac (eg, anaphylactoid reac-
necessary. tions, serious skin reactions) or bovine protein (Zipsor
Significant impairment or advanced renal disease: only) or any component of the formulation; history of
Use is not recommended. asthma, urticaria, or other allergic-type reactions after
424
taking aspirin or other NSAIDs; use in the setting of [US Boxed Warning]: NSAIDs cause an increased
CABG surgery; patients with moderate to severe renal risk of serious GI inflammation, ulceration, bleed-
impairment in the perioperative period and who are at ing, and perforation (may be fatal); elderly patients
risk for volume depletion (injection only). and patients with history of peptic ulcer disease
Canadian labeling: Additional contraindications (not in and/or GI bleeding are at greater risk for serious
US labeling): Severe uncontrolled heart failure; active GI events. These events may occur at any time
gastric/duodenal/peptic ulcer; active GI bleed or per- during therapy and without warning. Avoid use in
foration, regional ulcer or enteritis, gastritis, ulcerative patients with active GI bleeding. In patients with a
colitis, or recurrent ulceration; cerebrovascular bleed- history of acute lower GI bleeding, avoid use of non-
ing or other bleeding disorders; inflammatory bowel aspirin NSAIDs, especially if due to angioectasia or
disease; severe hepatic impairment; active hepatic diverticulosis (Strate 2016). Use caution with a history
disease; severe renal impairment (CrCl <30 mL/ of GI ulcers, concurrent therapy known to increase the
minute) or deteriorating renal disease; known hyper- risk of GI bleeding (eg, aspirin, anticoagulants and/or
kalemia; patients <16 years of age (suppository, tab- corticosteroids, selective serotonin reuptake inhibitors),
let) or <18 years of age (packet only); breastfeeding; advanced hepatic disease, coagulopathy, smoking, use
pregnancy (third trimester); recent history of bleeding of alcohol, or in elderly or debilitated patients. Use the
or inflammatory lesions of rectum/anus (supposi- lowest effective dose for the shortest duration of time,
tory only) consistent with individual patient goals, to reduce risk of
Warnings/Precautions [US Boxed Warning]: GI adverse events; alternate therapies should be con-
NSAIDs cause an increased risk of serious (and sidered for patients at high risk. When used concom-
potentially fatal) adverse cardiovascular thrombotic itantly with aspirin, a substantial increase in the risk of
events, including MI and stroke. Risk may occur gastrointestinal complications (eg, ulcer) occurs; con-
early during treatment and may increase with dura- comitant gastroprotective therapy (eg, proton pump
tion of use. Relative risk appears to be similar in those inhibitors) is recommended (Bhatt 2008).
with and without known cardiovascular disease or risk
Use the lowest effective dose for the shortest duration
factors for cardiovascular disease; however, absolute
of time, consistent with individual patient goals, to
incidence of serious cardiovascular thrombotic events
reduce risk of cardiovascular or GI adverse events.
(which may occur early during treatment) was higher in
Alternate therapies should be considered for patients
patients with known cardiovascular disease or risk
at high risk. Elderly patients are at greater risk for
factors and in those receiving higher doses. New onset
serious GI, cardiovascular, and/or renal adverse
hypertension or exacerbation of hypertension may
events.
occur (NSAIDs may also impair response to ACE
inhibitors, thiazide diuretics, or loop diuretics); may NSAIDs may cause potentially fatal serious skin
contribute to cardiovascular events; monitor blood pres- adverse events including exfoliative dermatitis, Ste-
sure; use with caution in patients with hypertension. vens-Johnson syndrome (SJS), and toxic epidermal
May cause sodium and fluid retention; use with caution necrolysis (TEN); may occur without warning; discon-
in patients with edema. Avoid use in heart failure tinue use at first sign of skin rash (or any other hyper-
(ACCF/AHA [Yancy 2013]). Avoid use in patients with sensitivity).
recent MI unless benefits outweigh risk of cardiovascu-
Anaphylactoid reactions may occur, even without prior
lar thrombotic events. Use the lowest effective dose for
exposure; patients with "aspirin triad" (bronchial
the shortest duration of time, consistent with individual
asthma, aspirin intolerance, rhinitis) may be at
patient goals, to reduce risk of cardiovascular events;
increased risk. Use is contraindicated in patients who
alternate therapies should be considered for patients at
experience bronchospasm, asthma, rhinitis, or urticaria
high risk. [US Boxed Warning]: Use is contraindi-
with NSAID or aspirin therapy. Use caution in other
cated in the setting of coronary artery bypass graft
forms of asthma. Platelet adhesion and aggregation
(CABG) surgery. Risk of MI and stroke may be
may be decreased; may prolong bleeding time; patients
increased with use following CABG surgery.
with coagulation disorders or who are receiving anti-
NSAID use may compromise existing renal function; coagulants should be monitored closely. Anemia may
dose-dependent decreases in prostaglandin synthesis occur; patients on long-term NSAID therapy should be
may result from NSAID use, reducing renal blood flow monitored for anemia. Rarely, NSAID use may cause
which may cause renal decompensation (usually rever- severe blood dyscrasias (eg, agranulocytosis, aplastic
sible). Patients with impaired renal function, dehydra- anemia, thrombocytopenia).
tion, hypovolemia, heart failure, hepatic impairment,
Use with caution in patients with hepatic impairment;
those taking diuretics and ACE inhibitors, and the
reduced doses may be required due to extensive hep-
elderly are at greater risk of renal toxicity. Rehydrate
atic metabolism. Patients with advanced hepatic dis-
patient before starting therapy; monitor function closely.
ease are at an increased risk of GI bleeding with
Long-term NSAID use may result in renal papillary
NSAIDs. Transaminase elevations have been reported
necrosis and other renal injury. NSAID use may
with use; closely monitor patients with any abnormal
increase the risk for hyperkalemia, particularly in elderly
LFT. Rare, sometimes fatal, severe hepatic reactions
patients, diabetic patients, those with renal disease,
(eg, fulminant hepatitis, hepatic necrosis, hepatic fail-
and with concomitant use of other agents capable of
ure) have occurred with NSAID use; discontinue imme-
inducing hyperkalemia (eg, ACE inhibitors). Monitor
diately if clinical signs or symptoms of liver disease
potassium closely. Avoid use in patients with advanced
develop or if systemic manifestations occur.
renal disease unless benefits are expected to outweigh
risk of worsening renal function; monitor closely if NSAIDS may cause drowsiness, dizziness, blurred
therapy must be initiated. Injection is not recommended vision, and other neurologic effects which may impair
in patients with moderate to severe renal impairment physical or mental abilities; patients must be cautioned
and is contraindicated in patients with moderate to about performing tasks which require mental alertness
severe renal impairment in the perioperative period (eg, operating machinery or driving). Discontinue use
and who are at risk for volume depletion. with blurred or diminished vision and perform
425
ophthalmologic exam. Monitor vision with long-term ADEK, Folate, Iron); Multivitamins/Minerals (with AE,
therapy. May increase the risk of aseptic meningitis, No Iron); Naftazone; Omega-3 Fatty Acids; Pelubipro-
especially in patients with systemic lupus erythemato- fen; Pentosan Polysulfate Sodium; Pentoxifylline;
sus (SLE) and mixed connective tissue disorders. Phenylbutazone; Probenecid; Prostacyclin Ana-
logues; Resveratrol; Selective Serotonin Reuptake
Withhold for at least 4 to 6 half-lives prior to surgical or
Inhibitors; Serotonin/Norepinephrine Reuptake Inhib-
dental procedures.
itors; Sodium Phosphates; Talniflumate; Tenoxicam;
Different formulations of oral diclofenac are not bioequi- Thiazide and Thiazide-Like Diuretics; Tipranavir; Tol-
valent, even if the milligram strength is the same; do not perisone; Tricyclic Antidepressants (Tertiary Amine);
interchange products. Vitamin E (Systemic); Voriconazole; Zaltoprofen
Decreased Effect
Zipsor (capsule) contains gelatin; use is contraindicated
Diclofenac (Systemic) may decrease the levels/effects
in patients with history of hypersensitivity to bovine
of: Aliskiren; Angiotensin II Receptor Blockers; Angio-
protein.
tensin-Converting Enzyme Inhibitors; Beta-Blockers;
Injection is not indicated for long-term use. Eplerenone; HydrALAZINE; Loop Diuretics; Macimor-
elin; Mifamurtide; Potassium-Sparing Diuretics; Pros-
Oral solution: Indicated only for the acute treatment of
taglandins (Ophthalmic); Salicylates; Selective
migraine (not indicated for migraine prophylaxis or
Serotonin Reuptake Inhibitors; Sincalide; Thiazide
cluster headache). Acute migraine agents (eg, NSAIDs,
and Thiazide-Like Diuretics
triptans, opioids, ergotamine, or a combination of the
agents) used for 10 or more days per month may lead to The levels/effects of Diclofenac (Systemic) may be
worsening of headaches (medication overuse head- decreased by: Bile Acid Sequestrants; CYP2C9
ache); withdrawal treatment may be necessary in the Inducers (Moderate); Salicylates
setting of overuse. Product may contain phenylalanine. Dietary Considerations Oral immediate-release for-
Drug Interactions mulations may be taken with food to decrease GI
Metabolism/Transport Effects Substrate of distress. However, food may reduce effectiveness of
CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), oral solution and diclofenac acid (capsule). Some prod-
CYP2C8 (minor), CYP2C9 (minor), CYP2D6 (minor), ucts may contain phenylalanine.
CYP3A4 (minor); Note: Assignment of Major/Minor Pharmacodynamics/Kinetics
substrate status based on clinically relevant drug Half-life Elimination Oral: ~2 hours, ~1 hour (liquid
interaction potential; Inhibits UGT1A6 filled capsule [Zipsor]); Injection: ~1.4 hours
Avoid Concomitant Use Time to Peak Serum: Note: Fasted values reported
Avoid concomitant use of Diclofenac (Systemic) with for oral products; may be delayed with food.
any of the following: Acemetacin; Aminolevulinic Acid Cambia: ~0.25 hours
(Systemic); Dexibuprofen; Dexketoprofen; Floctafe- Cataflam, Zorvolex: ~1 hour
nine; Ketorolac (Nasal); Ketorolac (Systemic); Maci- Zipsor: ~0.47 ± 0.17 hour
morelin; Mifamurtide; Morniflumate; Nonsteroidal Anti- Injection: ~5 minutes
Inflammatory Agents (COX-2 Selective); Omacetax- Tablet, delayed release (diclofenac sodium): 2.3 hours
ine; Pelubiprofen; Phenylbutazone; Talniflumate; Tablet, extended release (diclofenac sodium): 5.3
Tenoxicam; Urokinase; Zaltoprofen hours
Increased Effect/Toxicity Pregnancy Risk Factor C/D (≥30 weeks gestation)
Diclofenac (Systemic) may increase the levels/effects Pregnancy Considerations
of: 5-Aminosalicylic Acid Derivatives; Agents with Anti- Diclofenac crosses the placenta. Birth defects have
platelet Properties; Aliskiren; Aminoglycosides; Ami- been observed following in utero NSAID exposure in
nolevulinic Acid (Systemic); Aminolevulinic Acid some studies; however, data is conflicting (Bloor 2013).
(Topical); Anticoagulants; Apixaban; Bisphosphonate Nonteratogenic effects, including prenatal constriction
Derivatives; Cephalothin; Collagenase (Systemic); of the ductus arteriosus, persistent pulmonary hyper-
CycloSPORINE (Systemic); Dabigatran Etexilate; tension of the newborn, oligohydramnios, necrotizing
Deferasirox; Deferiprone; Deoxycholic Acid; Desmo- enterocolitis, renal dysfunction or failure, and intracra-
pressin; Dexibuprofen; Digoxin; Drospirenone; Edox- nial hemorrhage have been observed in the fetus/neo-
aban; Eplerenone; Haloperidol; Ibritumomab Tiuxetan; nate following in utero NSAID exposure. In addition,
Lithium; Methotrexate; Nalmefene; Nonsteroidal Anti- nonclosure of the ductus arteriosus postnatally may
Inflammatory Agents; Nonsteroidal Anti-Inflammatory occur and be resistant to medical management (Ber-
Agents (COX-2 Selective); Obinutuzumab; Omacetax- mas 2014; Bloor 2013). Because they may cause
ine; Porfimer; Potassium-Sparing Diuretics; PRALA- premature closure of the ductus arteriosus, product
trexate; Quinolones; Rivaroxaban; Salicylates; labeling for diclofenac specifically states use should
Tacrolimus (Systemic); Tenofovir Products; Thrombo- be avoided starting at 30-weeks gestation.
lytic Agents; Tolperisone; Urokinase; Vancomycin;
Verteporfin; Vitamin K Antagonists Use of NSAIDs can be considered for the treatment of
mild rheumatoid arthritis flares in pregnant women;
The levels/effects of Diclofenac (Systemic) may be however, use should be minimized or avoided early
increased by: Acemetacin; Alcohol (Ethyl); Angioten- and late in pregnancy (Bermas 2014; Saavedra Salinas
sin II Receptor Blockers; Angiotensin-Converting 2015). If treatment of migraine is needed in pregnant
Enzyme Inhibitors; Corticosteroids (Systemic); Cyclo- women, agents other than diclofenac are preferred
SPORINE (Systemic); CYP2C9 Inhibitors (Moderate);
(Amundsen 2015).
Dasatinib; Dexketoprofen; Fat Emulsion (Fish Oil
Based); Felbinac; Floctafenine; Glucosamine; Herbs The chronic use of NSAIDs, including diclofenac, in
(Anticoagulant/Antiplatelet Properties); Ibrutinib; Ino- women of reproductive age may be associated with
tersen; Ketorolac (Nasal); Ketorolac (Systemic); infertility that is reversible upon discontinuation of the
Limaprost; Loop Diuretics; Morniflumate; Multivita- medication. Consider discontinuing use in women hav-
mins/Fluoride (with ADE); Multivitamins/Minerals (with ing difficulty conceiving or those undergoing
426
DICLOFENAC (TOPICAL)
investigation of fertility. The use of NSAIDs close to Patch:

conception may be associated with an increased risk Flector: Treatment of acute pain due to minor strains,
of miscarriage (Bermas 2014; Bloor 2013). sprains, and contusions in adults and children ≥6
Breastfeeding Considerations years of age
Diclofenac is present in breast milk. Licart: Treatment of acute pain due to minor strains,
The relative infant dose (RID) of diclofenac is 0.5% to sprains, and contusions in adults
0.75% when calculated using the highest breast milk Solution: Treatment of osteoarthritis pain of the knee
concentration located and compared to an infant ther- Local Anesthetic/Vasoconstrictor Precautions
apeutic dose of 2 to 3 mg/kg/day. In general, breast- No information available to require special precautions
feeding is considered acceptable when the RID is Effects on Dental Treatment No significant effects or
<10%; when an RID is >25%, breastfeeding should complications reported
generally be avoided (Anderson 2016; Ito 2000). Effects on Bleeding No information available to
Using the highest milk concentration (100 mcg/L), require special precautions
the estimated daily infant dose via breast milk is Adverse Reactions
0.015 mg/kg/day. This milk concentration was Topical gel:
obtained following maternal administration of oral >10%:
diclofenac 150 mg/day. Dermatologic: Pruritus (≤52%), application site rash
In general, NSAIDs may be used in postpartum women (35% to 46%), contact dermatitis (2% to 33%),
who wish to breastfeed; however, agents other than xeroderma (3% to 27%), application site pain (15%
diclofenac may be preferred (Amundsen 2015; Mont- to 26%), desquamation (application site 6% to 24%)
gomery 2012) and use should be avoided in women Hepatic: Increased serum transaminases (<3 x ULN:
breastfeeding infants with platelet dysfunction or 15%; >3 x ULN: 2% to 4%; >8 x ULN: 1%)
thrombocytopenia (Bloor 2013; Sammaritano 2014). 1% to 10%:
Product Availability Dyloject (diclofenac injection) has Cardiovascular: Chest pain (1% to 2%), hypertension
been discontinued in the United States for more than 1 (1% to 2%)
year. Central nervous system: Headache (7%), hyperesthe-
Dosage Forms: US sia (3%), paresthesia (2%), pain (1% to 2%),
Capsule, Oral: migraine (1%)
Zipsor: 25 mg Dermatologic: Application site paresthesia (≤8%), ves-
iculobullous dermatitis (application site 4%), skin
Zorvolex: 18 mg, 35 mg
rash (4%), alopecia (application site 2%), skin photo-
Packet, Oral:
sensitivity (application site 3%), dermal ulcer (1% to
Cambia: 50 mg (1 ea, 9 ea)
2%), acne vulgaris (application site 1%)
Tablet, Oral:
Endocrine & metabolic: Application site edema (3% to
Generic: 50 mg
4%), hypercholesterolemia (1%), hyperglyce-
Tablet Delayed Release, Oral:
mia (1%)
Gastrointestinal: Diarrhea (2%), dyspepsia (2%),
abdominal pain (1% to 2%)
Generic: 100 mg Genitourinary: Hematuria (2%)
Dosage Forms: Canada Note: Refer also to Dosage Hepatic: Increased serum ALT (2% to 4%), increased
Forms; Zipsor and Zorvolex capsules are not currently serum AST (2% to 4%), increased liver enzymes
available in Canada. Neuromuscular and skeletal: Back pain (4%),
Suppository: increased creatine phosphokinase (4%), myalgia
Voltaren: 50 mg, 100 mg (2% to 3%), arthralgia (2%), arthropathy (2%), hypo-
Tablet, Oral, as potassium: kinesia (2%), neck pain (2%), weakness (2%)
Voltaren Rapide: 50 mg Ophthalmic: Conjunctivitis (2% to 4%), eye pain (2%)
Respiratory: Flu-like symptoms (10%), asthma (2%),
Diclofenac (Topical) (dye KLOE fen ak) dyspnea (2%), pneumonia (2%), sinusitis (2%)
Miscellaneous: Accidental injury (4%)
Brand Names: US Diclo Gel with Xrylix Sheets; Diclo <1%, postmarketing, and/or case reports: Application
Gel [DSC]; Diclozor; DSG Pak [DSC]; DST Plus Pak site irritation, application site reaction (skin carcinoma,
[DSC]; EnovaRX-Diclofenac Sodium; Flector; Klofen- hypertonia, skin hypertrophy lacrimation disorder,
said II [DSC]; Lexixryl; Pennsaid; Rexaphenac; Solar- maculopapular rash, purpuric rash, vasodilation),
aze [DSC]; Voltaren; Vopac MDS [DSC]; Xrylix edema, hepatic failure, hepatic necrosis, hepatitis
Brand Names: Canada Pennsaid; Voltaren Emulgel (fulfillment; with and without jaundice), hepatotoxicity,
Pharmacologic Category Nonsteroidal Anti-inflam- jaundice, papule (application site), paresthesia, sebor-
matory Drug (NSAID); Nonsteroidal Anti-inflammatory rhea, skin blister (application site), skin hypertrophy,
Drug (NSAID), Topical urticaria
Use Topical solution:
Gel 1%: Relief of osteoarthritis pain in joints amenable >10%: Dermatologic: Xeroderma (application site 22%
to topical therapy (eg, ankle, elbow, foot, hand, knee, to 32%; nonapplication site 2%)
wrist) 1% to 10%:
Gel 3%: Treatment of actinic keratosis (AK) in conjunc- Cardiovascular: Edema (3%)
tion with sun avoidance Dermatologic: Contact dermatitis (2% to 9%), desqua-
Gel 1.16% (Voltaren Emulgel), 2.32% (Voltaren Emul- mation (application site 7%), application site eryth-
gel Extra Strength) [Canadian products]: Relief of pain ema (4%), pruritus (application site 2% to 4%;
associated with acute, localized joint/muscle injuries nonapplication site 2%); skin rash (3%), application
(eg, sports injuries, strains) in patients ≥16 years of site pain (2%), application site rash (2%), skin scle-
age (1.16% gel) or ≥18 years of age (2.32% gel) rosis (application site: 2%)
427
DICLOFENAC (TOPICAL)
Gastrointestinal: Dyspepsia (8%), abdominal pain The chronic use of NSAIDs in females of reproductive
(6%), diarrhea (4%), flatulence (4%), nausea (2% potential may be associated with infertility that is rever-
to 4%), constipation (3%), halitosis (1%) sible upon discontinuation of the medication. Consider
Genitourinary: Urinary tract infection (3%) discontinuing use in females having difficulty conceiving
Hematologic & oncologic: Bruise (2%) or those undergoing investigation of fertility.
Infection: Infection (3%) Product Availability
Respiratory: Sinus congestion (2%), sinusitis (1%) Licart (diclofenac epolamine 1.3% topical system): FDA
Postmarketing and/or case reports: Accidental injury, approved December 2018; availability anticipated in
aphthous stomatitis, asthma, back pain, blurred vision, the fourth quarter of 2019. Consult the prescribing
body odor, burning sensation of skin, cardiac disease, information for additional information.
cataract, chest pain, crusted skin, decreased appetite, Solaraze gel has been discontinued in the US for
depression, dizziness, drowsiness, dysgeusia, dysp- >1 year.
nea, eczema, eye pain, facial edema, gastroenteritis,
headache, hypersensitivity reaction, hypertension,
increased blood pressure, increased serum creatinine,
Diclofenac and Misoprostol
(dye KLOE fen ak & mye soe PROST ole)
laryngismus, laryngitis, leg cramps, lethargy, lip
edema, myalgia, neck stiffness, ophthalmic signs Related Information
and symptoms, oral mucosa ulcer, otalgia, palpita- Diclofenac (Systemic) on page 422
tions, pharyngeal edema, pharyngitis, rectal hemor- MiSOPROStol on page 914
rhage, skin discoloration, tongue edema, urticaria, Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
visual disturbance, weakness, xerostomia on page 1484
Transdermal patch: Brand Names: US Arthrotec
1% to 10%: Brand Names: Canada ACT Diclo-Miso; Arthrotec;
Central nervous system: Dizziness (<1%), hypoesthe- GD-Diclofenac/Misoprostol
sia (<1%) Pharmacologic Category Analgesic, Nonopioid; Non-
Dermatologic: Hyperhidrosis (<4%), localized eryth- steroidal Anti-inflammatory Drug (NSAID), Oral; Pros-
ema (<4%), localized vesiculation (<4%), skin dis- taglandin
coloration (<4%), xeroderma (local: <4%), dermatitis Use Osteoarthritis/rheumatoid arthritis: Treatment of
(2%), hypersensitivity reaction (dermal) the signs and symptoms of osteoarthritis or rheumatoid
Gastrointestinal: Nausea (3%), upper abdominal pain arthritis in patients at high risk for NSAID-induced
(<3%), constipation (<3%), diarrhea (<3%), gastritis gastric and duodenal ulcers and their complications.
(<3%), vomiting (<3%), xerostomia (<3%), dysgeu- Local Anesthetic/Vasoconstrictor Precautions
sia (2%) No information available to require special precautions
Local: Application site atrophy (<4%), local irritation Effects on Dental Treatment The dentist should be
(<4%), localized edema, local pruritus aware of the potential of abnormal coagulation. Caution
Neuromuscular & skeletal: Hyperkinesia (<1%) should also be exercised in the use of NSAIDs in
Postmarketing and/or case reports: Cerebrovascular patients already on anticoagulant therapy with drugs
accident, edema, exfoliative dermatitis, fluid retention, such as warfarin (Coumadin). See Effects on Bleeding.
myocardial infarction, Stevens-Johnson syndrome, Effects on Bleeding Nonselective NSAIDs, such as
toxic epidermal necrolysis diclofenac, inhibit platelet aggregation and prolong
Mechanism of Action bleeding time in some patients. Unlike aspirin, the
Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and NSAID effect on platelet function is quantitatively less,
2) enzymes, which results in decreased formation of of shorter duration, and reversible.
prostaglandin precursors; has antipyretic, analgesic, Adverse Reactions Percentages reported with combi-
and anti-inflammatory properties nation product. Also see individual agents.
Other proposed mechanisms not fully elucidated (and >10%: Gastrointestinal: Abdominal pain (21%), diar-
possibly contributing to the anti-inflammatory effect to rhea (19%), dyspepsia (14%), nausea (11%)
varying degrees), include inhibiting chemotaxis, alter- 1% to 10%:
ing lymphocyte activity, inhibiting neutrophil aggrega- Gastrointestinal: Flatulence (9%)
tion/activation, and decreasing proinflammatory Hepatic: Increased serum ALT (2%)
cytokine levels. Frequency not defined:
Pharmacodynamics/Kinetics Central nervous system: Anxiety, depression, dizzi-
Half-life Elimination Patch: ~12 hours; Solution ness, drowsiness, fatigue, headache, insomnia, irri-
1.5%: 36.7 ± 20.8 hours (single application) tability, lack of concentration, malaise, paresthesia,
Time to Peak Serum: Patch: 4 to 20 hours; Solution vertigo
1.5%: 11 ± 6.4 hours (single application); Gel 3%: 4.5 Dermatologic: Alopecia, diaphoresis, eczema, pem-
± 8 hours; Gel 1%: 10 to 14 hours phigoid reaction, pruritus, skin photosensitivity
Pregnancy Considerations Endocrine & metabolic: Dehydration, hypermenor-
Diclofenac crosses the placenta following systemic rhea, hyponatremia, menstrual disease
administration. The amount of diclofenac available sys- Gastrointestinal: Anorexia, benign gastrointestinal
temically following topical application is less in compar- neoplasm, change in appetite, constipation, dysgeu-
ison to oral doses. Reversible constriction of the ductus sia, dysphagia, eructation, esophageal ulcer, esoph-
arteriosus in utero has been observed following topical agitis, gastritis, gastroesophageal reflux disease,
application of diclofenac (Torloni 2006). Because melena, peptic ulcer, tenesmus, vomiting, xero-
NSAIDs may cause premature closure of the ductus stomia
arteriosus, product labeling for diclofenac specifically Genitourinary: Dysmenorrhea, dysuria, mastalgia,
states use should be avoided starting at 30 weeks' nocturia, proteinuria, urinary tract infection, vaginal
gestation. hemorrhage
428
DICLOXACILLIN
Hematologic & oncologic: Decreased hematocrit, leu- Warning]: Use is contraindicated in pregnant
kopenia, purpura women; administration of misoprostol to pregnant
Hepatic: Increased serum AST women may cause abortion, premature birth, or
Neuromuscular & skeletal: Arthralgia, increased birth defects; uterine rupture has been reported.
serum alkaline phosphatase, myalgia, weakness Do not use in women of childbearing potential
Ophthalmic: Diplopia unless the woman requires NSAID therapy and is
Otic: Tinnitus at high risk of developing gastric or duodenal ulcer-
Renal: Polyuria ation or for developing complications from gastric
Respiratory: Asthma, cough, epistaxis, hyperventi- or duodenal ulcers associated with NSAID use. May
lation be prescribed to women of childbearing potential if
<1%, postmarketing, and/or case reports: Abnormal the patient is capable of complying with effective
dreams, abnormal lacrimation, acne vulgaris, ageusia, contraceptive measures; has a negative serum
agranulocytosis, amblyopia, anaphylactoid reaction, pregnancy test within 2 weeks prior to starting
anaphylaxis, anemia, angioedema, aphthous stomati- therapy; has received both oral and written commu-
tis, aplastic anemia, aseptic meningitis, atrial fibrilla- nication of the potential risks of misoprostol, the
tion, auditory impairment, blurred vision, bruise, risk of possible contraception failure, and danger to
bullous rash, cardiac arrhythmia, cerebral hemor- other women of childbearing potential should the
rhage, cerebrovascular accident, chills, coma, confu- drug be taken by mistake; and will start diclofenac/
sion, conjunctivitis, cystitis, decreased platelet misoprostol only on the second or third day of the
aggregation, dermal ulcer, disorientation, dyspnea, next normal menstrual period. In addition, diclofenac
ecchymosis, edema, enteritis, eosinophilia, erythema can cause premature closure of the ductus arteriosus
multiforme, exfoliative dermatitis, fever, fluid retention, and use should be avoided in pregnancy (particularly
fulminant hepatitis, gastrointestinal hemorrhage, gas- late pregnancy). Women should also avoid pregnancy
trointestinal perforation, gastrointestinal ulcer, GI through one menstrual cycle or one month after therapy
inflammation, glaucoma, glomerulonephritis, glomer- is complete. See individual agents.
ulopathy (glomerulonephritis minimal lesion), glossitis,
glycosuria, gout, hallucination, heartburn, hemateme-
sis, hematuria, hemolytic anemia, hemorrhoids, hep-
Dicloxacillin (dye kloks a SIL in)
atic failure, hepatic insufficiency, hepatic necrosis, Related Information
hepatitis, hepatotoxicity (idiosyncratic) (Chalasani Bacterial Infections on page 1525
2014), hyperbilirubinemia, hypercholesterolemia,
Pharmacologic Category Antibiotic, Penicillin
hyperesthesia, hyperglycemia, hypersensitivity reac-
tion, hypertension, hypertonia, hyperuricemia, hypo-
Use Staphylococcal infections: Treatment of infec-
tions caused by penicillinase-producing staphylococci.
esthesia, hypoglycemia, hypotension, impotence,
increased blood urea nitrogen, increased coagulation Local Anesthetic/Vasoconstrictor Precautions
time, increased creatine phosphokinase, increased No information available to require special precautions
lactate dehydrogenase, infection, intermenstrual Effects on Dental Treatment Key adverse event(s)
bleeding, interstitial nephritis, intestinal perforation, related to dental treatment: Prolonged use of penicillins
iritis, jaundice, laryngeal edema, leukocytosis, leukor- may lead to development of oral candidiasis.
rhea, lymphadenopathy, membranous glomerulo- Effects on Bleeding Thrombocytopenia has been
nephritis, meningitis, migraine, mood changes, reported.
mucocutaneous eruptions, myocardial infarction, Adverse Reactions Frequency not defined.
nephrotic syndrome, nervousness, neuralgia, night- 1% to 10%: Gastrointestinal: Abdominal pain diarrhea,
mares, nocturnal amblyopia, oliguria, palpitations, nausea
pancreatitis, pancytopenia, paranoia, perineal pain, <1%, postmarketing, and/or case reports: Agranulocy-
periorbital edema, pharyngeal edema, phlebitis, pneu- tosis, anemia, eosinophilia, fever, hematuria, hemo-
monia, porphyria, pruritus ani, psychotic reaction, lytic anemia, hepatotoxicity, hypersensitivity reaction,
pulmonary embolism, rectal bleeding, reduced fertility increased blood urea nitrogen, increased liver
(female), renal failure, renal insufficiency, renal papil- enzymes (transient), increased serum creatinine,
lary necrosis, respiratory depression, seizure, sepsis, interstitial nephritis, leukopenia, neutropenia, pro-
skin rash, Stevens-Johnson syndrome, stomatitis, longed prothrombin time, pseudomembranous colitis,
syncope, tachycardia, thrombocythemia, thrombocy- seizure (with extremely high doses and/or renal fail-
topenia, toxic epidermal necrolysis, transient ischemic ure), serum sickness-like reaction, skin rash (maculo-
attacks, tremor, urinary frequency, urticaria, uterine papular rash to exfoliative dermatitis),
cramps, uterine hemorrhage, vaginitis, vasculitis, ven- thrombocytopenia, vaginitis, vomiting
tricular premature contractions, visual disturbance, Mechanism of Action Inhibits bacterial cell wall syn-
weight changes thesis by binding to one or more of the penicillin-binding
Mechanism of Action proteins (PBPs) which in turn inhibits the final trans-
Diclofenac: Reversibly inhibits cyclooxygenase-1 and 2 peptidation step of peptidoglycan synthesis in bacterial
(COX-1 and 2) enzymes, which results in decreased cell walls, thus inhibiting cell wall biosynthesis. Bacteria
formation of prostaglandin precursors; has antipyretic, eventually lyse due to ongoing activity of cell wall
analgesic, and anti-inflammatory properties. autolytic enzymes (autolysins and murein hydrolases)
Misoprostol: Synthetic prostaglandin E1 analog that while cell wall assembly is arrested.
replaces the protective prostaglandins consumed with Pharmacodynamics/Kinetics
prostaglandin-inhibiting therapies (eg, NSAIDs). Half-life Elimination ~0.7 hours; prolonged with
Pregnancy Considerations Adverse events have not renal impairment (Nauta 1976)
been observed in animal reproduction studies with this Time to Peak Serum: 1 to 1.5 hours
combination; however, adverse fetal events have been Pregnancy Risk Factor B
observed following in utero exposure to both diclofenac Pregnancy Considerations Adverse events have not
and misoprostol in human pregnancy. [US Boxed been observed in animal reproduction studies.
429
DICLOXACILLIN
Dicloxacillin crosses the placenta (Depp 1970). Mater- Pharmacologic Category Antiretroviral, Reverse
nal use of penicillins has generally not resulted in an Transcriptase Inhibitor, Nucleoside (Anti-HIV)
increased risk of birth defects. Use HIV infection: Treatment of HIV-1 infection in combi-
nation with other antiretroviral agents.
Dicyclomine (dye SYE kloe meen) Local Anesthetic/Vasoconstrictor Precautions
Related Information Effects on Dental Treatment Key adverse event(s)
Dentin Hypersensitivity, Acid Erosion, High Caries related to dental treatment: Xerostomia (normal salivary
Index, Management of Alveolar Osteitis, and Xerosto- flow resumes upon discontinuation).
mia on page 1548 Effects on Bleeding Thrombocytopenia has been
Brand Names: US Bentyl reported in <1% of patients treated.
Brand Names: Canada Bentylol; Dicyclomine Hydro- Adverse Reactions As reported in monotherapy stud-
chloride Injection; Formulex; Protylol ies; risk of toxicity may increase when combined with
Pharmacologic Category Anticholinergic Agent other agents.
Use Gastrointestinal motility disorders/irritable >10%:
bowel : Treatment of functional bowel/irritable bowel Central nervous system: Peripheral neuropathy (17%
syndrome to 20%)
Local Anesthetic/Vasoconstrictor Precautions Endocrine & metabolic: Increased amylase (≥1.4 x
No information available to require special precautions ULN: 15% to 17%)
Effects on Dental Treatment Key adverse event(s) Gastrointestinal: Diarrhea (19% to 28%), abdominal
related to dental treatment: Xerostomia and changes in pain (7% to 13%)
salivation (normal salivary flow resumes upon discon- 1% to 10%:
tinuation) Dermatologic: Pruritus (≤9%), skin rash (≤9%)
Effects on Bleeding No information available to Endocrine & metabolic: Increased uric acid
require special precautions (>12 mg/dL: 2% to 3%)
Adverse Reactions Gastrointestinal: Pancreatitis (6% to 7%)
>10%: Hepatic: Increased serum AST (>5 x ULN: 7% to 9%),
Central nervous system: Dizziness (40%) increased serum ALT (>5 x ULN: 6% to 9%),
Gastrointestinal: Xerostomia (33%), nausea (14%) increased serum alkaline phosphatase (>5 x ULN:
Ophthalmic: Blurred vision (27%) 1% to 4%)
1% to 10%: <1%, postmarketing, and/or case reports: Acute renal
Central nervous system: Drowsiness (9%), nervous- failure, alopecia, anaphylactoid reaction, anemia, ano-
ness (6%) rexia, arthralgia, chills, diabetes mellitus, dyspepsia,
Neuromuscular & skeletal: Weakness (7%) fever, flatulence, hepatic failure, hepatitis, hyperglyce-
Postmarketing and/or case reports: Abdominal disten- mia, hypoglycemia, increased creatine phosphoki-
tion, abdominal pain, anaphylactic shock, angioe- nase, increased gamma-glutamyl transferase, lactic
d em a , c on fu s io n , c o ns ti pa ti o n, c yc l op le g ia , acidosis, leukopenia, lipoatrophy (buttocks, face,
decreased lactation, delirium, dermatitis (allergic), limbs), myalgia, myopathy, optic neuritis, pain, parotid
dyspepsia, dyspnea, erythema, facial edema, fatigue, gland enlargement, portal hypertension (noncirrhotic),
hallucination, headache, hypersensitivity, insomnia, retinal pigment changes (depigmentation), rhabdo-
malaise, mydriasis, nasal congestion, palpitations, myolysis, severe hepatomegaly with steatosis, siala-
skin rash, syncope, tachyarrhythmia, vomiting denitis, symptomatic hyperlactatemia,
Mechanism of Action Blocks the action of acetylcho- thrombocytopenia, weakness, xerophthalmia, xero-
line at parasympathetic sites in smooth muscle, secre- stomia
tory glands and the CNS Mechanism of Action Didanosine, a purine nucleo-
Pharmacodynamics/Kinetics side (adenosine) analog and the deamination product of
Onset of Action 1 to 2 hours dideoxyadenosine (ddA), inhibits HIV replication in vitro
Duration of Action Up to 4 hours in both T cells and monocytes. Didanosine is converted
within the cell to the mono-, di-, and triphosphates of
Half-life Elimination Initial phase: ~1.8 hours; Termi-
ddA. These ddA triphosphates act as substrate and
nal phase: Undetermined, but somewhat longer than
inhibitor of HIV reverse transcriptase substrate and
the initial phase
inhibitor of HIV reverse transcriptase thereby blocking
Time to Peak Oral: 60 to 90 minutes
viral DNA synthesis and suppressing HIV replication.
Pregnancy Considerations Adverse events have not Pharmacodynamics/Kinetics
been observed in animal reproduction studies. In epi- Half-life Elimination
demiologic studies, birth defects were not observed Plasma:
following maternal doses up to 40 mg daily throughout Newborns (1 day old): 2 ± 0.7 hours
the first trimester; information has not been located
Infants 2 weeks to 4 months: 1.2 ± 0.3 hours
when used in pregnant women at recommended doses
Infants 8 months to Adolescents 19 years: 0.8 ± 0.3
(80 to 160 mg daily). Agents other than dicyclomine
hours
may be preferred for the treatment of irritable bowel
Adults with normal renal function: 1.5 ± 0.4 hours
syndrome in pregnant women (Enck 2016).
Intracellular: Adults: 25 to 40 hours
Elimination: Increased as CrCl decreased
Didanosine (dye DAN oh seen) Children 20 kg to <25 kg: 0.75 ± 0.13 hours
Children 25 kg to <60 kg: 0.92 ± 0.09 hours
Related Information Children ≥60 kg: 1.26 ± 0.19 hours
HIV Infection and AIDS on page 1477 Adults ≥60 kg: 1.19 ± 0.21 hours; 2 ± 0.3 hours (renal
Brand Names: US Videx; Videx EC impairment [CrCl <30 mL/minute]); 4.1 ± 1.2 hours
Brand Names: Canada Videx EC (dialysis)
430
DIETHYLPROPION
Time to Peak Delayed release capsules: 2 hours; Local Anesthetic/Vasoconstrictor Precautions

Powder for suspension: 0.25 to 1.5 hours No information available to require special precautions
Pregnancy Considerations Effects on Dental Treatment No significant effects or
Didanosine has a low to moderate level of transfer complications reported
across the human placenta. Effects on Bleeding No information available to
Based on data from the Antiretroviral Pregnancy Regis-
Adverse Reactions
try, an increased rate of birth defects has been
1% to 10%:
observed following maternal use of didanosine during
Central nervous system: Headache (7%), depression
the first trimester and later during pregnancy; no pattern
(3%), disturbed sleep (2%), irritability (1%), migraine
of defects has been observed and clinical relevance is
(1%), nervousness (1%)
uncertain. Maternal antiretroviral therapy (ART) may
Dermatologic: Acne vulgaris (2%), alopecia (1%)
increase the risk of preterm delivery, although available
Endocrine & metabolic: Breast changes (discomfort:
information is conflicting possibly due to variability of
5%), weight gain (4%), ovarian cyst (3%), decreased
maternal factors (disease severity; gestational age at
libido (2%)
initiation of therapy). An increased risk of stillbirth, low
Gastrointestinal: Nausea (4%), abdominal pain (2%)
birth weight, and small for gestational age infants has Genitourinary: Vaginal hemorrhage (1%)
been observed in some but not all studies. Because Neuromuscular & skeletal: Weakness (2%)
there is clear benefit to appropriate treatment, maternal <1%, postmarketing, and/or case reports: Abdominal
ART should not be withheld due to concerns for adverse distress, anemia, anxiety, back pain, breast induration,
neonatal outcomes. Long-term follow-up is recom- constipation, decreased glucose tolerance, dermatitis,
mended for all infants exposed to antiretroviral medi- diarrhea, disturbance in attention, dysautonomia,
cations; children who develop significant organ system edema, feeling of heaviness (extremities), fibrocystic
abnormalities of unknown etiology (particularly of the breast disease, flatulence, genital discharge, GI
CNS or heart) should be evaluated for potential mito- inflammation, hot flash, increased appetite, limb pain,
chondrial dysfunction. lump in breast, mood changes, muscle spasm, ony-
[US Boxed Warning]: Fatal lactic acidosis has been choclasis, ostealgia, palpitations, pelvic pain, pruritus,
reported in pregnant individuals using didanosine skin pigmentation, skin photosensitivity, tinnitus, uri-
and stavudine in combination with other antiretro- nary tract infection, vulvovaginal candidiasis, vomiting,
viral agents. Cases of lactic acidosis and hepatic vulvar dryness, xeroderma, xerophthalmia
steatosis related to mitochondrial toxicity have been Mechanism of Action Dienogest is a steroid with
reported with use of NRTIs. These adverse events are antiandrogen properties that lacks androgen, mineralo-
similar to other rare but life-threatening syndromes that corticoid or glucocorticoid activity. Exhibits strong pro-
occur during pregnancy (eg, HELLP syndrome). In g e s t o g e n i c e ffe c t s a l th o u g h i t b i n d s u t e r i n e
addition to lactic acidosis, the combination of didano- progesterone receptors with an affinity much lower
sine and stavudine has been shown to increase the risk (about one-tenth) than that of progesterone. Decreases
of birth defects and neurodevelopmental disability. estradiol production and thus suppresses estradiol's
trophic effects on eutopic and ectopic endometrium.
The Health and Human Services (HHS) Perinatal HIV Inhibits cellular proliferation via direct antiproliferative,
Guidelines do not recommend didanosine for initial immunologic, and antiangiogenic effects.
therapy in antiretroviral-naive pregnant females due to Pharmacodynamics/Kinetics
toxicity. In addition, because of the high risk of toxicity, Half-life Elimination ~9 to 10 hours
didanosine should be stopped in females who become Time to Peak ~1.5 hours
pregnant during therapy and women should be Pregnancy Considerations Use is contraindicated
switched to a preferred or alternative regimen. during pregnancy and pregnancy should be ruled out
In general, ART is recommended for all pregnant prior to initiating therapy. Based on limited data, inad-
females with HIV to keep the viral load below the limit vertent exposure in pregnancy has not shown adverse
of detection and reduce the risk of perinatal trans- effects to the fetus. Use of hormonal contraceptives is
mission. Monitoring during pregnancy is more frequent not recommended during dienogest therapy. Nonhor-
than in non-pregnant adults. ART should be continued monal contraceptives should be employed during treat-
postpartum for all females living with HIV and can be ment. Ovulation is often inhibited during therapy
modified after delivery. although normal menstruation usually returns within 2
months of therapy discontinuation.
Health care providers are encouraged to enroll preg- Product Availability Not available in the US
Pregnancy Registry (1-800-258-4263 or http://www.- Diethylpropion (dye eth il PROE pee on)
APRegistry.com). Health care providers caring for Pharmacologic Category Anorexiant; Central Nerv-
HIV-infected females and their infants may contact the ous System Stimulant; Sympathomimetic
Use
Obesity: Short-term (few weeks) adjunct in the man-
agement of exogenous obesity
Dienogest (dye EN oh jest) Pharmacotherapy for weight loss is recommended only
for obese patients with a body mass index ≥30 kg/m2,
Brand Names: Canada Visanne or ≥27 kg/m2 in the presence of other risk factors such
Pharmacologic Category Antiandrogen as hypertension, diabetes, and/or dyslipidemia or a
Use Note: Not approved in the US high waist circumference; therapy should be used in
Endometriosis: Management of pelvic pain associated conjunction with a comprehensive weight manage-
with endometriosis ment program.
431
DIETHYLPROPION

Use vasoconstrictor with caution in patients taking require special precautions
diethylpropion. Amphetamine-like drugs such as dieth- Adverse Reactions Frequency not defined. Reactions
ylpropion enhance the sympathomimetic response of listed are based on reports for other agents in this same
epinephrine and norepinephrine leading to potential pharmacologic class and may not be specifically
hypertension and cardiotoxicity. reported for diflorasone. Diflorasone is classified as a
Effects on Dental Treatment Key adverse event(s) potent topical steroid.
related to dental treatment: Diethylpropion causes Central nervous system: Burning sensation
tachycardia, increases in blood pressure, and palpita- Dermatologic: Acneiform eruption, allergic contact der-
tions. Consider monitoring blood pressure prior to using matitis, atrophic striae, folliculitis, hypertrichosis, hypo-
local anesthetic with a vasoconstrictor. Symptoms asso- pigmentation, maceration of the skin, miliaria, perioral
ciated with bruxism have been observed in some dermatitis, pruritus, skin atrophy, skin irritation, xero-
patients. derma
Effects on Bleeding No information available to Endocrine & metabolic: HPA-axis suppression (children
require special precautions at greater risk)
Adverse Reactions Frequency not defined. Infection: Secondary infection
Cardiovascular: Cardiac arrhythmia, cerebrovascular <1%, postmarketing and/or case reports: Acne rosacea
accident, ECG changes, heart valve disease, hyper- (Hengge 2006), aggravation reaction (cutaneous can-
tension, palpitations, tachycardia didiasis, herpes, dermodex) (Hengge 2006), cataract
Central nervous system: Anxiety, depression, dizziness, (Hengge 2006), dermal ulcer (Hengge 2006), glau-
drowsiness, dysphoria, euphoria, headache, insom- coma (Hengge 2006), hirsutism (Hengge 2006),
nia, jitteriness, malaise, nervousness, overstimulation, hyperpigmentation (Hengge 2006), Kaposi's sarcoma
precordial pain, psychosis, restlessness, seizure (reactivation) (Hengge 2006), nonthrombocytopenic
Dermatologic: Alopecia, diaphoresis, ecchymoses, purpura (Hengge 2006), ocular hypertension (Hengge
erythema, skin rash, urticaria 2006), psoriasis flare (rebound) (Hengge 2006), pur-
Endocrine & metabolic: Changes in libido, gynecomas- pura (Hengge 2006), skin photosensitivity (Hengge
tia, menstrual disease 2006), spontaneous star-shaped scar-like lesions
Gastrointestinal: Abdominal distress, constipation, diar- (Hengge 2006), telangiectasia (Hengge 2006), tinea
rhea, dysgeusia, nausea, vomiting, xerostomia (tinea incognito) (Hengge 2006)
Genitourinary: Dysuria, impotence Mechanism of Action Topical corticosteroids have
Hematologic & oncologic: Agranulocytosis, bone mar- anti-inflammatory, antipruritic, and vasoconstrictive
row depression, leukopenia properties. May depress the formation, release, and
Neuromuscular & skeletal: Dyskinesia, myalgia, tremor activity of endogenous chemical mediators of inflam-
Ophthalmic: Blurred vision, mydriasis mation (kinins, histamine, liposomal enzymes, prosta-
Renal: Polyuria glandins) through the induction of phospholipase A2
Respiratory: Dyspnea, pulmonary hypertension inhibitory proteins (lipocortins) and sequential inhibition
Miscellaneous: Tachyphylaxis of the release of arachidonic acid. Diflorasone has high
Mechanism of Action Diethylpropion is a sympatho- range potency.
mimetic amine with pharmacologic properties similar to Pregnancy Risk Factor C
the amphetamines. It is also structurally similar to Pregnancy Considerations Adverse events have
bupropion. The mechanism of action in reducing appe- been observed in animal reproduction studies. Topical
tite appears to be secondary to CNS effects, including products are not recommended for extensive use, in
stimulation of the hypothalamus to release norepinephr- large quantities, or for long periods of time in pregnant
ine women.
Half-life Elimination Aminoketone metabolites: ~4-6 Diflunisal (dye FLOO ni sal)
hours
Pregnancy Risk Factor B Related Information
Pregnancy Considerations Adverse events have not Oral Pain on page 1520
been observed in animal reproduction studies. Crosses Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
the human placenta; spontaneous reports of congenital on page 1484
malformations have been reported, but an association Temporomandibular Dysfunction (TMD), Chronic Pain,
with diethylpropion has not been established. With- and Fibromyalgia on page 1559
drawal symptoms may occur in the neonate following Related Sample Prescriptions
maternal use of diethylpropion. Oral Pain - Sample Prescriptions on page 32
Controlled Substance C-IV Brand Names: Canada Apo-Diflunisal; Novo-Diflu-
nisal
Diflorasone (dye FLOR a sone) Generic Availability (US) Yes
Pharmacologic Category Analgesic, Nonopioid; Non-
Brand Names: US ApexiCon E; Psorcon steroidal Anti-inflammatory Drug (NSAID), Oral
Pharmacologic Category Corticosteroid, Topical Dental Use Treatment of postoperative pain
Use Dermatoses: Treatment of inflammation and pru- Use
ritic symptoms of corticosteroid-responsive dermatoses Osteoarthritis/Rheumatoid arthritis (RA): Treatment
(high to very high potency topical corticosteroid) of osteoarthritis and RA
Local Anesthetic/Vasoconstrictor Precautions Pain, mild to moderate: Treatment of mild to moder-
No information available to require special precautions ate pain
Effects on Dental Treatment No significant effects or Local Anesthetic/Vasoconstrictor Precautions
complications reported No information available to require special precautions
432
DIFLUNISAL
Effects on Dental Treatment The dentist should be Pain, mild to moderate: Oral: Initial: 500 mg, fol-
aware of the potential of abnormal coagulation. Caution lowed by 250 mg every 8 to 12 hours; maximum
should also be exercised in the use of NSAIDs in dose: 1,500 mg/day
patients already on anticoagulant therapy with drugs Renal Impairment: Adult There are no dosage
such as warfarin (Coumadin®). See Effects on Bleed- adjustments provided in the manufacturer’s labeling;
ing. avoid use in patients with advanced renal disease.
Effects on Bleeding As an inhibitor of prostaglandin The following adjustments have been used by some
synthetase, diflunisal has a dose-related effect on pla- clinicians (Aronoff, 2007):
telet function and bleeding time. In healthy volunteers, CrCl ≤50 mL/minute: Administer 50% of nor-
250 mg twice daily for 8 days had no effect on platelet mal dose.
function, and 500 mg twice daily (the usual recom- Hemodialysis: No supplement required.
mended dose) had a slight effect. However, at CAPD: No supplement required.
1000 mg twice daily (which exceeds the maximum KDIGO 2012 guidelines provide the following recom-
recommended dosage), diflunisal inhibited platelet mendations for NSAIDs:
function. In contrast with aspirin, these effects of diflu- eGFR 30 to <60 mL/minute/1.73 m2: Temporarily
discontinue in patients with intercurrent disease
nisal were reversible because diflunisal is a salicylic
that increases risk of acute kidney injury.
acid derivative.
eGFR <30 mL/minute/1.73 m2: Avoid use.
1% to 10%:
Central nervous system: Headache (3% to 9%), dizzi- use with caution.
ness (1% to 3%), drowsiness (1% to 3%), fatigue
Pediatric
(1% to 3%), insomnia (1% to 3%)
Osteoarthritis/Rheumatoid arthritis: Adolescents
Dermatologic: Skin rash (3% to 9%) ≥12 years: Oral: Refer to adult dosing.
Gastrointestinal: Diarrhea (3% to 9%), dyspepsia (3% Pain, mild to moderate: Adolescents ≥12 years: Oral:
to 9%), gastrointestinal pain (3% to 9%), nausea (3% Refer to adult dosing.
to 9%), constipation (1% to 3%), flatulence (1% to Renal Impairment: Pediatric
3%), vomiting (1% to 3%), gastrointestinal ulcer There are no dosage adjustments provided in the
Otic: Tinnitus (1% to 3%) manufacturer's labeling; avoid use in advanced dis-
<1%, postmarketing, and/or case reports: Agranulocy- ease.
tosis, anaphylactic reaction (acute), angioedema, ano- KDIGO 2012 guidelines provide the following rec-
rexia, auditory impairment, blurred vision, ommendations for NSAIDs: Children ≥12 years
bronchospasm, chest pain, cholestasis, confusion, and Adolescents:
cystitis, depression, diaphoresis, disorientation, eGFR 30 to <60 mL/minute/1.73 m2: Avoid use in
DRESS syndrome, dry mucous membranes, dyspnea, patients with intercurrent disease that increases
dysuria, edema, eructation, erythema multiforme, risk of acute kidney injury
esophagitis, exfoliative dermatitis, flushing, gastritis, eGFR <30 mL/minute/1.73 m2: Avoid use.
gastrointestinal hemorrhage, gastrointestinal perfora- Hepatic Impairment: Pediatric There are no dos-
tion, hallucination, hearing loss, hematuria, hemolytic age adjustments provided in the manufacturer’s label-
anemia, hepatitis, hepatotoxicity (idiosyncratic; Chala- ing; use with caution.
sani 2014), hypersensitivity angiitis, hypersensitivity Mechanism of Action Reversibly inhibits cyclooxyge-
reaction, interstitial nephritis, jaundice, muscle nase-1 and 2 (COX-1 and 2) enzymes, which results in
cramps, necrotizing fasciitis, nephrotic syndrome, decreased formation of prostaglandin precursors; has
nervousness, palpitations, paresthesia, peptic ulcer, antipyretic, analgesic, and anti-inflammatory properties.
peripheral neuropathy, proteinuria, pruritus, renal fail-
ure, renal insufficiency, seizure, skin photosensitivity, Other proposed mechanisms not fully elucidated (and
possibly contributing to the anti-inflammatory effect to
Stevens-Johnson syndrome, stomatitis, syncope,
varying degrees) include inhibiting chemotaxis, altering
tachycardia, thrombocytopenia, toxic epidermal nec-
lymphocyte activity, inhibiting neutrophil aggregation/
rolysis, tremor, urticaria, vasculitis, vertigo, weakness,
activation, and decreasing proinflammatory cytokine
wheezing
levels.
Dental Usual Dosage Mild-to-moderate pain: Adults: Contraindications Known hypersensitivity to diflunisal
Oral: Initial: 500-1000 mg followed by 250-500 mg
or any component of the formulation; in the setting of
every 8-12 hours; maximum daily dose: 1.5 g coronary artery bypass graft (CABG) surgery; history of
Dosing asthma, urticaria, or allergic-type reactions after taking
Adult aspirin or other NSAIDs.
Osteoarthritis/Rheumatoid arthritis: Oral: 500 mg Warnings/Precautions [US Boxed Warning]:
to 1,000 mg daily in 2 divided doses; maximum dose: NSAIDs cause an increased risk of serious (and
1,500 mg/day potentially fatal) adverse cardiovascular thrombotic
Pain, mild to moderate: Oral: Initial: 1,000 mg, fol- events, including MI and stroke. Risk may occur early
lowed by 500 mg every 12 hours; maintenance during treatment and may increase with duration of use.
doses of 500 mg every 8 hours may be necessary Relative risk appears to be similar in those with and
in some patients; maximum dose: 1,500 mg/day without known cardiovascular disease or risk factors for
Dosage adjustments: A lower dosage may be appro- cardiovascular disease; however, absolute incidence of
priate depending on pain severity, patient response, serious cardiovascular thrombotic events (which may
or weight; Initial: 500 mg, followed by 250 mg every occur early during treatment) was higher in patients with
8 to 12 hours; maximum dose: 1,500 mg/day known cardiovascular disease or risk factors and in
Geriatric those receiving higher doses. New onset hypertension
Osteoarthritis/Rheumatoid arthritis: Refer to adult or exacerbation of hypertension may occur (NSAIDs
dosing. may also impair response to ACE inhibitors, thiazide
433
DIFLUNISAL
diuretics, or loop diuretics); may contribute to cardio- increased risk of GI bleeding with NSAIDs. Transami-
vascular events; monitor blood pressure; use with cau- nase elevations have been reported with use; closely
tion in patients with hypertension. May cause sodium monitor patients with any abnormal LFT. Rare, some-
and fluid retention; use with caution in patients with times fatal severe hepatic reactions (eg, fulminant hep-
edema. Avoid use in heart failure (ACCF/AHA [Yancy atitis, hepatic necrosis, hepatic failure) have occurred
2013]). Avoid use in patients with recent MI unless with NSAID use; discontinue immediately if clinical
benefits outweigh risk of cardiovascular thrombotic signs or symptoms of hepatic disease develop or if
events. Use the lowest effective dose for the shortest systemic manifestations occur.
duration of time, consistent with individual patient goals,
Contraindicated in patients with aspirin-sensitive
to reduce risk of cardiovascular events; alternate thera-
asthma; severe, potentially fatal bronchospasm may
pies should be considered for patients at high risk.
occur. Use caution in patients with other forms of
[US Boxed Warning]: Use is contraindicated in the asthma. May cause drowsiness, dizziness, blurred
setting of coronary artery bypass graft (CABG) vision, and other neurologic effects which may impair
surgery. Risk of MI and stroke may be increased with physical or mental abilities; patients must be cautioned
use following CABG surgery. about performing tasks which require mental alertness
(eg, operating machinery or driving). Blurred vision has
[US Boxed Warning]: NSAIDs cause an increased
been reported; refer for ophthalmologic evaluation if
risk of serious GI inflammation, ulceration, bleed-
symptoms occur.
ing, and perforation (may be fatal); elderly patients
and patients with history of peptic ulcer disease NSAIDs may cause potentially fatal, serious skin
and/or GI bleeding are at greater risk of serious GI adverse events including exfoliative dermatitis, Ste-
events. These events may occur at any time during vens-Johnson syndrome (SJS), and toxic epidermal
therapy and without warning. Avoid use in patients necrolysis (TEN); may occur without warning; discon-
with active GI bleeding. In patients with a history of tinue use at first sign of skin rash (or any other hyper-
acute lower GI bleeding, avoid use of non-aspirin sensitivity). A potentially life-threatening,
NSAIDs, especially if due to angioectasia or divertic- hypersensitivity syndrome has been reported; monitor
ulosis (Strate 2016). Use caution with a history of GI for constitutional symptoms and cutaneous findings;
ulcers, concurrent therapy known to increase the risk of other organ dysfunction may be involved. Even in
GI bleeding (eg, aspirin, anticoagulants and/or cortico- patients without prior exposure anaphylactoid reactions
steroids, selective serotonin reuptake inhibitors), may occur; patients with "aspirin triad" (bronchial
advanced hepatic disease, coagulopathy, smoking, asthma, aspirin intolerance, rhinitis) may be at
use of alcohol, or in elderly or debilitated patients. increased risk. Contraindicated in patients who experi-
Use the lowest effective dose for the shortest duration ence bronchospasm, asthma, rhinitis, or urticaria with
of time, consistent with individual patient goals, to NSAID or aspirin therapy.
reduce risk of GI adverse events; alternate therapies
Diflunisal is a derivative of acetylsalicylic acid and
should be considered for patients at high risk. When
therefore may be associated with Reye’s syndrome.
used concomitantly with aspirin, a substantial increase
Elderly patients are at greater risk for serious GI,
in the risk of GI complications (eg, ulcer) occurs; con-
cardiovascular, and/or renal adverse events; use with
comitant gastroprotective therapy (eg, proton pump
caution. Withhold for at least 4 to 6 half-lives prior to
inhibitors) is recommended (Bhatt 2008).
surgical or dental procedures. Potentially significant
Platelet adhesion and aggregation may be decreased; interactions may exist, requiring dose or frequency
may prolong bleeding time; patients with coagulation adjustment, additional monitoring, and/or selection of
disorders or who are receiving anticoagulants should be alternative therapy.
monitored closely. Anemia may occur; patients on long- Drug Interactions
term NSAID therapy should be monitored for anemia. Metabolism/Transport Effects None known.
Rarely, NSAID use has been associated with potentially Avoid Concomitant Use
severe blood dyscrasias (eg, agranulocytosis, thrombo- Avoid concomitant use of Diflunisal with any of the
cytopenia, aplastic anemia). following: Acemetacin; Aminolevulinic Acid (Sys-
temic); Dexibuprofen; Dexketoprofen; Floctafenine;
NSAID use may compromise existing renal function;
Ketorolac (Nasal); Ketorolac (Systemic); Macimorelin;
dose-dependent decreases in prostaglandin synthesis
Mifamurtide; Morniflumate; Nonsteroidal Anti-Inflam-
may result from NSAID use, reducing renal blood flow
matory Agents (COX-2 Selective); Omacetaxine;
which may cause renal decompensation (usually rever-
Pelubiprofen; Phenylbutazone; Talniflumate; Tenoxi-
sible). Patients with impaired renal function, dehydra-
cam; Urokinase; Zaltoprofen
tion, hypovolemia, heart failure, hepatic impairment,
those taking diuretics and ACE inhibitors, and elderly
Diflunisal may increase the levels/effects of: 5-Amino-
patients are at greater risk of renal toxicity. Rehydrate
salicylic Acid Derivatives; Agents with Antiplatelet
patient before starting therapy; monitor renal function
Properties; Aliskiren; Aminoglycosides; Aminolevulinic
closely. Long-term NSAID use may result in renal
Acid (Systemic); Aminolevulinic Acid (Topical); Anti-
papillary necrosis and other renal injury. Avoid use in
coagulants; Apixaban; Bisphosphonate Derivatives;
patients with advanced renal disease unless benefits
Cephalothin; Collagenase (Systemic); CycloSPOR-
are expected to outweigh risk of worsening renal func-
INE (Systemic); Dabigatran Etexilate; Deferasirox;
tion; monitor renal function closely if therapy must be
Deoxycholic Acid; Desmopressin; Dexibuprofen;
initiated. NSAID use may increase the risk of hyper-
Digoxin; Drospirenone; Edoxaban; Eplerenone; Halo-
kalemia, particularly in the elderly, diabetics, renal dis-
peridol; Ibritumomab Tiuxetan; Lithium; Methotrexate;
ease, and with concomitant use of other agents capable
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selec-
of inducing hyperkalemia (eg, ACE-inhibitors). Monitor
tive); Obinutuzumab; Omacetaxine; Porfimer; Potas-
potassium closely.
sium-Sparing Diuretics; PRALAtrexate; Quinolones;
Use with caution in patients with hepatic impairment; Rivaroxaban; Salicylates; Tacrolimus (Systemic);
patients with advanced hepatic disease are at an Tenofovir Products; Thrombolytic Agents; Tolperisone;
434
DIGOXIN
Urokinase; Vancomycin; Verteporfin; Vitamin K Antag- Breastfeeding Considerations Diflunisal is present

onists in breast milk at concentrations of 2% to 7% of those in
The levels/effects of Diflunisal may be increased by: maternal plasma. In general, NSAIDs may be used in
Acemetacin; Alcohol (Ethyl); Angiotensin II Receptor postpartum women who wish to breastfeed; however,
Blockers; Angiotensin-Converting Enzyme Inhibitors; agents other than diflunisal are preferred (Montgomery
Corticosteroids (Systemic); CycloSPORINE (Sys- 2012) and use should be avoided in women breastfeed-
temic); Dasatinib; Dexketoprofen; Diclofenac (Sys- ing infants with platelet dysfunction or thrombocytope-
temic); Fat Emulsion (Fish Oil Based); Felbinac; nia (Bloor 2013; Sammaritano 2014). According to the
Floctafenine; Glucosamine; Herbs (Anticoagulant/ manufacturer, the decision to breastfeed during therapy
Antiplatelet Properties); Ibrutinib; Inotersen; Ketorolac should take into account the risk of exposure to the
(Nasal); Ketorolac (Systemic); Limaprost; Loop Diu- infant and the benefits of treatment to the mother.
retics; Morniflumate; Multivitamins/Fluoride (with Dosage Forms: US
ADE); Multivitamins/Minerals (with ADEK, Folate, Tablet, Oral:
Iron); Multivitamins/Minerals (with AE, No Iron); Nafta- Generic: 500 mg
zone; Omega-3 Fatty Acids; Pelubiprofen; Pentosan Dosage Forms: Canada
Polysulfate Sodium; Pentoxifylline; Phenylbutazone; Tablet, Oral: 250 mg
Probenecid; Prostacyclin Analogues; Selective Sero- Dental Health Professional Considerations The
tonin Reuptake Inhibitors; Serotonin/Norepinephrine advantage of diflunisal as a pain reliever is its 12-hour
Reuptake Inhibitors; Sodium Phosphates; Talniflu- duration of effect. In many cases, this long effect will
mate; Tenoxicam; Thiazide and Thiazide-Like Diu- ensure a full night sleep during the postoperative pain
r e t i c s ; T i p r a n a v i r ; To l p e r i s o n e ; T r i c y c l i c period.
Antidepressants (Tertiary Amine); Vitamin E (Sys-
temic); Zaltoprofen
Decreased Effect
Digoxin (di JOKS in)
Diflunisal may decrease the levels/effects of: Aliskiren; Related Information

Angiotensin II Receptor Blockers; Angiotensin-Con- Cardiovascular Diseases on page 1442
verting Enzyme Inhibitors; Beta-Blockers; Eplerenone; Brand Names: US Digitek; Digox; Lanoxin; Lanoxin
HydrALAZINE; Loop Diuretics; Macimorelin; Mifamur-
Pediatric
tide; Potassium-Sparing Diuretics; Prostaglandins
Brand Names: Canada Digoxin Injection CSD; Lan-
(Ophthalmic); Salicylates; Selective Serotonin Reup-
oxin; Pediatric Digoxin CSD; Toloxin
take Inhibitors; Sincalide; Thiazide and Thiazide-Like
Diuretics Pharmacologic Category Antiarrhythmic Agent, Mis-
cellaneous; Cardiac Glycoside
The levels/effects of Diflunisal may be decreased by: Use
Bile Acid Sequestrants; Salicylates Atrial fibrillation or atrial flutter, rate control: Control
Dietary Considerations May administer with food or of ventricular response rate in adults with chronic atrial
milk to decrease GI upset. fibrillation.
Pharmacodynamics/Kinetics Heart failure with reduced ejection fraction (HFrEF):
Onset of Action Analgesic: ~1 hour; maximal effect: 2 Treatment of mild to moderate (or stage C as recom-
to 3 hours mended by the ACCF/AHA) heart failure in adults; to
Duration of Action 8 to 12 hours increase myocardial contractility in pediatric patients
Half-life Elimination 8 to 12 hours; prolonged with with heart failure
renal impairment (Brogden 1980) Local Anesthetic/Vasoconstrictor Precautions
Time to Peak Serum: 2 to 3 hours Use vasoconstrictor with caution due to risk of cardiac
Pregnancy Risk Factor C arrhythmias with digoxin
Pregnancy Considerations Birth defects have been Effects on Dental Treatment Sensitive gag reflex
observed following in utero NSAID exposure in some may cause difficulty in taking a dental impression.
studies; however, data is conflicting (Bloor 2013). Non- Effects on Bleeding No information available to
teratogenic effects, including prenatal constriction of the require special precautions
ductus arteriosus, persistent pulmonary hypertension of Adverse Reactions Incidence not always reported.
the newborn, oligohydramnios, necrotizing enterocolitis, Cardiovascular: Accelerated junctional rhythm, asys-
renal dysfunction or failure, and intracranial hemor- tole, atrial tachycardia with or without block, AV dis-
rhage have been observed in the fetus/neonate follow- sociation, first-, second- (Wenckebach), or third-
ing in utero NSAID exposure. In addition, nonclosure of degree heart block, facial edema, PR prolongation,
the ductus arteriosus postnatally may occur and be PVCs (especially bigeminy or trigeminy), ST segment
resistant to medical management (Bermas 2014; Bloor depression, ventricular tachycardia or ventricular fibril-
2013). Because they may cause premature closure of lation
the ductus arteriosus, the use of NSAIDs late in preg- Central nervous system: Dizziness (6%), mental dis-
nancy should be avoided. Use of NSAIDs can be turbances (5%), headache (4%), apathy, anxiety, con-
considered for the treatment of mild rheumatoid arthritis fusion, delirium, depression, fever, hallucinations
flares in pregnant women; however, use should be Dermatologic: Rash (erythematous, maculopapular
minimized or avoided early and late in pregnancy [most common], papular, scarlatiniform, vesicular or
(Bermas 2014; Saavedra Salinas 2015).
bullous), pruritus, urticaria, angioneurotic edema
The chronic use of NSAIDs in women of reproductive Gastrointestinal: Nausea (4%), vomiting (2%), diarrhea
age may be associated with infertility that is reversible (4%), abdominal pain, anorexia
upon discontinuation of the medication (Micu 2011). Neuromuscular & skeletal: Weakness
The use of NSAIDs close to conception may be asso- Ophthalmic: Visual disturbances (blurred or yellow
ciated with an increased risk of miscarriage (Bloor vision)
2013; Bermas 2014). Respiratory: Laryngeal edema
435
DIGOXIN
<1%, postmarketing, and/or case reports (limited to Digoxin (administered either maternally or directly to the
important or life-threatening): Asymmetric chorea, fetus) may be considered for the in utero management
gynecomastia, thrombocytopenia, palpitation, intesti- of fetal SVT or atrial flutter with hydrops or ventricular
nal ischemia, hemorrhagic necrosis of the intestines, dysfunction. Digoxin may also be considered for SVT
vaginal cornification, eosinophilia, sexual dysfunction, without hydrops or ventricular dysfunction if heart rate is
diaphoresis ≥200 bpm, atrial flutter, or other rare tachycardias with
Mechanism of Action an average heart rate of ≥200 bpm (AHA [Dono-
Heart failure: Inhibition of the sodium/potassium frio 2014]).
ATPase pump in myocardial cells results in a transient
increase of intracellular sodium, which in turn pro- Dihydroergotamine (dye hye droe er GOT a meen)
motes calcium influx via the sodium-calcium exchange
pump leading to increased contractility. May improve Brand Names: US D.H.E. 45; Migranal
baroreflex sensitivity (Gheorghiade 1991). Brand Names: Canada Migranal
Supraventricular arrhythmias: Direct suppression of the Pharmacologic Category Antimigraine Agent; Ergot
AV node conduction to increase effective refractory Derivative
period and decrease conduction velocity - positive Use
inotropic effect, enhanced vagal tone, and decreased Cluster headaches (injection): Acute treatment of
ventricular rate to fast atrial arrhythmias. Atrial fibrilla- cluster headaches.
tion may decrease sensitivity and increase tolerance Migraines (intranasal; injection): Acute treatment of
to higher serum digoxin concentrations. migraine headaches with or without aura; not intended
for the prophylactic therapy of migraine or for the
Onset of Action management of hemiplegic or basilar migraine.
Heart rate control: Oral: 1 to 2 hours; IV: 5 to 60
minutes
Use vasoconstrictor with caution in patients taking
Peak effect: Heart rate control: Oral: 2 to 8 hours; IV: 1
dihydroergotamine; this ergot alkaloid derivative directly
to 6 hours; Note: In patients with atrial fibrillation,
stimulates vascular smooth muscle resulting in vaso-
median time to ventricular rate control in one study
constriction of peripheral vasculature
was 6 hours (range: 3 to 15 hours) (Siu 2009)
Duration of Action Adults: 3 to 4 days
related to dental treatment: Rhinitis and abnormal taste.
Age, renal and cardiac function dependent:
Neonates: Premature: 61 to 170 hours; Full-term: 35
Adverse Reactions
to 45 hours
>10%: Nasal spray: Respiratory: Rhinitis (26%)
Infants: 18 to 25 hours
1% to 10%: Nasal spray:
Children: 18 to 36 hours
Central nervous system: Taste disorder (8%), dizzi-
Adults: 36 to 48 hours
ness (4%), drowsiness (3%)
Adults, anephric: 3.5 to 5 days
Endocrine & metabolic: Hot flash (1%)
Parent drug: 38 hours; Metabolites: Digoxigenin: 4
Gastrointestinal: Nausea (10%), vomiting (4%), diar-
hours; Monodigitoxoside: 3 to 12 hours
rhea (2%)
Time to Peak Serum: Oral: 1 to 3 hours
Local: Application site reaction (6%)
Pregnancy Considerations Neuromuscular & skeletal: Stiffness (1%), weak-
Digoxin crosses the placenta. ness (1%)
Available guidelines note experience with digoxin in Respiratory: Pharyngitis (3%)
pregnancy is extensive (ESG [Regitz-Zagrosek 2018]). <1%, postmarketing, and/or case reports (Limited to
Based on available data, an increased risk of adverse important or life-threatening): Injection and nasal
pregnancy outcomes has not been observed. However, spray: Abdominal pain, anxiety, cerebral hemorrhage,
untreated maternal heart failure and atrial fibrillation cerebrovascular accident, coronary artery vasospasm,
may increase the risk of preterm birth and low birth diaphoresis, diarrhea, dizziness, dyspnea, edema,
weight, respectively. The manufacturer recommends fibrothorax (prolonged use), flushing, headache,
monitoring neonates for signs and symptoms of digoxin hyperkinesia, hypertension, ischemic heart disease,
toxicity following in utero exposure. muscle cramps, myalgia, myasthenia, myocardial
infarction, palpitations, paresthesia, peripheral cyano-
Due to pregnancy-induced physiologic changes, some sis, peripheral ischemia, retroperitoneal fibrosis (pro-
pharmacokinetic properties of digoxin may be altered. longed use), skin rash, subarachnoid hemorrhage,
Close monitoring of maternal serum digoxin is recom-
tremor, valvular sclerosis (associated with ergot alka-
mended (Hebert 2008; Luxford 1983; Martin-Suarez loids), ventricular fibrillation, ventricular tachycardia
2017); dose adjustments may be required during preg-
(transient)
nancy and postpartum.
Mechanism of Action Efficacy in migraine is attributed
Heart failure and atrial fibrillation may worsen during to the activation of 5-HT1D receptors located on intra-
pregnancy. Digoxin is recommended as a first-line cranial blood vessels resulting in vasoconstriction and/
agent for the chronic treatment of highly symptomatic or activation of 5-HT1D receptors on sensory nerve
supraventricular tachycardia (SVT) in pregnancy; the endings of the trigeminal system resulting in the inhib-
lowest effective dose is recommended (ACC/AHA/HRS ition of pro-inflammatory neuropeptide release. Dihy-
[Page 2015]). Digoxin may be considered for long-term droergotamine binds with high affinity to serotonin
rate control of maternal atrial tachycardia or atrial 5-HT1Dα, 5-HT1Dβ, 5-HT1A, 5-HT2A, and 5-HT2C recep-
fibrillation when preferred agents fail (ESG [Regitz- tors, noradrenaline α2A, α2B and α1 receptors, and
Zagrosek 2018]). Monitor for an increased risk of mater- dopamine D2L and D3 receptors. Dihydroergotamine
nal arrhythmias during labor and delivery. also possesses oxytocic properties.
436
DIMENHYDRINATE
Pharmacodynamics/Kinetics <2%, postmarketing, and/or case reports: Abnormal

Half-life Elimination ~9 to 10 hours dreams, abnormal gait, albuminuria, alopecia, amblyo-
Time to Peak Serum: IM: 24 minutes; IV: 1 to 2 pia, amnesia, angina pectoris, angioedema, anorexia,
minutes; Intranasal: 30 to 60 minutes (Saper 2006); asystole, atrioventricular block (second or third
SubQ 15 to 45 minutes (Schran 1985) degree), bruise, bundle branch block, cardiac arrhyth-
Pregnancy Risk Factor X mia, cardiac failure, crystalluria, depression, drowsi-
Pregnancy Considerations Dihydroergotamine is ness, dysgeusia, ECG abnormality, epistaxis,
oxytocic and should not be used during pregnancy. erythema multiforme, exfoliative dermatitis, extrapyr-
amidal reaction, gingival hyperplasia, gynecomastia,
DilTIAZem (dil TYE a zem) hallucination, hemolytic anemia, hyperglycemia,
hypersensitivity angiitis, hypersensitivity reaction,
Related Information hyperuricemia, impotence, increased creatine phos-
Calcium Channel Blockers and Gingival Hyperplasia on phokinase, increased lactate dehydrogenase,
page 1601 increased serum alkaline phosphatase, increased
Cardiovascular Diseases on page 1442 serum ALT, increased serum AST, increased serum
Brand Names: US Cardizem; Cardizem CD; Cardizem bilirubin, increased thirst, insomnia, leukopenia,
LA; Cartia XT; Dilt-XR; dilTIAZem CD [DSC]; Matzim muscle cramps, myopathy, nausea, neck stiffness,
LA; Taztia XT; Tiazac nocturia, pain, paresthesia, personality changes, pete-
Brand Names: Canada ACT Diltiazem CD; ACT Dil- chia, polyuria, prolonged bleeding time, pruritus, pur-
tiazem T; Apo-Diltiaz; Apo-Diltiaz CD; Apo-Diltiaz SR;
pura, retinopathy, skin photosensitivity, Stevens-
Apo-Diltiaz TZ; Cardizem CD; Diltiazem Hydrochloride
Johnson syndrome, syncope, tachycardia, thrombocy-
Injection; Diltiazem TZ; Diltiazem-CD; PMS-Diltiazem
CD; Sandoz-Diltiazem CD; Sandoz-Diltiazem T; Teva- topenia, tinnitus, toxic epidermal necrolysis, tremor,
Diltiazem; Teva-Diltiazem CD; Teva-Diltiazem HCL ER urticaria, ventricular premature contractions, weight
Capsules; Tiazac; Tiazac XC gain, xerostomia
Pharmacologic Category Antianginal Agent; Antiar- Mechanism of Action Inhibits calcium ion from enter-
rhythmic Agent, Class IV; Antihypertensive; Calcium ing the "slow channels" or select voltage-sensitive
Channel Blocker; Calcium Channel Blocker, Nondihy- areas of vascular smooth muscle and myocardium
dropyridine during depolarization; produces relaxation of coronary
Use vascular smooth muscle and coronary vasodilation;
Oral: Hypertension, chronic stable angina, vasospastic increases myocardial oxygen delivery in patients with
angina vasospastic angina.
Injection: Atrial fibrillation or atrial flutter for acute Pharmacodynamics/Kinetics
ventricular rate control, conversion of supraventricular Onset of Action Oral: Immediate release tablet: 30 to
tachycardia 60 minutes; IV: Bolus: 3 minutes
Local Anesthetic/Vasoconstrictor Precautions Duration of Action IV: Bolus: 1 to 3 hours; Continu-
No information available to require special precautions ous infusion (after discontinuation): 0.5 to 10 hours
Effects on Dental Treatment Key adverse event(s) Half-life Elimination Immediate release tablet: 3 to
related to dental treatment: Diltiazem has been reported
4.5 hours; Extended release tablet: 6 to 9 hours;
to cause >10% incidence of gingival hyperplasia; usu-
Extended release capsules: 4 to 9.5 hours; IV: single
ally disappears with discontinuation (consultation with
physician is suggested). dose: ~3.4 hours; continuous infusion: 4 to 5 hours
Effects on Bleeding No information available to Time to Peak Serum: Immediate release tablet: 2 to 4
require special precautions hours; Extended release tablet: 11 to 18 hours;
Adverse Reactions Note: Frequencies represent Extended release capsule: 10 to 14 hours
ranges for various dosage forms. Patients with impaired Pregnancy Risk Factor C
ventricular function and/or conduction abnormalities Pregnancy Considerations Adverse events have
may have higher incidence of adverse reactions. been observed in animal reproduction studies.
>10%: Untreated chronic maternal hypertension is associated
Cardiovascular: Edema (2% to 15%) with adverse events in the fetus, infant, and mother. If
Central nervous system: Headache (5% to 12%) treatment for hypertension during pregnancy is needed,
2% to 10%: other agents are preferred (ACOG 2013). Women with
Cardiovascular: Atrioventricular block (2% to 8%; first hypertrophic cardiomyopathy who are controlled with
degree), edema (2% to 8%; lower limb), bradycardia diltiazem prior to pregnancy may continue therapy, but
(2% to 6%), hypotension (<2% to 4%), vasodilatation increased fetal monitoring is recommended (Gersh
(2% to 3%), extrasystoles (2%), flushing (1% to 2%), 2011).
palpitations (1% to 2%)
Central nervous system: Dizziness (3% to 10%), pain
(6%), nervousness (2%)
DimenhyDRINATE (dye men HYE dri nate)
Dermatologic: Skin rash (1% to 4%) Brand Names: US Dramamine [OTC]; Driminate
Endocrine & metabolic: Gout (1% to 2%)
[OTC]; Motion Sickness [OTC]
Gastrointestinal: Dyspepsia (1% to 6%), constipation
(<2% to 4%), vomiting (2%), diarrhea (1% to 2%)
Brand Names: Canada Children’s Motion Sickness
Local: Injection site reaction (4%; itching, burning) Liquid [OTC]; Dimenhydrinate Injection; Dinate [OTC];
Neuromuscular & skeletal: Weakness (1% to 4%), Gravol IM; Gravol [OTC]; Nauseatol [OTC]; Sandoz-
myalgia (2%) Dimenhydrinate [OTC]; Travel Tabs [OTC]
Respiratory: Rhinitis (<2% to 10%), pharyngitis (2% to Pharmacologic Category Ethanolamine Derivative;
6%), dyspnea (1% to 6%), bronchitis (1% to 4%), Histamine H1 Antagonist; Histamine H1 Antagonist,
cough (≤3), sinus congestion (1% to 2%) First Generation
437
DIMENHYDRINATE
Use Adverse Reactions

US labeling: Motion sickness: Treatment and preven- >10%:
tion of nausea, vertigo, and vomiting associated with Cardiovascular: Flushing (40%)
motion sickness. Gastrointestinal: Abdominal pain (18%), diarrhea
Canadian labeling: Nausea, vomiting and/or ver- (14%), nausea (12%)
tigo: Treatment and prevention of nausea, vomiting Infection: Infection (60%)
and/or vertigo associated with motion sickness, radi- 1% to 10%:
ation sickness, postoperative recovery, use of other Dermatologic: Pruritus (8%), skin rash (8%), eryth-
drugs, Mènière disease and other labyrinthine distur- ema (5%)
bances. Endocrine & metabolic: Albuminuria (6%)
Local Anesthetic/Vasoconstrictor Precautions Gastrointestinal: Vomiting (9%), dyspepsia (5%)
No information available to require special precautions Hematologic & oncologic: Lymphocytopenia (2%
Effects on Dental Treatment Key adverse event(s) to 6%)
related to dental treatment: Significant xerostomia (nor- Hepatic: Increased serum AST (4%)
hepatic function tests, anaphylaxis, angioedema, eosi-
nophilia (transient), progressive multifocal leukoence-
phalopathy
Adverse Reactions Frequency not defined. Mechanism of Action DMF and its active metabolite,
Cardiovascular: Tachycardia monomethyl fumarate (MMF), have been shown to
Central nervous system: Dizziness, drowsiness, excite- activate the nuclear factor (erythroid-derived 2)-like 2
ment, headache, insomnia, lassitude, nervousness, (Nrf2) pathway, which is involved in cellular response to
restlessness oxidative stress. The mechanism by which dimethyl
Dermatologic: Skin rash fumarate (DMF) exerts a therapeutic effect in MS is
Gastrointestinal: Anorexia, epigastric distress, nausea, unknown, although it is believed to result from its anti-
xerostomia inflammatory and cytoprotective properties via activa-
Genitourinary: Dysuria tion of the Nrf2 pathway (Fox, 2012; Gold, 2012).
Ophthalmic: Blurred vision Pharmacodynamics/Kinetics
Respiratory: Thickening of bronchial secretions Half-life Elimination MMF: ~1 hour
Mechanism of Action Competes with histamine for Time to Peak 2 to 2.5 hours; delayed to 5.5 hours with
H1-receptor sites on effector cells in the gastrointestinal food
tract, blood vessels, and respiratory tract; blocks che- Pregnancy Considerations
moreceptor trigger zone, diminishes vestibular stimula- Adverse events were observed in animal reproduction
tion, and depresses labyrinthine function through its studies.
central anticholinergic activity
Pharmacodynamics/Kinetics Women exposed to dimethyl fumarate during preg-
Onset of Action Antiemetic: IV: immediate; IM: 20 to nancy are encouraged to enroll in the Pregnancy Regis-
30 minutes; Oral: 15 to 30 minutes (Gravol Canadian try by calling 866-810-1462 or visiting
labeling 2016) www.tecfiderapregnancyregistry.com.
Duration of Action 4 to 6 hours (Gravol Canadian
labeling 2016) DiphenhydrAMINE (Systemic)
Half-life Elimination 5 to 8 hours (Gravol Canadian (dye fen HYE dra meen)
labeling 2016) Related Information
Pregnancy Risk Factor B Bacterial Infections on page 1525
Pregnancy Considerations Perioral Premalignant Lesions and Management of
Dimenhydrinate crosses the placenta. The risk of fetal Patients Undergoing Cancer Therapy on page 1567
abnormalities was not increased following maternal use Ulcerative, Erosive, and Painful Oral Mucosal Disorders
of dimenhydrinate during any trimester of pregnancy. on page 1544
Dimenhydrinate may be used for the adjunctive treat- Viral Infections on page 1540
ment of nausea and vomiting of pregnancy (ACOG Brand Names: US Aler-Dryl [OTC]; Allergy Relief
189 2018; Campbell 2016). Dimenhydrinate may have Childrens [OTC]; Allergy Relief [OTC]; Altaryl [OTC]
an oxytocic effect if used during labor. [DSC]; Anti-Hist Allergy [OTC]; Banophen [OTC];
Benadryl Allergy Childrens [OTC]; Benadryl Allergy
[OTC]; Benadryl Dye-Free Allergy [OTC] [DSC]; Com-
Dimethyl Fumarate (dye meth il FYOO ma rate)
plete Allergy Medication [OTC] [DSC]; Complete Allergy
Brand Names: US Tecfidera Relief [OTC] [DSC]; Diphen [OTC]; Diphenhist [OTC];
Genahist [OTC]; Geri-Dryl [OTC]; GoodSense Allergy
Brand Names: Canada Tecfidera
Relief [OTC]; GoodSense Sleep Aid [OTC]; Naramin
Pharmacologic Category Fumaric Acid Derivative; [OTC]; Nighttime Sleep Aid [OTC]; Nytol Maximum
Immunomodulator, Systemic Strength [OTC]; Nytol [OTC]; Ormir [OTC]; PediaCare
Use Multiple sclerosis: Treatment of patients with Childrens Allergy [OTC]; Pharbedryl [OTC]; Q-Dryl
relapsing forms of multiple sclerosis [OTC] [DSC]; QlearQuil Nighttime Allergy [OTC]
Local Anesthetic/Vasoconstrictor Precautions [DSC]; Quenalin [OTC] [DSC]; Scot-Tussin Allergy
No information available to require special precautions Relief [OTC] [DSC]; Siladryl Allergy [OTC]; Silphen
Effects on Dental Treatment No significant effects or Cough [OTC] [DSC]; Simply Sleep [OTC]; Sleep Tabs
complications reported [OTC]; Sominex Maximum Strength [OTC] [DSC];
Effects on Bleeding No information available to Sominex [OTC] [DSC]; Tetra-Formula Nighttime Sleep
require special precautions [OTC]; Total Allergy Medicine [OTC]; Total Allergy
438
DIPHENHYDRAMINE (TOPICAL)
[OTC]; Triaminic Cough/Runny Nose [OTC] [DSC]; Pharmacodynamics/Kinetics

ZzzQuil [OTC] Duration of Action
Brand Names: Canada Allerdryl; Allernix; Benadryl; Histamine-induced wheal suppression: ≤10 hours
Nytol; Nytol Extra Strength; PMS-Diphenhydramine; (Simons, 1990)
Simply Sleep; Sominex Histamine-induced flare suppression: ≤12 hours
Pharmacologic Category Ethanolamine Derivative; (Simons, 1990)
Histamine H1 Antagonist; Histamine H1 Antagonist, Half-life Elimination Children: 5 hours (range: 4 to 7
First Generation hours); Adults: 9 hours (range: 7 to 12 hours); Elderly:
Use 13.5 hours (range: 9 to 18 hours) (Blyden, 1986;
Symptomatic relief of allergic symptoms caused by Simons, 1990)
histamine release including nasal allergies and allergic Time to Peak Serum: ~2 hours (Blyden, 1986;
dermatosis; adjunct to epinephrine in the treatment of Simons, 1990)
anaphylaxis; insomnia, occasional; prevention or Pregnancy Risk Factor B
treatment of motion sickness; antitussive; manage- Pregnancy Considerations
ment of Parkinsonian syndrome including drug- Diphenhydramine crosses the placenta (Miller 2000;
induced extrapyramidal symptoms (dystonic reac- Parkin 1974).
tions) alone or in combination with centrally acting In general, the use of first generation antihistamines
anticholinergic agents immediately before parturition may cause respiratory
Guideline recommendations: depression in the newborn (Zuberbier 2014).
Anaphylaxis: Antihistamines are considered second-
line treatment only after epinephrine administration in Diphenhydramine may be used for the treatment of
the adjunct management of anaphylaxis (AAAAI allergic conditions in pregnant women when a first
[Lieberman 2015]). generation antihistamine is indicated (Babalola 2013;
Insomnia: The American Academy of Sleep Medicine Murase 2014; Zuberbier 2014). Diphenhydramine may
guidelines for the management of chronic insomnia be used as adjunctive therapy in the management of
suggest diphenhydramine not be used for sleep- nausea and vomiting of pregnancy when the preferred
onset or sleep-maintenance insomnia in adults due agents do not provide initial symptom improvement
to the absence of evidence for clinically significant (ACOG 189 2018). Antihistamines are not recom-
improvement (AASM [Sateia 2017]). mended for treatment of pruritus associated with intra-
hepatic cholestasis in pregnancy (Ambros-Rudolph
2011; Kremer 2014).
25-50 mg of diphenhydramine orally every 4-6 hours
can be used to treat mild dermatologic manifestations of
flow resumes upon discontinuation) and dry mucous
allergic reactions to penicillin and other antibiotics.
membranes. Chronic use of antihistamines will inhibit
Diphenhydramine is not recommended as local anes-
salivary flow, particularly in elderly patients; may con- thetic for either infiltration route or nerve block since the
tribute to periodontal disease and oral discomfort. See vehicle has caused local necrosis upon injection. A
Dental Health Professional Considerations. 50:50 mixture of diphenhydramine liquid (12.5 mg/5
Effects on Bleeding No information available to mL) in Kaopectate® or Maalox® is used as a local
require special precautions application for recurrent aphthous ulcers; swish 15 mL
Adverse Reactions for 2 minutes 4 times/day.
Cardiovascular: Chest tightness, extrasystoles, hypo-
tension, palpitations, tachycardia DiphenhydrAMINE (Topical)
(dye fen HYE dra meen)
Central nervous system: Ataxia, chills, confusion, diz-
ziness, drowsiness, euphoria, excitement, fatigue, Brand Names: US Anti-Itch Maximum Strength [OTC];
headache, irritability, nervousness, neuritis, paradox- Anti-Itch [OTC]; Banophen [OTC]; Benadryl Itch Relief
ical excitation, paresthesia, restlessness, sedation, [OTC] [DSC]; Benadryl Itch Stopping [OTC]; Itch Relief
seizure, vertigo [OTC]
Dermatologic: Diaphoresis, skin photosensitivity, skin Brand Names: Canada Benadryl® Cream; Benadryl®
rash, urticaria Itch Relief Stick; Benadryl® Spray
Gastrointestinal: Anorexia, constipation, diarrhea, dry Pharmacologic Category Ethanolamine Derivative;
mucous membranes, epigastric distress, nausea, Histamine H1 Antagonist; Histamine H1 Antagonist,
vomiting, xerostomia First Generation; Topical Skin Product
Genitourinary: Difficulty in micturition, urinary fre- Use Relief of pain and itching: Temporary relief of pain
quency, urinary retention and itching associated with insect bites; sunburn;
Hematologic & oncologic: Agranulocytosis, hemolytic scrapes; minor cuts, minor skin irritations, and minor
anemia, thrombocytopenia burns; or rashes due to poison ivy, poison oak, and
Hypersensitivity: Anaphylactic shock poison sumac
Neuromuscular & skeletal: Tremor Local Anesthetic/Vasoconstrictor Precautions
Ophthalmic: Blurred vision, diplopia No information available to require special precautions
Respiratory: Nasal congestion, pharyngeal edema, Effects on Dental Treatment No significant effects or
thickening of bronchial secretions, wheezing complications reported
Mechanism of Action Competes with histamine for Effects on Bleeding No information available to
H1-receptor sites on effector cells in the gastrointestinal require special precautions
tract, blood vessels, and respiratory tract; anticholiner- Adverse Reactions Frequency not defined.
gic and sedative effects are also seen Dermatologic: Photosensitivity, rash, urticaria
439
DIPHENHYDRAMINE (TOPICAL)
Pregnancy Considerations When administered Adverse Reactions

orally, diphenhydramine crosses the placenta. Diphen- Oral: Frequency not always defined.
hydramine can also be measurable in the serum follow- Cardiovascular: Angina pectoris, flushing
ing topical administration to large areas of the body. Central nervous system: Dizziness (14%), head-
Refer to the Diphenhydramine (Systemic) monograph. ache (2%)
Dermatologic: Skin rash (2%), pruritus
Gastrointestinal: Abdominal distress (6%), diarrhea,
Diphenoxylate and Atropine vomiting
(dye fen OKS i late & A troe peen)
Hepatic: Hepatic insufficiency
Related Information Postmarketing and/or case reports: Alopecia, arthritis,
Dentin Hypersensitivity, Acid Erosion, High Caries cholelithiasis, dyspepsia, fatigue, hepatitis, hypersen-
Index, Management of Alveolar Osteitis, and Xerosto- sitivity reaction, hypotension, laryngeal edema,
mia on page 1548 malaise, myalgia, nausea, palpitations, paresthesia,
Brand Names: US Lomotil tachycardia, thrombocytopenia
Brand Names: Canada Lomotil IV:
Pharmacologic Category Antidiarrheal >10%:
Use Diarrhea, adjunct therapy: Adjunctive manage- Cardiovascular: Exacerbation of angina pecto-
ment of diarrhea in patients ≥13 years of age. ris (20%)
Local Anesthetic/Vasoconstrictor Precautions Central nervous system: Dizziness (12%), head-
No information available to require special precautions ache (12%)
Effects on Dental Treatment Key adverse event(s) 1% to 10%:
Cardiovascular: ECG abnormality (5% to 8%; ST-T
related to dental treatment: Significant xerostomia (nor-
changes, extrasystoles), hypotension (5%), flushing
(3%), tachycardia (3%), altered blood pressure (2%),
Effects on Bleeding No information available to hypertension (2%)
require special precautions Central nervous system: Pain (3%), fatigue (1%),
Adverse Reactions Frequency not defined. paresthesia (1%)
Cardiovascular: Flushing, tachycardia Gastrointestinal: Nausea (5%)
Central nervous system: Confusion, depression, dizzi- Respiratory: Dyspnea (3%)
ness, drowsiness, euphoria, hallucination, headache, <1%, postmarketing, and/or case reports (Limited to
hyperthermia, lethargy, malaise, numbness, restless- important or life-threatening): Abdominal pain, arthral-
ness, sedation gia, ataxia, back pain, bronchospasm, cardiac arrhyth-
Dermatologic: Pruritus, urticaria, xeroderma mia (ventricular tachycardia, bradycardia, AV block,
Gastrointestinal: Abdominal distress, anorexia, gingival SVT, atrial fibrillation, asystole), cardiomyopathy,
swelling, nausea, pancreatitis, paralytic ileus, toxic cough, depersonalization, diaphoresis, dysgeusia,
megacolon, vomiting, xerostomia dyspepsia, dysphagia, ECG abnormality (unspeci-
Genitourinary: Urinary retention fied), edema, eructation, flatulence, hypersensitivity
Hypersensitivity: Anaphylaxis, angioedema reaction, hypertonia, hyperventilation, increased
Mechanism of Action Diphenoxylate inhibits exces- appetite, increased thirst, injection site reaction, leg
sive GI motility and GI propulsion; commercial prepa- cramps (intermittent claudication), malaise, mastalgia,
rations contain a subtherapeutic amount of atropine to muscle rigidity, myalgia, myocardial infarction, ortho-
discourage abuse static hypotension, otalgia, palpitations, perineal pain,
Pharmacodynamics/Kinetics pharyngitis, pleuritic chest pain, pruritus, renal pain,
Onset of Action Within 45 to 60 minutes rhinitis, skin rash, syncope, tenesmus, tinnitus, tremor,
Half-life Elimination Diphenoxylate: 2.5 hours; urticaria, vertigo, visual disturbance, vomiting, weak-
Diphenoxylic acid: 12 to 14 hours ness, xerostomia
Time to Peak Diphenoxylate: Serum: ~2 hours Mechanism of Action Inhibits the activity of adeno-
sine deaminase and phosphodiesterase, which causes
Pregnancy Considerations Animal reproduction
an accumulation of adenosine, adenine nucleotides,
studies have not been conducted with this combination.
and cyclic AMP; these mediators then inhibit platelet
Refer to individual agents. aggregation and may cause vasodilation; may also
Controlled Substance C-V stimulate release of prostacyclin or PGD2; causes cor-
onary vasodilation
Dipyridamole (dye peer ID a mole) Pharmacodynamics/Kinetics
Half-life Elimination Terminal: 10-12 hours
Brand Names: US Persantine [DSC] Time to Peak Serum: 2-2.5 hours
Brand Names: Canada Persantine Pregnancy Risk Factor B
Pharmacologic Category Antiplatelet Agent; Vaso- Pregnancy Considerations Adverse events have not
dilator been observed in animal reproduction studies.
Use
Oral: Used with warfarin to decrease thrombosis in Disopyramide (dye soe PEER a mide)
patients after artificial heart valve replacement
IV: Diagnostic agent in CAD Related Information
Local Anesthetic/Vasoconstrictor Precautions Clinical Risk Related to Drugs Prolonging QT Interval
No information available to require special precautions on page 1462
Effects on Dental Treatment No significant effects or Brand Names: US Norpace; Norpace CR
complications reported Brand Names: Canada Rythmodan
Effects on Bleeding Dipyridamole inhibits platelet Pharmacologic Category Antiarrhythmic Agent,
aggregation and may increase the risk of bleeding. Class Ia
440
DISULFIRAM
Use Life-threatening ventricular arrhythmias (eg, sus- Pharmacodynamics/Kinetics

tained ventricular tachycardia) Onset of Action 0.5 to 3.5 hours
Local Anesthetic/Vasoconstrictor Precautions Duration of Action Immediate release: 1.5 to 8.5
Disopyramide is one of the drugs confirmed to prolong hours
the QT interval and is accepted as having a risk of Half-life Elimination Children 5 to 12 years: 3.15 ±
causing torsade de pointes. The risk of drug-induced 0.64 hours (Chiba 1992); Adults: 4 to 10 hours;
torsade de pointes is extremely low when a single QT prolonged with heart failure and hepatic or renal
interval prolonging drug is prescribed. In terms of epi- impairment
nephrine, it is not known what effect vasoconstrictors in Time to Peak Serum: Immediate release: Within 2
the local anesthetic regimen will have in patients with a hours; Controlled release: 4 to 7 hours
known history of congenital prolonged QT interval or in Pregnancy Risk Factor C
patients taking any medication that prolongs the QT Pregnancy Considerations Adverse events have
interval. Until more information is obtained, it is sug- been observed in animal reproduction studies. Disopyr-
gested that the clinician consult with the physician prior amide levels have been reported in human fetal blood.
to the use of a vasoconstrictor in suspected patients, Disopyramide may stimulate contractions in pregnant
and that the vasoconstrictor (epinephrine, mepivacaine women. In a case report, disopyramide use in the third
and levonordefrin [Carbocaine® 2% with Neo-Cobe- trimester resulted in painful uterine contractions after
frin®]) be used with caution. the first dose and hemorrhage after the second dose
Effects on Dental Treatment Key adverse event(s) (Abbi, 1999).
related to dental treatment: Xerostomia (normal salivary Dental Health Professional Considerations See
flow resumes upon discontinuation). Local Anesthetic/Vasoconstrictor Precautions
require special precautions Disulfiram (dye SUL fi ram)
The most common adverse effects are related to chol- Brand Names: US Antabuse
inergic blockade. The most serious adverse effects of Pharmacologic Category Aldehyde Dehydrogenase
disopyramide are hypotension and cardiac failure. Inhibitor
Use Alcohol use disorder: Management of chronic
>10%: alcohol use disorder.
Gastrointestinal: Xerostomia (32%), constipa- Note: Suggested for use in patients with alcohol use
tion (11%) disorder (moderate to severe) who want to abstain
Genitourinary: Urinary hesitancy (14% to 23%) from alcohol and either prefer disulfiram or are unable
1% to 10%: to tolerate or are unresponsive to naltrexone and
Cardiovascular: Cardiac conduction disturbance, car- acamprosate (APA [Reus 2018]).
diac failure, chest pain, edema, hypotension, Local Anesthetic/Vasoconstrictor Precautions
syncope No information available to require special precautions
Central nervous system: Dizziness, fatigue, head- Effects on Dental Treatment No significant effects or
ache, malaise, myasthenia, nervousness complications reported
Dermatologic: Generalized dermatosis, pruritus, Effects on Bleeding No information available to
skin rash require special precautions
Endocrine & metabolic: Hypokalemia, increased Adverse Reactions Frequency not defined.
serum cholesterol, increased serum triglycerides, Central nervous system: Bitter taste (garlic), drowsi-
weight gain ness, fatigue, headache, metallic taste, peripheral
Gastrointestinal: Abdominal distention, anorexia, neuritis, peripheral neuropathy, polyneuropathy, psy-
bloating, diarrhea, flatulence, nausea, vomiting chosis
Genitourinary: Impotence (1% to 3%), urinary fre- Dermatologic: Acneiform eruption, allergic dermatitis,
quency, urinary retention, urinary urgency skin rash
Neuromuscular & skeletal: Myalgia Genitourinary: Impotence
Ophthalmic: Blurred vision, xerophthalmia Hepatic: Cholestatic hepatitis, fulminant hepatitis, hep-
Respiratory: Dry throat, dyspnea atic failure (multiple case reports)
<1%, postmarketing, and/or case reports: Agranulocy- Ophthalmic: Optic neuritis
tosis, atrioventricular block, cardiac arrhythmia (new Mechanism of Action Disulfiram is a thiuram deriva-
or worsened; proarrhythmic effect), cholestatic jaun- tive which blocks the oxidation of alcohol at the acetal-
dice, decreased hematocrit, decreased hemoglobin, dehyde stage. When taken concomitantly with alcohol,
depression, dysuria, fever, gynecomastia, hepatotox- there is an increase in serum acetaldehyde levels. High
icity, hypoglycemia, increased blood urea nitrogen, acetaldehyde causes uncomfortable symptoms includ-
increased serum creatinine, increased serum trans- ing flushing, throbbing in head and neck, nausea,
aminases, insomnia, mydriasis, numbness, paresthe- vomiting, diaphoresis, thirst, palpitations, chest pain,
sia, peripheral neuropathy, psychosis, psychotic dyspnea, hyperventilation, tachycardia, syncope, weak-
reaction, respiratory distress, skin blister (toxic), sys- ness, blurred vision, confusion, vertigo, and hypoten-
temic lupus erythematosus (rare; generally in patients sion. This reaction is the basis for disulfiram use in post-
previously receiving procainamide), thrombocytope- withdrawal long-term care of alcohol use disorder.
nia, tingling sensation Pharmacodynamics/Kinetics
Mechanism of Action Class Ia antiarrhythmic: Onset of Action Full effect: 12 hours
Decreases myocardial excitability and conduction Duration of Action ~1 to 2 weeks after last dose
velocity; reduces disparity in refractory between normal Pregnancy Considerations
and infarcted myocardium; possesses anticholinergic, Safety in pregnancy has not been established; there is
peripheral vasoconstrictive, and negative inotropic limited data on maternal use during pregnancy (Reitna-
effects uer 1997).
441
DISULFIRAM
Pharmacological agents should not be used for the Respiratory: Dyspnea (1% to 3%)
treatment of alcohol use disorder in pregnant women Miscellaneous: Fever (1% to 3%)
unless needed for the treatment of acute alcohol with- Mechanism of Action Dobutamine, a racemic mixture,
drawal or a coexisting disorder; agents other than stimulates myocardial beta1-adrenergic receptors pri-
disulfiram are recommended for acute alcohol with- marily by the (+) enantiomer and some alpha1 receptor
drawal. agonism by the (-) enantiomer, resulting in increased
contractility and heart rate, and stimulates both beta2-
DOBUTamine (doe BYOO ta meen)
and alpha1-receptors in the vasculature. Although beta2
and alpha1 adrenergic receptors are also activated, the
Brand Names: Canada Dobutamine Injection, USP; effects of beta2 receptor activation may equally offset or
Dobutrex be slightly greater than the effects of alpha1 stimulation,
Pharmacologic Category Adrenergic Agonist Agent; resulting in some vasodilation in addition to the inotropic
Inotrope and chronotropic actions (Leier 1988; Majerus 1989;
Use Ruffolo 1987). Lowers central venous pressure and
Cardiac decompensation: Short-term management of wedge pressure, but has little effect on pulmonary
patients with cardiac decompensation vascular resistance (Leier 1977; Leier 1978).
Guideline recommendations: Onset of Action IV: 1 to 10 minutes; Peak effect: 10
Cardiogenic shock: The 2017 American Heart Asso- to 20 minutes
ciation (AHA) scientific statement for the Contempo- Half-life Elimination 2 minutes
rary Management of Cardiogenic Shock Pregnancy Considerations Dobutamine should not
recommends dobutamine to maintain systemic per- be used as a diagnostic agent for stress testing during
fusion and preserve end-organ performance in pregnancy; use should be avoided when other options
patients with cardiogenic shock. A vasopressor such are available (ESC [Regitz-Zagrosek 2018]). Medica-
as norepinephrine (preferred), vasopressin, or dop- tions used for the treatment of cardiac arrest in preg-
amine is typically the initial preferred therapy until
nancy are the same as in the non-pregnant female.
hemodynamically stable. Once stable, consider add-
Appropriate medications should not be withheld due to
ing or transitioning to an inotrope. However, an
concerns of fetal teratogenicity. Dobutamine use during
inotrope may be the preferred therapy for cardio-
the post-resuscitation phase may be considered; how-
genic shock due to acute decompensated heart fail-
ever, the effects of inotropic support on the fetus should
ure or in other cases when systolic blood pressure
also be considered. Doses and indications should fol-
>90 mm Hg (ACCF/AHA [Yancy 2013]); AHA [van
low current Advanced Cardiovascular Life Support
Diepen 2017]).
(ACLS) guidelines (AHA [Jeejeebhoy 2015 ]).
Inotropic support in advanced heart failure: Bridge
therapy in stage D HF unresponsive to guideline-
directed medical therapy and device therapy in DOCEtaxel (doe se TAKS el)
patients awaiting heart transplant or mechanical cir-
culatory support; short-term management of hospi- Brand Names: US Docefrez [DSC]; Taxotere
talized patients with severe systolic dysfunction Brand Names: Canada Docetaxel for Injection; Doce-
presenting with low blood pressure and significantly taxel Injection; Taxotere
depressed cardiac output; long-term management Pharmacologic Category Antineoplastic Agent, Anti-
(palliative therapy) in select patients with stage D microtubular; Antineoplastic Agent, Taxane Derivative
HF unresponsive to guideline-directed medical ther- Use
apy and device therapy who are not candidates for Docefrez:
heart transplant or mechanical circulatory support Breast cancer: Treatment of breast cancer (locally
(ACCF/AHA [Yancy 2013]). advanced/metastatic) after prior chemotherapy
Local Anesthetic/Vasoconstrictor Precautions failure
No information available to require special precautions Non-small cell lung cancer: Treatment of locally
Effects on Dental Treatment No significant effects or advanced or metastatic non–small cell lung cancer
complications reported (NSCLC) after prior platinum-based chemotherapy
Effects on Bleeding No information available to failure; treatment of previously untreated unresect-
require special precautions able locally advanced or metastatic NSCLC (in com-
Adverse Reactions Incidence of adverse events is not bination with cisplatin)
always reported. Prostate cancer: Treatment of hormone-refractory
Cardiovascular: Ventricular premature contractions metastatic prostate cancer (in combination with pre-
(5%; dose related), angina pectoris (1% to 3%), chest dnisone)
pain (1% to 3%; nonspecific), palpitations (1% to 3%), Taxotere (and various generic brands):
hypotension, increased blood pressure, increased Breast cancer: Treatment of breast cancer (locally
heart rate, localized phlebitis, ventricular ectopy advanced/metastatic) after prior chemotherapy fail-
(increased) ure; adjuvant treatment (in combination with doxor-
Central nervous system: Headache (1% to 3%), par- ubicin and cyclophosphamide) of operable node-
esthesia positive breast cancer
Dermatologic: Skin necrosis (isolated cases) Gastric cancer: Treatment of advanced gastric
Endocrine & metabolic: Decreased serum potassium adenocarcinoma, including gastroesophageal junc-
(slight) tion adenocarcinoma (in combination with cisplatin
Gastrointestinal: Nausea (1% to 3%) and fluorouracil) in patients who have not received
Hematologic & oncologic: Thrombocytopenia (isolated prior chemotherapy for advanced disease
cases) Head and neck cancer: Treatment (induction) of
Local: Local inflammation, local pain (from infiltration) locally advanced squamous cell head and neck
Neuromuscular & skeletal: Leg cramps (mild) cancer (in combination with cisplatin and fluorouracil)
442
DOCOSANOL
NSCLC: Treatment of locally advanced or metastatic intoxication, alopecia (permanent), anaphylactic

NSCLC after failure of prior platinum-based chemo- shock, anorexia, atrial fibrillation, atrial flutter, back
therapy; treatment of previously untreated unresect- pain, bronchospasm, cardiac arrhythmia, cardiac fail-
able locally advanced or metastatic NSCLC (in ure, chest pain, chest tightness, chills, colitis, confu-
combination with cisplatin) sion, conjunctivitis, constipation, cutaneous lupus
Prostate cancer: Treatment of metastatic castration- erythematosus, cystoid macular edema, deafness,
resistant prostate cancer (in combination with pre- deep vein thrombosis, dehydration, dermatological
dnisone) reaction (injection site recall at previous site of extrav-
Local Anesthetic/Vasoconstrictor Precautions asation), disease of the lacrimal apparatus (duct
No information available to require special precautions obstruction), disseminated intravascular coagulation,
Effects on Dental Treatment Key adverse event(s) drug fever, duodenal ulcer, dyspnea, ECG abnormal-
related to dental treatment: Mucositis, stomatitis, and ity, electrolyte disorder, enterocolitis, epiphora (more
taste perversion. common with weekly administration [Kintzel 2006]),
Effects on Bleeding Thrombocytopenia (8% to 14%) erythema multiforme, esophagitis, flushing, gastroin-
and bleeding episodes have been reported. A medical testinal hemorrhage, gastrointestinal perforation,
consult is recommended. hearing loss, hemorrhagic diathesis, hepatitis, hyper-
Adverse Reactions Percentages reported for doce- tension, hypocalcemia, hypokalemia, hypomagnese-
taxel monotherapy; frequency may vary depending on mia, hyponatremia, intestinal obstruction, interstitial
diagnosis, dose, liver function, prior treatment, and pulmonary disease, ischemic colitis, lacrimation, loss
premedication. of consciousness (transient), lymphedema (periph-
eral), multiorgan failure, myelodysplastic syndrome,
>10%:
myocardial infarction, neutropenic enterocolitis, ony-
Central nervous system: Neurotoxicity (23% to 58%)
cholysis, ototoxicity, pain, palmar-plantar erythrody-
Dermatologic: Alopecia (56% to 76%), dermatological
sesthesia, pneumonia (interstitial), pneumonitis,
reaction (20% to 48%), nail disease (11% to 41%)
pruritus, pulmonary edema, pulmonary embolism, pul-
Endocrine & metabolic: Fluid retention (26% to 60%)
monary fibrosis, radiation pneumonitis, radiation recall
Gastrointestinal: Stomatitis (26% to 53%; grades 3/4:
phenomenon, renal failure syndrome, renal insuffi-
2%), diarrhea (23% to 43%), nausea (34% to 42%),
vomiting (22% to 23%) ciency, respiratory failure, skin changes (sclero-
Hematologic & oncologic: Neutropenia (84% to 99%; derma-like), seizure, sepsis, sinus tachycardia, skin
grade 4: 75% to 86%; grades 3/4: 65%; nadir rash, Stevens-Johnson syndrome, syncope, tachycar-
[median]: 7 days, duration [severe neutropenia]: 7 dia, thrombophlebitis, toxic epidermal necrolysis,
days), leukopenia (84% to 99%; grades 3/4: 49%; unstable angina pectoris, ventricular arrhythmia, ven-
grade 4: 32% to 44%), anemia (87% to 97%; grades tricular tachycardia, visual disturbance (transient)
3/4: 8% to 9%), thrombocytopenia (7% to 12%; Mechanism of Action Docetaxel promotes the
grades 3/4: 3%; grade 4: 1%), febrile neutropenia assembly of microtubules from tubulin dimers, and
(5% to 14%) inhibits the depolymerization of tubulin which stabilizes
Hepatic: Increased serum transaminases (4% to 19%) microtubules in the cell. This results in inhibition of
Hypersensitivity: Hypersensitivity reaction (6% DNA, RNA, and protein synthesis. Most activity occurs
to 21%) during the M phase of the cell cycle.
Infection: Infection (22% to 34%; severe: 6%) Pharmacodynamics/Kinetics
Neuromuscular & skeletal: Asthenia (53% to 66%), Half-life Elimination Terminal: ~11 hours
myalgia (6% to 23%), neuromuscular reaction (16%) Pregnancy Risk Factor D
Respiratory: Pulmonary disorder (41%) Pregnancy Considerations Adverse events have
Miscellaneous: Fever (31% to 35%) been observed in animal reproduction studies. An ex
1% to 10%: vivo human placenta perfusion model illustrated that
Cardiovascular: Hypotension (3%) docetaxel crossed the placenta at term. Placental trans-
Central nervous system: Peripheral motor neuropathy fer was low and affected by the presence of albumin;
(4%; severe; mainly distal extremity weakness) higher albumin concentrations resulted in lower doce-
Gastrointestinal: Dysgeusia (6%) taxel placental transfer (Berveiller 2012). Some phar-
Hepatic: Increased serum bilirubin (9%), increased macokinetic properties of docetaxel may be altered in
serum alkaline phosphatase (7%) pregnant women (van Hasselt 2014). Women of child-
Infection: Severe infection (2% to 6%) bearing potential should avoid becoming pregnant dur-
Local: Infusion site reaction (4%) ing therapy. A pregnancy registry is available for all
Neuromuscular and skeletal: Arthralgia (3% to 9%) cancers diagnosed during pregnancy at Cooper Health
Frequency not defined: (877-635-4499).
Cardiovascular: Cardiac tamponade, decreased left Product Availability Docefrez has been discontinued
ventricular ejection fraction, localized phlebitis, in the US for more than 1 year.
peripheral edema
Central nervous system: Fatigue
Dermatologic: Exfoliation of skin, local dryness, local- Docosanol (doe KOE san ole)
ized erythema of the extremities, nail depigmenta-
tion, nail hyperpigmentation, skin discoloration at
injection site Viral Infections - Sample Prescriptions on page 44
Hepatic: Ascites Brand Names: US Abreva [OTC]
Local: Erythema at injection site, inflammation at Generic Availability (US) Yes
injection site Pharmacologic Category Antiviral Agent, Topical
Respiratory: Pleural effusion Dental Use Treatment of herpes simplex of the face or
<1%, postmarketing, and/or case reports: Abdominal lips
pain, acute hepatic failure (Morgan 2011), acute mye- Use Cold sore/fever blister: Treatment of cold sores/
locytic leukemia, acute respiratory distress, alcohol fever blisters on the face or lips.
443
DOCOSANOL
Local Anesthetic/Vasoconstrictor Precautions Dosage Forms: US

No information available to require special precautions Cream, External:
Effects on Dental Treatment No significant effects or Abreva [OTC]: 10% (2 g)
complications reported (see Dental Health Professional Generic: 10% (2 g)
Considerations) Dental Health Professional Considerations Wash
Effects on Bleeding No information available to hands before and after applying cream. Begin treatment
require special precautions at first tingle of cold sore or fever blister. Rub into area
Adverse Reactions Frequency not defined. gently, but completely. Do not apply directly to inside of
Hypersensitivity: Hypersensitivity reaction mouth or around eyes. Contact healthcare provider if
Dental Usual Dosage Herpes simplex (face/lips): Chil- sore gets worse or does not heal within 10 days. Do not
dren ≥12 years and Adults: Topical: Apply 5 times/day share this product with others, may spread infection.
to affected area of face or lips. Start at first sign of cold Notify healthcare professional if pregnant or breastfeed-
sore or fever blister and continue until healed. ing.
Dosing
Adult & Geriatric Cold sore/fever blister: Topical: Docusate (DOK yoo sate)
Apply 5 times daily to affected area of face or lips.
Start at first sign of cold sore or fever blister and Brand Names: US Colace Clear [OTC] [DSC]; Colace
continue until healed. If not healed within 10 days, [OTC]; Diocto [OTC]; DocQLace [OTC] [DSC]; Docu
discontinue use and contact health care provider. Soft [OTC]; Docu [OTC]; Docuprene [OTC] [DSC];
Renal Impairment: Adult There are no dosage Docusil [OTC]; DocuSol Kids [OTC]; DocuSol Mini
adjustments provided in the manufacturer’s labeling. [OTC]; DOK [OTC]; Dulcolax Stool Softener [OTC];
Hepatic Impairment: Adult There are no dosage Enemeez Mini [OTC]; Healthy Mama Move It Along
adjustments provided in the manufacturer’s labeling. [OTC]; Kao-Tin [OTC]; KS Stool Softener [OTC]; Laxa
Pediatric Cold sore/fever blister: Children ≥12 years Basic [OTC]; Pedia-Lax [OTC]; Promolaxin [OTC];
and Adolescents: Refer to adult dosing. Silace [OTC]; Sof-Lax [OTC] [DSC]; Stool Softener
Renal Impairment: Pediatric There are no dosage Laxative DC [OTC] [DSC]; Stool Softener [OTC]
adjustments provided in the manufacturer’s labeling. Brand Names: Canada Apo-Docusate Calcium
Hepatic Impairment: Pediatric There are no dos- [OTC]; Apo-Docusate Sodium [OTC]; Calax [OTC];
age adjustments provided in the manufacturer’s label- Colace [OTC]; Docusate Sodium Odan [OTC]; Dom-
ing. Docusate Sodium [OTC]; Dosolax [OTC]; Dulcocomfort
Mechanism of Action Prevents viral entry and repli- Stool Softener [OTC]; Euro-Docusate C [OTC]; Jamp-
cation at the cellular level Docusate [OTC]; Novo-Docusate Calcium [OTC]; Novo-
Contraindications OTC labeling: When used for self- Docusate Sodium [OTC]; PHL-Docusate Sodium
medication, do not use if you have hypersensitivity to [OTC]; PMS-Docusate Calcium [OTC]; PMS-Docusate
docosanol or any component of the formulation Sodium [OTC]; ratio-Docusate Sodium [OTC]; Selax
Warnings/Precautions For external use only; do not [OTC]; Silace [OTC]; Sirop Docusate De Sodium
apply to inside of mouth or around eyes. Apply at the [OTC]; Soflax C [OTC]; Soflax [OTC]; Taro-Docusate
first sign of cold sore/fever blister (tingle); early treat- [OTC]; Teva-Docusate Calcium [OTC]; Teva-Docusate
ment ensures best results. Do not share product with Sodium [OTC]
others. Discontinue use and contact a health care Pharmacologic Category Stool Softener
provider if the condition gets worse or is not healed Use Stool softener: Prevention of straining during def-
within 10 days. Severe allergic reactions (eg, hives, ecation and constipation associated with hard, dry
facial swelling, wheezing/difficulty breathing, rash, stools; relief of occasional constipation
shock) may occur with use; discontinue and seek Local Anesthetic/Vasoconstrictor Precautions
medical attention immediately if an allergic reaction No information available to require special precautions
occurs. Effects on Dental Treatment Key adverse event(s)
Some dosage forms may contain benzyl alcohol; large related to dental treatment: Throat irritation.
amounts of benzyl alcohol (≥99 mg/kg/day) have been Effects on Bleeding No information available to
associated with a potentially fatal toxicity ("gasping require special precautions
syndrome") in neonates; the "gasping syndrome" con- Adverse Reactions 1% to 10%: Respiratory: Throat
sists of metabolic acidosis, respiratory distress, gasping irritation (liquid)
respirations, CNS dysfunction (including convulsions, Mechanism of Action Reduces surface tension of the
intracranial hemorrhage), hypotension and cardiovas- oil-water interface of the stool resulting in enhanced
cular collapse (AAP ["Inactive" 1997]; CDC, 1982); incorporation of water and fat allowing for stool soften-
some data suggests that benzoate displaces bilirubin ing (Roering, 2010)
from protein binding sites (Ahlfors, 2001); avoid or use Pharmacodynamics/Kinetics
dosage forms containing benzyl alcohol with caution in Onset of Action Oral: 12 to 72 hours; Rectal: 2 to 15
neonates. See manufacturer’s labeling. minutes
Drug Interactions Pregnancy Considerations Hypomagnesemia was
Metabolism/Transport Effects None known. reported in a newborn following chronic maternal over-
Avoid Concomitant Use There are no known inter- use of docusate sodium throughout pregnancy (Schin-
actions where it is recommended to avoid concomitant dler 1984). Treatment of constipation in pregnant
use. women is similar to that of nonpregnant patients and
Increased Effect/Toxicity There are no known sig- medications may be used when diet and lifestyle mod-
nificant interactions involving an increase in effect. ifications are not effective. Agents other than docusate
Decreased Effect are preferred for initial treatment. Docusate sodium may
Docosanol may decrease the levels/effects of: Talimo- be used if needed, but may not be as effective as other
gene Laherparepvec agents (ACG [Christie 2007]).
444
DOLASETRON
rectifier potassium current. Dofetilide has no effect on

Dofetilide (doe FET il ide) sodium channels, adrenergic alpha-receptors, or adre-
nergic beta-receptors. It increases the monophasic
Related Information action potential duration due to delayed repolarization.
Cardiovascular Diseases on page 1442 The increase in the QT interval is a function of prolon-
Clinical Risk Related to Drugs Prolonging QT Interval gation of both effective and functional refractory periods
on page 1462 in the His-Purkinje system and the ventricles. Changes
Brand Names: US Tikosyn in cardiac conduction velocity and sinus node function
Pharmacologic Category Antiarrhythmic Agent, have not been observed in patients with or without
Class III structural heart disease. PR and QRS width remain
Use Atrial fibrillation/atrial flutter: Maintenance of the same in patients with preexisting heart block and
normal sinus rhythm in patients with chronic atrial or sick sinus syndrome.
fibrillation/atrial flutter of longer than 1-week duration Pharmacodynamics/Kinetics
who have been converted to normal sinus rhythm; Half-life Elimination ~10 hours; prolonged with renal
conversion of atrial fibrillation and atrial flutter to normal impairment
sinus rhythm. Time to Peak Serum: Fasting: 2 to 3 hours
Local Anesthetic/Vasoconstrictor Precautions Pregnancy Risk Factor C
Dofetilide is one of the drugs confirmed to prolong the Pregnancy Considerations Adverse events have
QT interval and is accepted as having a risk of causing
torsade de pointes. The risk of drug-induced torsade de
pointes is extremely low when a single QT interval
prolonging drug is prescribed. In terms of epinephrine,
it is not known what effect vasoconstrictors in the local
anesthetic regimen will have in patients with a known Dolasetron (dol A se tron)
history of congenital prolonged QT interval or in patients
taking any medication that prolongs the QT interval. Related Information
Until more information is obtained, it is suggested that Clinical Risk Related to Drugs Prolonging QT Interval
the clinician consult with the physician prior to the use of on page 1462
a vasoconstrictor in suspected patients, and that the Brand Names: US Anzemet
vasoconstrictor (epinephrine, mepivacaine and levonor- Pharmacologic Category Antiemetic; Selective
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used 5-HT3 Receptor Antagonist
with caution. Use
Effects on Dental Treatment No significant effects or Chemotherapy-associated nausea and vomiting
complications reported (oral): Prevention of nausea and vomiting associated
Effects on Bleeding No information available to with initial and repeat course of moderately emeto-
require special precautions genic cancer chemotherapy in adults and children ≥2
Adverse Reactions years
>10%: Postoperative nausea and vomiting (injection): Pre-
Cardiovascular: Torsades de pointes (patients receiv- vention and treatment of postoperative nausea and
ing doses in excess of those recommended: ≤11%; vomiting (PONV) in adults and children ≥2 years
cardiac failure patients: 3%; patients with recent Limitations of use: Routine PONV prophylaxis is not
myocardial infarction: <1%; occurs most frequently recommended if there is little expectation that nau-
within the first 3 days of therapy) sea and/or vomiting will occur postoperatively. In
Central nervous system: Headache (11%) patients in whom nausea and/or vomiting must be
1% to 10%: avoided postoperatively, dolasetron (injection) is rec-
Cardiovascular: Chest pain (10%), ventricular fibrilla- ommended even if the anticipated incidence of post-
tion (≤5%), ventricular tachycardia (3% to 4%), bra- operative nausea and/or vomiting is low. If
dycardia (≤2%), cardiac arrest (≤2%), cerebral prophylaxis has failed, a repeat dose should not be
ischemia (≤2%), cerebrovascular accident (≤2%),
utilized as rescue therapy.
edema (≤2%), myocardial infarction (≤2%), syncope
(≤2%), atrioventricular block (<2%), heart block (1%)
Dolasetron is one of the drugs confirmed to prolong
Central nervous system: Dizziness (8%), insomnia
(4%), facial paralysis (≤2%), flaccid paralysis the QT interval and is accepted as having a risk of
(≤2%), migraine (≤2%), paralysis (≤2%), paresthesia causing torsade de pointes. The risk of drug-induced
(≤2%) torsade de pointes is extremely low when a single QT
Dermatologic: Skin rash (3%) interval prolonging drug is prescribed. In terms of epi-
Gastrointestinal: Nausea (5%), abdominal pain (3%), nephrine, it is not known what effect vasoconstrictors in
diarrhea (3%) the local anesthetic regimen will have in patients with a
Hepatic: Hepatotoxicity (≤2%), hepatic injury (<2%) known history of congenital prolonged QT interval or in
Hypersensitivity: Angioedema (≤2%) patients taking any medication that prolongs the QT
Neuromuscular & skeletal: Back pain (3%) interval. Until more information is obtained, it is sug-
Respiratory: Respiratory tract infection (7%), dyspnea gested that the clinician consult with the physician prior
(6%), flu-like symptoms (4%), increased cough to the use of a vasoconstrictor in suspected patients,
(≤2%), cough (<2%) and that the vasoconstrictor (epinephrine, mepivacaine
Miscellaneous: Accidental injury (3%), surgery (3%) and levonordefrin [Carbocaine® 2% with Neo-Cobe-
<1%, postmarketing, and/or case reports: Bundle frin®]) be used with caution.
branch block Effects on Dental Treatment Key adverse event(s)
Mechanism of Action Vaughan Williams Class III related to dental treatment: Taste alterations.
antiarrhythmic activity. Blockade of the cardiac ion Effects on Bleeding No information available to
channel carrying the rapid component of the delayed require special precautions
445
DOLASETRON
Adverse Reactions Adverse events may vary accord- IV: Children: 4.8 hours; Adults: 7.3 hours
ing to indication and route of administration. Severe renal impairment: 11 hours
>10%: Central nervous system: Headache (oral: 18% to Severe hepatic impairment: 11 hours
23%; IV: 9%) Time to Peak Hydrodolasetron: IV: 0.6 hours; Oral: ~1
1% to 10%: hour
Cardiovascular: Bradycardia (4% to 5%; may be Pregnancy Considerations Adverse events have not
severe after IV administration), tachycardia (≤3%), been observed in animal reproduction studies.
edema (<2%), facial edema (<2%), flushing (<2%), Product Availability Anzemet injection has been dis-
hypotension (<2%; may be severe after IV adminis- continued in the US for more than 1 year.
tration), orthostatic hypotension (<2%), peripheral Dental Health Professional Considerations See
edema (<2%), peripheral ischemia (<2%), phlebitis Local Anesthetic/Vasoconstrictor Precautions
(<2%), sinus arrhythmia (<2%), thrombophlebi-
tis (<2%)
Central nervous system: Fatigue (oral: 3% to 6%), Dolutegravir (doe loo TEG ra vir)
dizziness (1% to 6%), pain (≤3%), abnormal dreams
(<2%), agitation (<2%), anxiety (<2%), ataxia (<2%), Brand Names: US Tivicay
chills (≤2%), confusion (<2%), depersonalization Brand Names: Canada Tivicay
(<2%), paresthesia (<2%), shivering (≤2%), sleep Pharmacologic Category Antiretroviral, Integrase
disorder (<2%), twitching (<2%), vertigo (<2%) Inhibitor (Anti-HIV)
Dermatologic: Diaphoresis (<2%), skin rash (<2%), Use HIV-1 infection, treatment: Treatment of HIV-1
urticaria (<2%) infection in combination with other antiretroviral agents
Endocrine & metabolic: Increased gamma-glutamyl in adult and pediatric patients weighing at least 30 kg, or
transferase (<2%) in combination with rilpivirine in adults to replace the
Gastrointestinal: Diarrhea (oral: 2% to 5%), dyspepsia current antiretroviral regimen in those who are virolog-
(≤3%), abdominal pain (<2%), anorexia (<2%), con- ically suppressed (HIV-1 RNA <50 copies per mL) on a
stipation (<2%), dysgeusia (<2%), pancreatitis (<2%) stable antiretroviral regimen for at least 6 months with
Genitourinary: Dysuria (<2%), hematuria (<2%) no history of treatment failure or known substitutions
Hematologic and oncologic: Anemia (<2%), hema- associated with resistance to either antiretroviral agent.
toma (<2%), prolonged prothrombin time (<2%), Local Anesthetic/Vasoconstrictor Precautions
prolonged partial thromboplastin time (<2%), purpura No information available to require special precautions
(<2%), thrombocytopenia (<2%) Effects on Dental Treatment No significant effects or
Hepatic: Hyperbilirubinemia (<2%), increased serum complications reported
alkaline phosphatase (<2%) Effects on Bleeding No information available to
Hypersensitivity: Anaphylaxis (<2%) require special precautions
Local: Burning sensation at injection site (IV: <2%), Adverse Reactions Adverse reactions reported with
pain at injection site (IV: <2%) combination therapy.
Neuromuscular & skeletal: Arthralgia (<2%), myalgia >10%:
(<2%), tremor (<2%) Endocrine & metabolic: Hyperglycemia (≤14%)
Ophthalmic: Photophobia (<2%), visual disturb-
ance (<2%)
(≤18%; includes patients with hepatitis B and/or C
Otic: Tinnitus (<2%)
infections)
Renal: Acute renal failure (<2%), polyuria (<2%)
1% to 10%:
Respiratory: Bronchospasm (<2%), dyspnea (<2%),
Central nervous system: Insomnia (≤7%), fatigue
epistaxis (<2%)
(≤2%), headache (≤2%), suicidal ideation (<2%),
<1%, postmarketing, and/or case reports: Abnormal T
suicidal tendencies (<2%), depression (≤1%)
waves on ECG, appearance of U waves on ECG,
Dermatologic: Pruritus (<2%)
atrial fibrillation, atrial flutter, atrioventricular block,
bundle branch block (left and right), cardiac arrest, Gastrointestinal: Increased serum lipase (2% to 10%),
chest pain, extrasystoles (APCs or VPCs), increased diarrhea (≤2%), abdominal distress (<2%), abdomi-
serum ALT (transient), increased serum AST (transi- nal pain (<2%), flatulence (<2%), upper abdominal
ent), ischemic heart disease, nodal arrhythmia, palpi- pain (<2%), vomiting (<2%), nausea (≤1%)
tations, prolongation P-R interval on ECG (dose Hematologic & oncologic: Neutropenia (3% to 4%;
dependent), prolonged Q-T interval on ECG, serotonin grades 3/4: 2%), leukopenia (2% to 3%)
syndrome, slow R wave progression, ST segment Hepatic: Increased serum aspartate aminotransferase
changes on ECG, syncope (may be severe after IV (≤8%), hyperbilirubinemia (≤3%), hepatitis (<2%)
administration), torsades de pointes, ventricular Hypersensitivity: Hypersensitivity reaction (≤1%)
arrhythmia, ventricular fibrillation cardiac arrest (IV), Neuromuscular & skeletal: Increased creatine phos-
ventricular tachycardia (IV), wide complex tachycardia phokinase (1% to 7%), myositis (<2%)
(IV), widened QRS complex on ECG (dose- Renal: Renal insufficiency (<2%)
dependent) <1%, postmarketing, and/or case reports: Abnormal
Mechanism of Action Dolasetron is a selective sero- dreams, acute hepatic failure, anxiety, arthralgia, diz-
tonin receptor (5-HT3) antagonist which blocks seroto- ziness, hepatotoxicity, immune reconstitution syn-
nin both peripherally (primary site of action) and drome, increased serum creatinine, myalgia, skin
centrally at the chemoreceptor trigger zone rash, weight gain
Pharmacodynamics/Kinetics Mechanism of Action Binds to the integrase active
Half-life Elimination site and inhibits the strand transfer step of HIV-1 DNA
Dolasetron: IV: ≤10 minutes integration necessary for the HIV replication cycle.
Hydrodolasetron: Pharmacodynamics/Kinetics
Oral: Children: 5.5 hours; Adolescents: 6.4 hours; Half-life Elimination ~14 hours
Adults: 8.1 hours Time to Peak 2 to 3 hours
446
DOLUTEGRAVIR AND RILPIVIRINE
Pregnancy Considerations Health care providers are encouraged to enroll preg-

Dolutegravir has a high level of transfer across the nant females exposed to antiretroviral medications as
human placenta. early in pregnancy as possible in the Antiretroviral
Data collected by the antiretroviral pregnancy registry APRegistry.com). Health care providers caring for
are insufficient to evaluate human teratogenic risk. A HIV-infected females and their infants may contact the
preliminary report of observational data has found an National Perinatal HIV Hotline (888-448-8765) for clin-
increased risk of neural tube defects (NTDs) in women ical consultation (HHS [infants] 2018; HHS [perina-
who became pregnant during dolutegravir treatment; tal] 2018).
this risk was not observed in women who started treat-
ment during pregnancy. Maternal antiretroviral therapy
(ART) may increase the risk of preterm delivery, Dolutegravir and Rilpivirine
(doe loo TEG ra vir & ril pi VIR een)
due to variability of maternal factors (disease severity; Brand Names: US Juluca
gestational age at initiation of therapy). An increased Brand Names: Canada Juluca
risk of stillbirth, low birth weight, and small for gesta- Pharmacologic Category Antiretroviral, Integrase
tional age infants has been observed in some but not all Inhibitor (Anti-HIV); Antiretroviral, Reverse Transcrip-
studies. Because there is clear benefit to appropriate tase Inhibitor, Non-nucleoside (Anti-HIV)
treatment, maternal ART should not be withheld due to Use HIV-1 infection, treatment: Treatment of HIV-1
concerns for adverse neonatal outcomes. Long-term infection in adults virologically suppressed on a stable
follow-up is recommended for all infants exposed to antiretroviral regimen for ≥6 months with no history of
antiretroviral medications; children who develop signifi- treatment failure and no known resistance to the indi-
cant organ system abnormalities of unknown etiology vidual components
(particularly of the CNS or heart) should be evaluated Local Anesthetic/Vasoconstrictor Precautions
for potential mitochondrial dysfunction. QTc prolongation: In healthy subjects, supratherapeutic
Use of dolutegravir during the first trimester is not doses of rilpivirine (ie, 75 mg daily, 300 mg daily) have
recommended. Based on available data, the Health been associated with QTc prolongation. The risk of
and Human Services (HHS) Perinatal HIV Guidelines drug-induced torsades de pointes is extremely low
when a single QT interval prolonging drug is prescribed.
consider dolutegravir a preferred integrase strand trans-
In terms of epinephrine, it is not known what effect
fer inhibitor (ISTI) after the first trimester for HIV-
vasoconstrictors in the local anesthetic regimen will
infected pregnant females who are antiretroviral-naive
have in patients with a known history of congenital
and those with acute HIV infection. Due to the potential
prolonged QT interval or in patients taking any medi-
risk of NTDs, dolutegravir should not be initiated
cation that prolongs the QT interval. Until more informa-
during the first trimester (<14 weeks [up to 13 6 /7
tion is obtained, it is suggested that the clinician consult
weeks]; gestational age by last menstrual period). with the physician prior to the use of a vasoconstrictor in
Based on available data, the HHS Perinatal HIV Guide- suspected patients, and that the vasoconstrictor (epi-
lines also consider dolutegravir a preferred ISTI after nephrine, mepivacaine, and levonordefrin [Carbocaine
the first trimester for HIV-infected pregnant females 2% with Neo-Cobefrin]) be used with caution.
who have had ART therapy in the past but are restart- Effects on Dental Treatment No significant effects or
ing, or who require a new ART regimen (due to poor complications reported
tolerance or poor virologic response of current regi- Effects on Bleeding No information available to
men). When pregnancy is diagnosed during dolutegra- require special precautions
vir therapy, treatment may be continued if the patient is Adverse Reactions Also see individual agents.
in the second or third trimester if viral suppression is 1% to 10%:
effective and the regimen is well tolerated. When preg- Central nervous system: Headache (2%)
nancy is diagnosed during the first trimester, the risks Endocrine & metabolic: Hyperglycemia (4%)
and benefits of continuing dolutegravir or changing ART Gastrointestinal: Increased serum lipase (5%), diar-
should be discussed. Pharmacokinetics of dolutegravir rhea (2%)
may be altered, but dosing adjustments are not needed Hepatic: Increased serum ALT (2%), increased serum
during pregnancy. bilirubin (2%)
Neuromuscular & skeletal: Decreased bone mineral
The HHS Perinatal HIV Guidelines do not recommend density (2%), increased creatine phosphoki-
use of dolutegravir in patients who are not yet pregnant nase (≤1%)
but are trying to conceive. Evaluate pregnancy status in <1%, postmarketing, and/or case reports: Bone frac-
females of reproductive potential; a pregnancy test ture, increased serum AST
should be completed prior to therapy with dolutegravir. Mechanism of Action Dolutegravir, an integrase
Patients who wish to become pregnant or who cannot inhibitor, inhibits HIV integrase by binding to the inte-
use effective contraception during therapy should not grase active site and blocking the strand transfer step of
be prescribed dolutegravir-based regimens. Options for retroviral DNA integration. Rilpivirine, a non-nucleoside
postpartum contraception should be evaluated when reverse transcriptase inhibitor, binds to reverse tran-
dolutegravir is continued following delivery. scriptase and blocks the RNA-dependent and DNA-
dependent polymerase activities, including HIV-1 repli-
In general, ART is recommended for all pregnant
cation.
females with HIV to keep the viral load below the limit
of detection and reduce the risk of perinatal trans-
Use of dolutegravir during the first trimester is not
mission. Monitoring during pregnancy is more frequent
recommended.
than in nonpregnant adults. ART should be continued
postpartum for all females living with HIV and can be Based on available data, the Health and Human Serv-
modified after delivery. ices (HHS) Perinatal HIV Guidelines do not recommend
447
DOLUTEGRAVIR AND RILPIVIRINE
use of this fixed-dose combination regimen in HIV- Dermatologic: Ecchymosis (4% to 5%), eczema (3%),
infected pregnant females who are antiretroviral-naive, dermal ulcer (≥1%), diaphoresis (≥1%), pruritus
who have had antiretroviral therapy (ART) in the past (≥1%), skin rash (≥1%), urticaria (≥1%)
but are restarting, or who require a new ART regimen Endocrine & metabolic: Weight loss (3% to 5%; dose
(due to poor tolerance or poor virologic response of related), hyperlipidemia (2%), dehydration (1% to
current regimen). When pregnancy is diagnosed during 2%), glycosuria (≥1%), hot flash (≥1%), increased
therapy with this combination, treatment may be con- lactate dehydrogenase (≥1%), increased
tinued if the patient is in the second or third trimester if libido (≥1%)
viral suppression is effective and the regimen is well Gastrointestinal: Vomiting (3% to 9%; dose related),
tolerated. When pregnancy is diagnosed during the first anorexia (2% to 8%), abdominal pain (≥1%), bloating
trimester, the risks and benefits of continuing this regi- (≥1%), constipation (≥1%), dyspepsia (≥1%), epigas-
men or changing ART should be discussed. In addition tric pain (≥1%), fecal incontinence (≥1%), gastro-
this fixed-dose combination should not be used as a enteritis (≥1%), gastrointestinal hemorrhage (≥1%),
complete regimen during pregnancy (2-drug regimens sore throat (≥1%), toothache (≥1%)
are not recommended in pregnant females). Genitourinary: Urinary incontinence (1% to 3%), uri-
nary frequency (2%), cystitis (≥1%), hematuria
The HHS Perinatal HIV Guidelines do not recommend (≥1%), nocturia (≥1%), urinary tract infection (≥1%)
use of this combination in females who are not yet Hematologic & oncologic: Bruise (2%), hemorrhage
pregnant but are trying to conceive. Evaluate preg- (2%), anemia (≥1%)
nancy status in females of reproductive potential; a Hepatic: Increased serum alkaline phosphatase (≥1%)
pregnancy test should be completed prior to therapy Infection: Fungal infection (≥1%), influenza (≥1%)
with dolutegravir. Patients who wish to become preg- Neuromuscular & skeletal: Muscle cramps (3% to
nant or who cannot use effective contraception during 8%), back pain (3%), increased creatine phosphoki-
therapy should not be prescribed dolutegravir-based nase (3%), arthritis (1% to 2%), weakness (1% to
regimens. Options for postpartum contraception should 2%), bone fracture (≥1%), tremor (≥1%)
be evaluated when dolutegravir is continued following Ophthalmic: Blurred vision (≥1%), cataract (≥1%), eye
delivery (HHS [perinatal] 2018). irritation (≥1%)
Refer to individual monographs for additional infor- Respiratory: Bronchitis (≥1%), dyspnea (≥1%), flu-like
mation. symptoms (≥1%), increased cough (≥1%), pharyng-
itis (≥1%), pneumonia (≥1%)
Donepezil (doh NEP e zil) ≤1%, postmarketing, and/or case reports: Abnormal
Brand Names: US Aricept hepatic function tests, abnormal lacrimation, abnormal
vision, abscess, acute rhinitis, albuminuria, alopecia,
Brand Names: Canada Aricept; Aricept RDT
angina pectoris, apathy, arteritis, arthralgia, arthrop-
Pharmacologic Category Acetylcholinesterase Inhib- athy, asthma, atelectasis, atrophic striae, benign pro-
itor (Central) static hypertrophy, blepharitis, breast fibroadenosis,
Use Alzheimer disease: Treatment of mild, moderate, cachexia, cardiomegaly, cellulitis, cerebral hemor-
or severe dementia of the Alzheimer type rhage, cerebral infarction, cerebral ischemia, cerebro-
Local Anesthetic/Vasoconstrictor Precautions vascular accident, chills, cholecystitis, cholelithiasis,
No information available to require special precautions conjunctival hemorrhage, conjunctivitis, convulsions,
Effects on Dental Treatment No significant effects or decreased libido, deep vein thrombosis, dementia,
complications reported dermatitis, diabetes mellitus, diverticulitis, duodenal
Effects on Bleeding No information available to ulcer, dysarthria, dysgeusia, dysphagia, dysphoria,
require special precautions dysuria, emotional disturbance, eosinophilia, epigas-
Adverse Reactions tric distress, epistaxis, eructation, erythema, esopha-
>10%: gitis, euphoria, extrapyramidal reaction, facial edema,
Central nervous system: Insomnia (2% to 14%) fasciculations, fibrocystic breast changes, first degree
Gastrointestinal: Nausea (3% to 19%; dose related), atrioventricular block, flatulence, gastritis, gastric
diarrhea (5% to 15%; dose related) ulcer, gingivitis, glaucoma, goiter, gout, hearing loss,
Infection: Infection (11%) heart block, hemiplegia, hemolytic anemia, hemor-
Miscellaneous: Accidental injury (7% to 13%) rhoids, hepatitis, hernia, herpes zoster, hiatal hernia,
≥1% to 10%: hirsutism, hyperbilirubinemia, hyperglycemia, hyper-
Cardiovascular: Hypertension (3%), chest pain (2%), keratosis, hypersensitivity reaction, hypertonia, hypo-
syncope (2%), atrial fibrillation (≥1%), bradycardia kalemia, hypokinesia, hyponatremia,
(≥1%), cardiac failure (≥1%), ECG abnormality hypoproteinemia, hypoxia, increased appetite,
(≥1%), edema (≥1%), hypotension (≥1%), peripheral increased blood urea nitrogen, increased gamma-glu-
edema (≥1%), vasodilation (≥1%) tamyl transferase, increased post-void residual urine
Central nervous system: Headache (3% to 10%), pain volume, increased serum ALT, increased serum AST,
(3% to 9%), dizziness (2% to 8%), fatigue (1% to increased serum creatinine, increased serum trans-
8%), abnormal dreams (3%), hallucination (3%), aminases, increased thirst, intestinal obstruction,
hostility (3%), depression (2% to 3%), nervousness intracranial hemorrhage, iron deficiency anemia, irri-
(1% to 3%), confusion (2%), drowsiness (2%), emo- table bowel syndrome, jaundice, leg cramps, leukocy-
tional lability (2%; including crying), personality dis- tosis, localized coldness, malaise, mastitis, melena,
order (2%), abnormal gait (≥1%), aggressive motion sickness, muscle spasm, myalgia, myasthenia,
behavior (≥1%), agitation (≥1%), anxiety (≥1%), myocardial infarction, neuralgia, neurodermatitis, neu-
aphasia (≥1%), ataxia (≥1%), convulsions (≥1%), roleptic malignant syndrome, night sweats, nystag-
delusions (≥1%), irritability (≥1%), paresthesia mus, orthostatic hypotension, osteoporosis, otalgia,
(≥1%), restlessness (≥1%), vertigo (≥1%), wandering otitis externa, otitis media, pacing, pancreatitis, para-
(≥1%) noia, peptic ulcer disease, periodontal abscess,
448
DORAVIRINE, LAMIVUDINE, AND TENOFOVIR DISOPROXIL FUMARATE
periodontitis, periorbital edema, peripheral vascular Mechanism of Action Doravirine is a pyridinone non-
disease, pernicious anemia, pleurisy, polydipsia, post nucleoside reverse transcriptase inhibitor that inhibits
nasal drip, prolonged Q-T interval on ECG, psoriasis, HIV-1 replication by noncompetitive inhibition of HIV-1
pulmonary congestion, pyelonephritis, pyuria, rectal reverse transcriptase.
hemorrhage, renal failure, retinal hemorrhage, rhab- Pharmacodynamics/Kinetics
domyolysis, rhinitis, seeing spots, sensation of cold, Half-life Elimination 15 hours
sepsis, severe depression, sialorrhea, skin discolora- Time to Peak 2 hours
tion, sleep apnea, snoring, supraventricular extrasys- Pregnancy Considerations
tole, supraventricular tachycardia, thrombocythemia, Data collected by the antiretroviral registry related to the
thrombocytopenia, tinnitus, tongue edema, tonic- use of doravirine in pregnancy are insufficient to eval-
clonic seizures, torsades de pointes, transient ische- uate teratogenicity.
mic attacks, urinary urgency, uterine hemorrhage,
vaginitis, vasodilation, ventricular premature contrac- Maternal antiretroviral therapy (ART) may increase the
tions, ventricular tachycardia, vertigo, vesiculobullous risk of preterm delivery, although available information
dermatitis, weight gain, wheezing, xeroderma, xeroph- is conflicting possibly due to variability of maternal
thalmia, xerostomia factors (disease severity; gestational age at initiation
Mechanism of Action Alzheimer's disease is charac- of therapy). An increased risk of stillbirth, low birth
terized by cholinergic deficiency in the cortex and basal weight, and small for gestational age infants has been
forebrain, which contributes to cognitive deficits. Done- observed in some but not all studies. Because there is
pezil reversibly and noncompetitively inhibits centrally- clear benefit to appropriate treatment, maternal ART
active acetylcholinesterase, the enzyme responsible for should not be withheld due to concerns for adverse
hydrolysis of acetylcholine. This appears to result in neonatal outcomes. Long-term follow-up is recom-
increased concentrations of acetylcholine available for mended for all infants exposed to antiretroviral medi-
synaptic transmission in the central nervous system. cations; children who develop significant organ system
Pharmacodynamics/Kinetics abnormalities of unknown etiology (particularly of the
Half-life Elimination 70 hours; time to steady-state: CNS or heart) should be evaluated for potential mito-
15 days chondrial dysfunction. Hypersensitivity reactions
Time to Peak Plasma: Tablet, 10 mg: 3 hours; Tablet, (including hepatic toxicity and rash) are more common
23 mg: ~8 hours; Note: Peak plasma concentrations in women on NNRTI therapy; it is not known if preg-
almost twofold higher for the 23 mg tablet compared nancy increases this risk.
to the 10 mg tablet
Pregnancy Considerations Adverse events have The Health and Human Services (HHS) Perinatal HIV
been observed in some animal reproduction studies. Guidelines note data are insufficient to recommend
doravirine for HIV-infected pregnant females who are
antiretroviral naive, who have had ART therapy in the
Doravirine (DOR a VIR een) past but are restarting, who require a new ART regimen
(due to poor tolerance or poor virologic response of
Brand Names: US Pifeltro
current regimen), who are not yet pregnant but are
Brand Names: Canada Pifeltro
trying to conceive, or who become pregnant during
Pharmacologic Category Antiretroviral, Reverse therapy. Pharmacokinetic studies of doravirine are not
Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)
available to make dosing recommendations for preg-
Use HIV-1 infection, treatment: Treatment of HIV-1 nant females.
infection in combination with other antiretroviral agents
in adult patients with no prior antiretroviral treatment In general, ART is recommended for all pregnant
history. females with HIV to keep the viral load below the limit
Local Anesthetic/Vasoconstrictor Precautions of detection and reduce the risk of perinatal trans-
No information available to require special precautions mission. Monitoring during pregnancy is more frequent
Effects on Dental Treatment No significant effects or than in nonpregnant adults. ART should be continued
complications reported postpartum for all females living with HIV and can be
Effects on Bleeding No information available to modified after delivery.
Adverse Reactions Incidences reflect adverse reac- nant females exposed to antiretroviral medications as
tions that occur with combination therapy.
1% to 10%:
Central nervous system: Fatigue (6%), headache
APRegistry.com). Health care providers caring for
(6%), dizziness (3%), abnormal dreams (1%), insom-
HIV-infected females and their infants may contact the
nia (1%)
Gastrointestinal: Nausea (7%), abdominal pain (5%),
diarrhea (5%), increased serum lipase (3% to 4%)
Hepatic: Increased serum bilirubin (2% to 5%), Doravirine, Lamivudine, and Tenofovir
increased serum aspartate aminotransferase Disoproxil Fumarate
(≤4%), increased serum alanine aminotransferase (DOR a VIR een, la MI vyoo deen & ten OF oh vir dye soe PROX il
(1% to 3%) FUE ma rate)
phokinase in blood specimen (2% to 3%) Brand Names: US Delstrigo
Renal: Increased serum creatinine (2% to 3%) Brand Names: Canada Delstrigo
<1%, postmarketing, and/or case reports: Increased Pharmacologic Category Antiretroviral, Reverse
LDL cholesterol, increased serum alkaline phospha- Transcriptase Inhibitor, Non-nucleoside (Anti-HIV); Anti-
tase, increased serum triglycerides retroviral, Reverse Transcriptase Inhibitor, Nucleoside
449
DORAVIRINE, LAMIVUDINE, AND TENOFOVIR DISOPROXIL FUMARATE
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhib- Use

itor, Nucleotide (Anti-HIV) Intra-abdominal infections, complicated: Treatment
Use HIV-1 infection, treatment: Treatment of HIV-1 of complicated intra-abdominal infections caused by
infection in adult patients with no prior antiretroviral Bacteroides caccae, Bacteroides fragilis, Bacteroides
treatment history. thetaiotaomicron, Bacteroides uniformis, Bacteroides
Local Anesthetic/Vasoconstrictor Precautions vulgatus, Escherichia coli, Klebsiella pneumoniae,
No information available to require special precautions Peptostreptococcus micros, Pseudomonas aerugi-
Effects on Dental Treatment No significant effects or nosa, Streptococcus intermedius, and Streptococcus
complications reported constellatus.
Effects on Bleeding No information available to Urinary tract infections, complicated (including
require special precautions pyelonephritis): Treatment of complicated urinary
Adverse Reactions Also see individual agents. tract infections (UTIs), including pyelonephritis,
1% to 10%: caused by E. coli (including cases with concurrent
Central nervous system: Sleep disorder (≤12%), sleep bacteremia), Acinetobacter baumannii, K. pneumo-
disturbance (≤12%), dizziness (7% to 9%), suicide niae, Proteus mirabilis, and P. aeruginosa.
(7%), abnormal dreams (5%), depression (4%), Local Anesthetic/Vasoconstrictor Precautions
impaired consciousness (4%), insomnia (4%), No information available to require special precautions
drowsiness (3%) Effects on Dental Treatment Prolonged use of dor-
Dermatologic: Skin rash (2%) ipenem may lead to development of oral candidiasis.
Gastrointestinal: Increased serum lipase (5%), nausea Effects on Bleeding Thrombocytopenia has been
(5%), diarrhea (3%) reported through postmarketing surveillance
Hepatic: Increased serum bilirubin (≤4%), increased Adverse Reactions
serum alanine aminotransferase (≤3), increased >10%:
serum aspartate aminotransferase (≤2%) Central nervous system: Headache (3% to 16%)
Neuromuscular & skeletal: Increased creatine phos- Gastrointestinal: Diarrhea (6% to 12%), nausea (4%
phokinase (2%) to 12%)
Renal: Increased serum creatinine (2%) 1% to 10%:
<1%, postmarketing, and/or case reports: Increased Cardiovascular: Phlebitis (2% to 8%)
LDL cholesterol, increased serum cholesterol, Dermatologic: Skin rash (1% to 6%; includes allergic/
increased serum triglycerides bullous dermatitis, erythema, macular/papular erup-
Mechanism of Action tions, urticaria, and erythema multiforme), pruritus
Doravirine: Pyridinone non-nucleoside reverse tran- (1% to 3%)
scriptase inhibitor that inhibits HIV-1 replication by Gastrointestinal: Oral candidiasis (1% to 3%), Clos-
non-competitive inhibition of HIV-1 reverse transcrip- tridioides (formerly Clostridium) difficile-associated
tase. diarrhea (≤1%)
Lamivudine: Cytosine analog that is phosphorylated Genitourinary: Vaginal infection (1% to 2%)
Hematologic & oncologic: Anemia (2% to 10%)
intracellularly to its active 5'-triphosphate metabolite.
Hepatic: Increased serum transaminases (2% to 7%)
The principal mode of action is inhibition of HIV
reverse transcription via viral DNA chain termination;
interstitial pneumonitis, leukopenia, neutropenia, renal
inhibits RNA- and DNA-dependent DNA polymerase
failure, renal insufficiency, seizure, Stevens-Johnson
activities of reverse transcriptase.
syndrome, thrombocytopenia, toxic epidermal nec-
Tenofovir disoproxil fumarate: Nucleotide reverse tran-
rolysis
scriptase inhibitor; analog of adenosine 5' monophos-
phate that interferes with the HIV viral RNA dependent
thesis by binding to several of the penicillin-binding
DNA polymerase resulting in inhibition of viral repli-
proteins (PBP-2, PBP-3, PBP-4), which in turn inhibits
cation. TDF is first converted intracellularly by hydrol-
the final transpeptidation step of peptidoglycan syn-
ysis to tenofovir and subsequently phosphorylated to
thesis in bacterial cell walls, thus inhibiting cell wall
the active tenofovir diphosphate.
biosynthesis; bacteria eventually lyse due to ongoing
Pregnancy Considerations activity of cell wall autolytic enzymes (autolysins and
The Health and Human Services (HHS) Perinatal HIV murein hydrolases) while cell wall assembly is arrested.
Guidelines consider information related to this fixed- Pharmacodynamics/Kinetics
dose combination insufficient to make recommenda- Half-life Elimination ~1 hour
tions for use in HIV-infected pregnant females who Pregnancy Risk Factor B
are antiretroviral-naive, who have had antiretroviral
therapy (ART) in the past but are restarting, who require
been observed in animal reproduction studies. Informa-
a new ART regimen (due to poor tolerance or poor
tion related to use during pregnancy has not been
virologic response of current regimen), who are not
located.
yet pregnant but are trying to conceive, or who become
pregnant while taking the regimen (HHS [perinatal]
2018). Dornase Alfa (DOOR nase AL fa)
Refer to individual monographs for additional infor- Brand Names: US Pulmozyme

mation. Brand Names: Canada Pulmozyme
Pharmacologic Category Enzyme; Mucolytic Agent
Doripenem (dore i PEN em) Use Cystic fibrosis: Management of cystic fibrosis
patients, in conjunction with standard therapies, to
Brand Names: US Doribax [DSC] improve pulmonary function; reduce the risk of respira-
Pharmacologic Category Antibiotic, Carbapenem tory tract infections requiring parenteral antibiotics in
450
DORZOLAMIDE AND TIMOLOL
patients with a forced vital capacity (FVC) ≥40% of Local Anesthetic/Vasoconstrictor Precautions
predicted. Epinephrine has interacted with nonselective beta-
Local Anesthetic/Vasoconstrictor Precautions blockers, such as propranolol, to result in initial hyper-
No information available to require special precautions tensive episode followed by bradycardia. Timolol is also
Effects on Dental Treatment Key adverse event(s) a nonselective beta-blocker. The significance of a
related to dental treatment: Pharyngitis potential systemic interaction with epinephrine is
Effects on Bleeding No information available to unknown. However, it is suggested that cautionary
require special precautions procedures be used, particularly if vasoconstrictor is
Adverse Reactions Adverse events were similar in used immediately following a dose of timolol taken by
children using the PARI BABY nebulizer (facemask as the patient.
opposed to mouthpiece) with the addition of cough. Effects on Dental Treatment Key adverse event(s)
>10%: related to dental treatment: Taste perversion.
Cardiovascular: Chest pain (18% to 25%)
Central nervous system: Voice disorder (12% to 18%)
Dermatologic: Skin rash (3% to 12%) require special precautions
Respiratory: Cough (PARI-BABY nebulizer facemask: Adverse Reactions Frequency not always defined.
children 3 months to <5 years: 45%; children 5 to ≤10 Percentages as reported with combination product.
years: 30%), pharyngitis (32% to 40%), rhinitis (30%; Also see individual agents.
in patients with FVC: <40%), decrease in forced vital >5%:
capacity (≥10% decrease of predicted: 22%; in Gastrointestinal: Dysgeusia (≤30%)
patients with FVC: <40%), dyspnea (17%; in patients Ophthalmic: Burning sensation of eyes (≤30%), sting-
with FVC: <40%) ing of eyes (≤30%), blurred vision (5% to 15%),
Miscellaneous: Fever (32% in patients with conjunctival hyperemia (5% to 15%), eye pruritus
FVC <40%) (5% to 15%), superficial punctate keratitis (5%
1% to 10%: to 15%)
Gastrointestinal: Dyspepsia (≤3%) 1% to 5%:
Immunologic: Antibody development (to dornase alfa: Cardiovascular: Hypertension
2% to 4%) Central nervous system: Dizziness, headache
Ophthalmic: Conjunctivitis (1% to 5%) Dermatologic: Erythema of eyelid
Respiratory: Laryngitis (3% to 4%) Gastrointestinal: Abdominal pain, dyspepsia, nausea
<1%, postmarketing and/or case reports: Headache, Genitourinary: Urinary tract infection
urticaria
Infection: Influenza
Mechanism of Action The hallmark of cystic fibrosis Local: Local discoloration (lens nucleus)
lung disease is the presence of abundant, purulent
Neuromuscular & skeletal: Back pain
airway secretions composed primarily of highly poly-
Ophthalmic: Blepharitis, cataract (including post-sub-
merized DNA. The principal source of this DNA is the
nuclei of degenerating neutrophils, which is present in capsular), cloudy vision, conjunctival discharge, con-
large concentrations in infected lung secretions. The junctival edema, conjunctivitis, corneal erosion,
presence of this DNA produces a viscous mucous that corneal staining, dry eye syndrome, eye discharge
may contribute to the decreased mucociliary transport (including eyelid), eye disease (debris in eye), eye
and persistent infections that are commonly seen in this pain (includes eyelid), eyelid edema, follicular con-
population. Dornase alfa is a deoxyribonuclease (DNA) junctivitis, foreign body sensation of eye, lacrimation,
enzyme produced by recombinant gene technology. ocular exudate (eyelid), optic disk cupping (glaucom-
Dornase selectively cleaves DNA, thus reducing atous), scaling of eyelid, visual field defect, vitreous
mucous viscosity and as a result, airflow in the lung is detachment
improved and the risk of bacterial infection may be Respiratory: Bronchitis, cough, pharyngitis, sinusitis,
decreased. upper respiratory tract infection
Pharmacodynamics/Kinetics <1%, postmarketing, and/or case reports: Bradycardia,
Onset of Action Nebulization: Enzyme levels are cardiac failure, cerebrovascular accident, chest pain,
measured in sputum in ~15 minutes and decline choroidal detachment (following filtration procedures),
rapidly thereafter depression, diarrhea, dyspnea, heart block, hypoten-
Duration of Action Sputum concentrations decline sion, iridocyclitis, myocardial infarction, nasal conges-
within 2 hours of inhalation tion, paresthesia, photophobia, respiratory failure, skin
Pregnancy Considerations Adverse events have not rash, Stevens-Johnson syndrome, toxic epidermal
been observed in animal reproduction studies. necrolysis, urolithiasis, vomiting, xerostomia
Mechanism of Action
Dorzolamide and Timolol Dorzolamide: Inhibits carbonic anhydrase in the ciliary
(dor ZOLE a mide & TYE moe lole) processes of the eye resulting decreased bicarbonate
Brand Names: US Cosopt; Cosopt PF ion formation which decreases sodium and fluid trans-
port, thus decreasing aqueous humor secretion and
Brand Names: Canada Apo-Dorzo-Timop; Cosopt;
Cosopt Preservative Free; Sandoz-Dorzolamide/Timo- reduces intraocular pressure.
lol Timolol: Blocks both beta1- and beta2-adrenergic recep-
Pharmacologic Category Beta-Adrenergic Blocker, tors, reduces intraocular pressure by reducing aque-
Nonselective; Carbonic Anhydrase Inhibitor (Ophthal- ous humor production or possibly increases the
mic); Ophthalmic Agent, Antiglaucoma outflow of aqueous humor
Use Elevated intraocular pressure: Reduction of ele- Pregnancy Risk Factor C
vated intraocular pressure (IOP) in patients with open- Pregnancy Considerations Reproductive studies
angle glaucoma or ocular hypertension who are insuffi- have not been conducted with this combination. Refer
ciently responsive to beta-blockers to individual agents.
451
DOXAPRAM
Doxapram (DOKS a pram) Doxazosin (doks AY zoe sin)
Brand Names: US Dopram Related Information

Pharmacologic Category Respiratory Stimulant Cardiovascular Diseases on page 1442
Use Respiratory stimulant for respiratory depression Brand Names: US Cardura; Cardura XL
secondary to anesthesia, mild-to-moderate drug- Brand Names: Canada Apo-Doxazosin; Cardura-1;
induced respiratory and CNS depression; acute hyper- Cardura-2; Cardura-4; Dom-Doxazosin; Doxazosin-1;
Doxazosin-2; Doxazosin-4; Mylan-Doxazosin; PMS-
capnia secondary to COPD
Doxazosin; Teva-Doxazosin
Note: In general, the use of doxapram as a respiratory Pharmacologic Category Alpha1 Blocker; Antihyper-
stimulant in adults is limited; alternate therapies are tensive
preferred. Use
Local Anesthetic/Vasoconstrictor Precautions Benign prostatic hyperplasia: Treatment of signs and
No information available to require special precautions symptoms of benign prostatic hyperplasia (BPH).
Hypertension (immediate release only): Manage-
ment of hypertension. Note: Alpha blockers are not
complications reported recommended as first line therapy (ACC/AHA [Whel-
Effects on Bleeding No information available to ton 2017]).
Adverse Reactions Frequency not defined. No information available to require special precautions
Cardiovascular: Cardiac arrhythmia, change in pulse, Effects on Dental Treatment Key adverse event(s)
chest pain, chest tightness, flattened T wave on ECG, related to dental treatment: Xerostomia (normal salivary
flushing, increased blood pressure, phlebitis, ventric- flow resumes upon discontinuation); Patients may
ular fibrillation, ventricular tachycardia experience orthostatic hypotension as they stand up
Central nervous system: Apprehension, clonus, disori- after treatment; especially if lying in dental chair for
entation, dizziness, hallucination, headache, hyper- extended periods of time. Use caution with sudden
changes in position during and after dental treatment.
a c t i v i t y, h y p e r r e f l e x i a , i n v o l u n t a r y m u s c l e
movements, paresthesia, positive Babinski sign,
seizure Adverse Reactions
Dermatologic: Burning sensation of skin, diaphoresis, >10%: Central nervous system: Dizziness (5% to 19%),
pruritus malaise (≤12%), fatigue (8% to ≤12%), headache (6%
Endocrine & metabolic: Albuminuria to 10%)
Gastrointestinal: Bowel urgency, diarrhea, hiccups, 1% to 10%:
nausea, vomiting Cardiovascular: Edema (3% to 4%), hypotension (1%
Genitourinary: Urinary incontinence, urinary retention to 2%), orthostatic hypotension (<1% to 2%), cardiac
Hematologic & oncologic: Decreased hematocrit, arrhythmia (1%), facial edema (1%), flushing (1%),
decreased hemoglobin, hemolysis, decreased red palpitations (1%)
blood cells Central nervous system: Drowsiness (1% to 5%),
vertigo (2% to 4%), pain (2%), anxiety (1%), ataxia
Neuromuscular & skeletal: Fasciculations, laryngo-
(1%), hypertonia (1%), insomnia (1%), movement
spasm, muscle spasm
disorder (1%), myasthenia (1%)
Ophthalmic: Mydriasis Endocrine & metabolic: Sexual disorder (2%)
Renal: Increased blood urea nitrogen Gastrointestinal: Abdominal pain (2%), nausea (1% to
Respiratory: Bronchospasm, cough, dyspnea, hyper- 2%), dyspepsia (1%), xerostomia (1%)
ventilation, hypoventilation (rebound), tachypnea Genitourinary: Urinary incontinence (1%), urinary tract
Miscellaneous: Fever infection (1%)
<1%, postmarketing, and/or case reports: Agitation Neuromuscular & skeletal: Weakness (4% to 7%),
(emergence), prolonged Q-T interval on ECG (prema- muscle cramps (1%), myalgia (1%), arthralgia
ture neonates), second degree atrioventricular block (≤1%), arthritis (≤1%)
(premature neonates) Ophthalmic: Visual disturbance (2%)
Otic: Tinnitus (1%)
Mechanism of Action Stimulates respiration through
Renal: Polyuria (2%)
action on peripheral carotid chemoreceptors; respira- Respiratory: Respiratory tract infection (5%), rhinitis
tory center in medulla is also directly stimulated as (3%), dyspnea (1% to 3%), epistaxis (1%)
dosage is increased <1%, postmarketing, and/or case reports: Abnormal
Pharmacodynamics/Kinetics hepatic function tests, abnormal lacrimation, abnor-
Onset of Action Respiratory stimulation: Single IV mality in thinking, agitation, alopecia, altered sense
injection: 20 to 40 seconds; Peak effect: Single IV of smell, amnesia, angina pectoris, anorexia, back
injection: 1 to 2 minutes pain, blurred vision, bradycardia, bronchospasm
Duration of Action Single IV injection: 5 to 12 (aggravated), cerebrovascular accident, chest pain,
minutes cholestasis, cholestatic hepatitis, confusion, cough,
Half-life Elimination Serum: Neonates, premature: decreased libido, depersonalization, diaphoresis, diar-
rhea, dysgeusia, dysuria, eczema, emotional lability,
6.6 to 12 hours; Adults: Mean: 3.4 hours (range: 2.4 to
fecal incontinence, fever, flu-like symptoms, gastro-
4.1 hours) enteritis, gastrointestinal obstruction, gout, gyneco-
Pregnancy Risk Factor B mastia, hematuria, hepatitis, hot flash,
Pregnancy Considerations Adverse events have not hypersensitivity reaction, hypoesthesia, hypokalemia,
been observed in animal reproduction studies. impotence, increased appetite, increased thirst,
452
DOXEPIN (SYSTEMIC)
infection, intraoperative floppy iris syndrome (cataract vasoconstrictor in suspected patients, and that the
surgery), jaundice, lack of concentration, leukopenia, vasoconstrictor (epinephrine, mepivacaine, and levo-
lymphadenopathy, mastalgia, migraine, myocardial nordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be
infarction, nephrolithiasis, nervousness, neutropenia, used with caution.
nocturia, orthostatic dizziness, otalgia, pallor, para- Effects on Dental Treatment Key adverse event(s)
noia, paresis, paresthesia, peripheral ischemia, phar- related to dental treatment: Xerostomia and changes in
yngitis, photophobia, priapism, pruritus, purpura, salivation (normal salivary flow resumes upon discon-
rigors, sinusitis, skin rash, syncope, tachycardia, tinuation)
thrombocytopenia, tremor, twitching, urinary fre-
quency, urination disorder, urticaria, vomiting, weight Oral: Aphthous stomatitis, unpleasant taste, trouble
gain, weight loss, xeroderma with gums
Long-term treatment with TCAs increases the risk of
Mechanism of Action
caries by reducing salivation and salivary buffer
Hypertension: Competitively inhibits postsynaptic
capacity.
alpha1-adrenergic receptors which results in vasodila-
tion of veins and arterioles and a decrease in total
peripheral resistance and blood pressure; ~50% as
potent on a weight by weight basis as prazosin. Adverse Reactions Actual frequency may be depend-
ent on diagnosis.
BPH: Competitively inhibits postsynaptic alpha1-adre- Cardiovascular: Hypertension (chronic insomnia
nergic receptors in prostatic stromal and bladder neck patients ≤3%), edema, flushing, hypotension, tachy-
tissues. This reduces the sympathetic tone-induced cardia
urethral stricture causing BPH symptoms. Central nervous system: Sedation (chronic insomnia
Pharmacodynamics/Kinetics patients 6% to 9%), dizziness (chronic insomnia
Duration of Action >24 hours patients ≥1%), ataxia, chills, confusion, disorientation,
Half-life Elimination Immediate release: ~22 hours; drowsiness, extrapyramidal reaction, fatigue, halluci-
Extended release: 15 to 19 hours nation, headache, numbness, paresthesia, seizure,
Time to Peak Serum: Immediate release: 2 to 3 hours; tardive dyskinesia
Extended release: 8 ± 3.7 to 9 ± 4.7 hours Dermatologic: Alopecia, diaphoresis (excessive), pruri-
Pregnancy Considerations Adverse events were tus, skin photosensitivity, skin rash
observed in some animal reproduction studies. Doxa- Endocrine & metabolic: Altered serum glucose, change
zosin crosses the placenta (Versmissen 2016). in libido, galactorrhea, gynecomastia, SIADH,
Untreated chronic maternal hypertension is associated weight gain
with adverse events in the fetus, infant, and mother. If Gastrointestinal: Nausea (chronic insomnia patients
treatment for hypertension during pregnancy is needed, 2%), gastroenteritis (chronic insomnia patients ≤2%),
other agents are generally preferred (ACOG, 2013). anorexia, aphthous stomatitis, constipation, diarrhea,
dysgeusia, dyspepsia, vomiting, xerostomia
Genitourinary: Breast hypertrophy, testicular swelling,
Doxepin (Systemic) (DOKS e pin) urinary retention
Related Information Hematologic & oncologic: Agranulocytosis, eosino-
philia, leukopenia, purpura, thrombocytopenia
Hepatic: Jaundice
Neuromuscular & skeletal: Tremor, weakness
mia on page 1548
Management of the Patient With Anxiety or Depression Otic: Tinnitus
on page 1564 Respiratory: Upper respiratory tract infection (chronic
Vasoconstrictor Interactions With Antidepressants on insomnia patients 4%), exacerbation of asthma
page 1606 <1%, postmarketing, and/or case reports: Abdominal
Brand Names: US Silenor pain, abnormal dreams, abnormal gait, acne rosacea,
Brand Names: Canada Silenor; Sinequan; Zonalon adenocarcinoma (lung, stage I), adjustment disorder,
Pharmacologic Category Antidepressant, Tricyclic ageusia, altered blood pressure (inadequately con-
(Tertiary Amine) trolled), anemia, angle-closure glaucoma, anxiety,
Use arthralgia, atrioventricular block, back injury, back
Depression and/or anxiety: Treatment of psychoneur- pain, blepharospasm, bone fracture, breast cyst, bron-
otic patients with depression and/or anxiety; depres- chitis, cerebrovascular accident, change in appetite,
sion and/or anxiety associated with alcoholism; chest pain, confusion, cough, decreased heart rate,
depression and/or anxiety associated with organic decreased lacrimation, decreased neutrophils,
disease; psychotic depressive disorders with associ- decreased performance on neuropsychometrics,
ated anxiety, including involutional depression and decreased range of motion (joints), depression, der-
manic-depressive disorders. matitis, diplopia, disturbance in attention, dysmenor-
Insomnia (Silenor only): Treatment of insomnia char- rhea, dyspnea, dysuria, ECG abnormality (ST-T
acterized by difficulty with sleep maintenance. segment, QRS complex, QRS axis), erythema, eye
Local Anesthetic/Vasoconstrictor Precautions infection, eye pain, eye redness, falling, feeling of
Doxepin is one of the drugs confirmed to prolong the heaviness, folliculitis, fungal infection, gastroesopha-
QT interval and is accepted as having a risk of causing geal reflux disease, gum line erosion, hematochezia,
torsade de pointes. In terms of epinephrine, it is not hematoma, hemoglobinuria, herpes zoster, hot flash,
known what effect vasoconstrictors in the local anes- hyperbilirubinemia, hyperhidrosis, hyperkalemia,
thetic regimen will have in patients with a known history hypermagnesemia, hypersensitivity, hypoacusis,
of congenital prolonged QT interval or in patients taking hypokalemia, increased serum ALT, increased serum
any medication that prolongs the QT interval. Until more transaminases, influenza, joint sprain, laceration, lar-
information is obtained, it is suggested that the clinician yngitis, lethargy, limb pain, lip blister, lower respiratory
consult with the physician prior to the use of a tract infection, malignant melanoma, migraine, mood
453
DOXEPIN (SYSTEMIC)
elevation, motion sickness, muscle cramps, myalgia, Use Pruritus: Short-term (≤8 days) management of
nasal congestion, nasopharyngeal disorder, neck moderate pruritus in adults with atopic dermatitis or
pain, nightmares, nocturia, onychomycosis, otalgia, lichen simplex chronicus.
pallor, palpitations, perforated tympanic membrane, Local Anesthetic/Vasoconstrictor Precautions
peripheral edema, pharyngitis, pharyngolaryngeal No information available to require special precautions
pain, pneumonia, rales, rhinorrhea, sinus congestion, Effects on Dental Treatment Key adverse event(s)
sinusitis, skin irritation, sleep paralysis, somnambu- related to dental treatment: Xerostomia and changes in
lism (complex sleep-related behavior [sleep-driving, salivation (normal salivary flow resumes upon discon-
cooking or eating food, making phone calls]), staph- tinuation)
ylococcal cellulitis, syncope, tenosynovitis, tooth infec-
Topical: Taste alteration
tion, urinary incontinence, urinary tract infection, Long-term treatment with TCAs increases the risk of
vasodepressor syncope, ventricular premature con- caries by reducing salivation and salivary buffer
tractions, viral infection, wheezing capacity.
Mechanism of Action Effects on Bleeding No information available to
Increases the synaptic concentration of serotonin and require special precautions
norepinephrine in the central nervous system by inhib- Adverse Reactions
ition of their reuptake by the presynaptic neuronal >10%:
membrane (Pinder, 1977); antagonizes the histamine Central nervous system: Drowsiness (22%)
(H1) receptor for sleep maintenance. Dermatologic: Burning sensation of skin (≤23%), sting-
Efficacy of doxepin in the off-label use of chronic ing of the skin (≤23%)
urticaria is believed to be related to its potent H1 and 1% to 10%:
H2 receptor antagonist activity (Kozel 2004). Cardiovascular: Edema (1%)
Pharmacodynamics/Kinetics Central nervous system: Dizziness (2%), emotional
Onset of Action Individual responses may vary; 4-8 lability (2%)
weeks of treatment are needed before determining if a Gastrointestinal: Xerostomia (10%), dysgeusia (2%)
patient with depression is partially or nonresponsive <1%, postmarketing, and/or case reports: Anxiety, con-
(APA 2010); onset of anxiolytic effects may have a tact dermatitis, numbness of tongue
latency of 2-6 weeks (Bandelow 2008) Mechanism of Action Doxepin has H1 and H2 hista-
Half-life Elimination Adults: Doxepin: ~15 hours; N- mine receptor blocking actions, the exact mechanism
desmethyldoxepin: 31 to 51 hours (Hiemke 2018) by which it exerts its antipruritic effect is unknown.
Time to Peak Serum: Fasting: Silenor: 3.5 hours Pharmacodynamics/Kinetics
Pregnancy Risk Factor C Half-life Elimination 28 to 52 hours (desmethyldox-
Pregnancy Considerations Adverse events were epin)
observed in animal reproduction studies. Tricyclic anti- Pregnancy Considerations Adverse effects were not
depressants may be associated with irritability, jitteri- observed in animal reproduction studies. Following top-
ness, and convulsions (rare) in the neonate (Yonkers ical application, plasma levels may be similar to those
2009). achieved with oral administration. Also refer to the
doxepin (systemic) monograph.
The ACOG recommends that therapy for depression
during pregnancy be individualized; treatment should
incorporate the clinical expertise of the mental health
Doxercalciferol (doks er kal si fe FEER ole)
clinician, obstetrician, primary health care provider, and Brand Names: US Hectorol
pediatrician (ACOG 2008). According to the American Brand Names: Canada Hectorol
Psychiatric Association (APA), the risks of medication Pharmacologic Category Vitamin D Analog
treatment should be weighed against other treatment Use
options and untreated depression. For women who Secondary hyperparathyroidism (patients on dialy-
discontinue antidepressant medications during preg- sis): Injection, oral: Treatment of secondary hyper-
nancy and who may be at high risk for postpartum parathyroidism in patients with chronic kidney
depression, the medications can be restarted following disease (CKD) on dialysis
delivery (APA 2010). Treatment algorithms have been Secondary hyperparathyroidism (patients not on
developed by the ACOG and the APA for the manage- dialysis): Oral: Treatment of secondary hyperpara-
ment of depression in women prior to conception and thyroidism in patients with stage 3 or 4 CKD
during pregnancy (Yonkers 2009). Local Anesthetic/Vasoconstrictor Precautions
Pregnant women exposed to antidepressants during No information available to require special precautions
pregnancy are encouraged to enroll in the National Effects on Dental Treatment No significant effects or
Pregnancy Registry for Antidepressants (NPRAD). complications reported
Women 18 to 45 years of age or their health care Effects on Bleeding No information available to
providers may contact the registry by calling require special precautions
844-405-6185. Enrollment should be done as early in Adverse Reactions
pregnancy as possible. >10%:
Dental Health Professional Considerations See Cardiovascular: Edema (7% to 34%)
Central nervous system: Headache (28%), malaise
(28%), insomnia (15%), paresthesia (15%), dizzi-
ness (12%), hypertonia (11%)
Doxepin (Topical) (DOKS e pin) Gastrointestinal: Constipation (26%), nausea and
vomiting (21%)
Brand Names: US Prudoxin; Zonalon Hematologic & oncologic: Anemia (19%)
Brand Names: Canada Zonalon Infection: Infection (30%)
Pharmacologic Category Topical Skin Product Neuromuscular & skeletal: Asthenia (15%)
454
DOXORUBICIN (CONVENTIONAL)
Respiratory: Rhinitis (22%), cough (19%), dyspnea Effects on Bleeding Severe myelosuppression with
(12% to 19%) thrombocytopenia and anemia occur. Medical consult
1% to 10%: suggested.
Cardiovascular: Angina pectoris (8%), bradycardia Adverse Reactions Frequency not always defined.
(7%), chest pain (7%) Cardiovascular:
Central nervous system: Depression (7%), sleep dis- Acute cardiotoxicity: Atrioventricular block, bradycar-
order (3%) dia, bundle branch block, ECG abnormality, extra-
Dermatologic: Pruritus (7% to 8%) systoles (atrial or ventricular), nonspecific ST or T
Endocrine & metabolic: Dehydration (7%), weight
wave changes on ECG, sinus tachycardia, supra-
gain (5%)
ventricular tachycardia, tachyarrhythmia, ventricular
Gastrointestinal: Dyspepsia (5% to 7%), ano-
tachycardia
rexia (5%)
Delayed cardiotoxicity: Cardiac failure (manifestations
include ascites, cardiomegaly, dyspnea, edema, gal-
Hematologic & oncologic: Leukopenia (7%)
Infection: Abscess (3%) lop rhythm, hepatomegaly, oliguria, pleural effusion,
Neuromuscular & skeletal: Arthralgia (5%) pulmonary edema, tachycardia), decreased left ven-
Respiratory: Sinusitis (7%) tricular ejection fraction, myocarditis, pericarditis
Frequency not defined: Central nervous system: Malaise
Endocrine & metabolic: Hypercalcemia, hyperphos- Dermatologic: Alopecia, discoloration of sweat, pruritus,
phatemia skin photosensitivity, skin rash; urticaria
<1%, postmarketing, and/or case reports: Anaphylaxis, Endocrine & metabolic: Amenorrhea, dehydration,
angioedema, burning sensation of skin, chest discom- hyperuricemia
fort, hypersensitivity reaction, hypotension, unrespon- Gastrointestinal: Abdominal pain, anorexia, diarrhea,
sive to stimuli discoloration of saliva, gastrointestinal ulcer, mucosi-
Mechanism of Action Doxercalciferol is metabolized tis, nausea, vomiting
to the active form of vitamin D. The active form of Genitourinary: Urine discoloration, infertility (may be
vitamin D controls the intestinal absorption of dietary temporary)
calcium, the tubular reabsorption of calcium by the Hematologic & oncologic: Leukopenia (≤75%; nadir: 10
kidneys, and in conjunction with PTH, the mobilization to 14 days; recovery: by day 21), neutropenia (≤75%;
of calcium from the skeleton. nadir: 10 to 14 days; recovery: by day 21), anemia,
Pharmacodynamics/Kinetics thrombocytopenia
Half-life Elimination Major metabolite: ~32 to 37 Local: Post-injection flare
hours (range: up to 96 hours) Neuromuscular & skeletal: Weakness
Time to Peak Major metabolite: 8 hours (injection); 11 Ophthalmic: Discoloration of tears
to 12 hours (oral). Miscellaneous: Necrosis (colon), radiation recall phe-
Pregnancy Considerations Adverse events have not nomenon
been observed in animal reproduction studies <1%, postmarketing, and/or case reports: Acute mye-
locytic leukemia (secondary), anaphylaxis, azoosper-
DOXOrubicin (Conventional) mia, chills, coma (when in combination with cisplatin
(doks oh ROO bi sin con VEN sha nal) or vincristine), conjunctivitis, dysgeusia (Rehwaldt
2009), febrile neutropenia, fever, gonadal disease
Related Information
(gonadal impairment; children), growth suppression
DOXOrubicin (Liposomal) on page 456
(prepubertal), hepatitis, hyperpigmentation (nail, oral
Brand Names: US Adriamycin mucosa, skin), hypersensitivity reaction (systemic;
Brand Names: Canada Adriamycin PFS; Doxorubicin including angioedema, dysphagia, and dyspnea, pru-
Hydrochloride For Injection, USP; Doxorubicin Hydro-
ritus, urticaria), increased serum bilirubin, increased
chloride Injection
serum transaminases, infection, keratitis, lacrimation,
Pharmacologic Category Antineoplastic Agent, myelodysplastic syndrome, oligospermia, onycholysis,
Anthracycline; Antineoplastic Agent, Topoisomerase II
peripheral neurotoxicity (with intra-arterial doxorubi-
Inhibitor
cin), phlebosclerosis, pneumonitis (radiation recall;
Use
children), seizure (when in combination with cisplatin
Breast cancer: Treatment component of adjuvant ther-
or vincristine), sepsis, shock, Stevens-Johnson syn-
apy (multi-agent) in women with evidence of axillary
drome, toxic epidermal necrolysis, typhlitis (neutro-
lymph node involvement following resection of primary
breast cancer penic)
Metastatic cancers or disseminated neoplastic con- Mechanism of Action Doxorubicin inhibits DNA and
ditions: Treatment of acute lymphoblastic leukemia, RNA synthesis by intercalation between DNA base
acute myeloid leukemia, Wilms tumor, neuroblastoma, pairs by inhibition of topoisomerase II and by steric
soft tissue and bone sarcomas, breast cancer, ovarian obstruction. Doxorubicin intercalates at points of local
cancer, transitional cell bladder carcinoma, thyroid uncoiling of the double helix. Although the exact mech-
carcinoma, gastric carcinoma, Hodgkin lymphoma, anism is unclear, it appears that direct binding to DNA
non-Hodgkin lymphoma, and bronchogenic carcinoma (intercalation) and inhibition of DNA repair (topoisomer-
in which the small cell histologic type is the most ase II inhibition) result in blockade of DNA and RNA
responsive compared with other cell types synthesis and fragmentation of DNA. Doxorubicin is
Local Anesthetic/Vasoconstrictor Precautions also a powerful iron chelator; the iron-doxorubicin com-
No information available to require special precautions plex can bind DNA and cell membranes and produce
Effects on Dental Treatment Key adverse event(s) free radicals that immediately cleave the DNA and cell
related to dental treatment: Stomatitis and mucositis. membranes.
455
DOXORUBICIN (CONVENTIONAL)
Pharmacodynamics/Kinetics Effects on Bleeding Severe myelosuppression with

Half-life Elimination thrombocytopenia and anemia occur. Medical consult
Distribution: ~5 minutes suggested.
Terminal: 20 to 48 hours Adverse Reactions Frequency not always defined.
Male: 54 hours; Female: 35 hours >10%:
Pregnancy Risk Factor D Cardiovascular: Cardiomyopathy (dose related: 11%;
Pregnancy Considerations Adverse events have Kaposi sarcoma: <1%), cardiotoxicity (11%), chest
been observed in animal reproduction studies. Based tightness (11%), flushing (11%), hypotension (1%
on the mechanism of action, doxorubicin may cause to 11%)
fetal harm if administered during pregnancy (according Central nervous system: Fatigue (>20%), head-
to the manufacturer’s labeling). Advise patients ache (≤11%)
(females of reproductive potential and males with Dermatologic: Palmar-plantar erythrodysesthesia
female partners of reproductive potential) to use effec- (ovarian cancer: ≤51%), skin rash (29%, Kaposi
tive nonhormonal contraception during and for 6 sarcoma: 1% to 5%), alopecia (9% to 19%), facial
months following therapy. Limited information is avail- swelling (11%)
able from a retrospective study of women who received Gastrointestinal: Nausea (ovarian cancer: 46%;
doxorubicin (in combination with cyclophosphamide) Kaposi sarcoma: 17% to 18%), stomatitis (41%,
during the second or third (prior to week 35) trimester Kaposi sarcoma: 5% to 8%), vomiting (33%; Kaposi
for the treatment of pregnancy-associated breast can- sarcoma: 8%), constipation (>20%), diarrhea (21%;
cer (Ring 2005). Some pharmacokinetic properties of Kaposi sarcoma: 3% to 8%), anorexia (20%; Kaposi
doxorubicin may be altered in pregnant women (van sarcoma: 1% to 5%), mucous membrane disease
Hasselt 2014). The European Society for Medical (14%), dyspepsia 12%
Oncology (ESMO) has published guidelines for diag- Hematologic & oncologic: Thrombocytopenia (dose
nosis, treatment, and follow-up of cancer during preg- related, Kaposi sarcoma: 1% to 61%), neutropenia
nancy (Peccatori 2013); the guidelines recommend (dose related: 4% to 49%), leukopenia (37%), ane-
referral to a facility with expertise in cancer during mia (16% to 58%; dose related <1% to 5%)
Neuromuscular & skeletal: Weakness (40%; Kaposi
pregnancy and encourage a multidisciplinary team
sarcoma: 7% to 10%), back pain (12%; Kaposi
(obstetrician, neonatologist, oncology team). If chemo-
sarcoma: 1% to 5%)
therapy is indicated, it should not be administered in the
Respiratory: Pharyngitis (16%; Kaposi sarcoma <1%),
first trimester, but may begin in the second trimester.
dyspnea (1% to 15%)
There should be a 3-week time period between the last
Miscellaneous: Fever (21%; Kaposi sarcoma: 8% to
chemotherapy dose and anticipated delivery, and che-
9%), infusion related reaction (7% to 11%)
motherapy should not be administered beyond week 33
1% to 10%:
of gestation.
Cardiovascular: Cardiac arrest (≤10%), chest pain
A pregnancy registry is available for all cancers diag- (Kaposi sarcoma: 1% to 5%), deep thrombophlebitis
nosed during pregnancy at Cooper Health (ovarian cancer: 1% to 10%), tachycardia (1% to
(877-635-4499). 10%), vasodilation (ovarian cancer: 1% to 10%)
Central nervous system: Depression (ovarian cancer:
1% to 10%), dizziness (1% to 10%), drowsiness (1%
DOXOrubicin (Liposomal) to 10%), chills (Kaposi sarcoma: 1% to 5%)
(doks oh ROO bi sin lye po SO mal)
Dermatologic: Acne vulgaris (ovarian cancer: 1% to
Related Information 10%), ecchymoses (ovarian cancer: 1% to 10%),
DOXOrubicin (Conventional) on page 455 exfoliative dermatitis (ovarian cancer: 1% to 10%),
Brand Names: US Doxil; Lipodox 50 [DSC]; Lipodox fungal dermatitis (ovarian cancer: 1% to 10%), furun-
[DSC] culosis (ovarian cancer: 1% to 10%), herpes simplex
Brand Names: Canada Caelyx dermatitis (1% to 10%), pruritus (1% to 10%), skin
discoloration (ovarian cancer: 1% to 10%), vesiculo-
Pharmacologic Category Antineoplastic Agent,
bullous dermatitis (ovarian cancer: 1% to 10%),
Anthracycline; Antineoplastic Agent, Topoisomerase II
xeroderma (ovarian cancer: 1% to 10%), maculopap-
Inhibitor
ular rash (≤10%)
Use Endocrine & metabolic: Hypercalcemia (ovarian can-
AIDS-related Kaposi sarcoma: Treatment of AIDS- cer: 1% to 10%), hypokalemia (ovarian cancer: 1% to
related Kaposi sarcoma (after failure of or intolerance 10%), hyponatremia (ovarian cancer: 1% to 10%),
to prior systemic therapy) weight loss (1% to 10%), dehydration (≤10%), hyper-
Multiple myeloma: Treatment of multiple myeloma (in glycemia (1% to 5%)
combination with bortezomib) in patients who are Gastrointestinal: Dysphagia (1% to 10%), esophagitis
bortezomib-naïve and have received at least 1 prior (ovarian cancer: 1% to 10%), intestinal obstruction
therapy (ovarian cancer: 1% to 10%), oral candidiasis (1% to
Ovarian cancer, advanced: Treatment of progressive 10%), oral mucosa ulcer (1% to 10%), dysgeusia
or recurrent ovarian cancer (after platinum-based (1% to ≤10%), abdomen enlarged (ovarian cancer
treatment) 1% to 5%), glossitis (1% to 5%), cachexia
Local Anesthetic/Vasoconstrictor Precautions Genitourinary: Hematuria (ovarian cancer: 1% to
No information available to require special precautions 10%), hemorrhagic cystitis, urinary tract infection
Effects on Dental Treatment Key adverse event(s) (ovarian cancer: 1% to 10%), vulvovaginal candidia-
related to dental treatment: Xerostomia (normal salivary sis (ovarian cancer 1% to 10%)
flow resumes upon discontinuation), mucositis, gingivi- Hematologic & oncologic: Rectal hemorrhage (ovarian
tis, glossitis, mouth ulceration, taste perversion, and cancer: 1% to 10%), hemolysis (1% to 5%), pro-
stomatitis. longed prothrombin time (1% to 5%), bone marrow
456
DOXYCYCLINE
depression (Kaposi sarcoma), progression of cancer

(Kaposi sarcoma) Doxycycline (doks i SYE kleen)
Hepatic: Hyperbilirubinemia (1% to 10%), increased
Related Information
serum alkaline phosphatase (Kaposi sarcoma 1% to
Periodontal Diseases on page 1534
8%), increased serum ALT (Kaposi sarcoma 1%
Sexually-Transmitted Diseases on page 1494
to 5%) Related Sample Prescriptions
Hypersensitivity: Hypersensitivity reaction (Kaposi Bacterial Infections and Periodontal Diseases - Sample
sarcoma 1% to 5%) Prescriptions on page 36
Infection: Infection (1% to 12%), herpes zoster Brand Names: US Acticlate; Adoxa Pak 1/100 [DSC];
(≤10%), paresthesia (5%), myalgia (ovarian cancer: Adoxa Pak 1/150 [DSC]; Adoxa Pak 2/100 [DSC];
1% to 5%), neuropathy (ovarian cancer 1% to 5%), Adoxa [DSC]; Alodox Convenience [DSC]; Avidoxy;
toxoplasmosis (Kaposi sarcoma) Doryx; Doryx MPC; Doxy 100; Mondoxyne NL; Mono-
Ophthalmic: Dry eye syndrome (ovarian cancer: 1% to dox [DSC]; Morgidox; Ocudox [DSC]; Okebo; Oracea;
10%), conjunctivitis (≤10%), retinitis (Kaposi sar- Soloxide; TargaDOX; Vibramycin
coma 1% to 5%) optic neuritis (Kaposi sarcoma) Brand Names: Canada Apo-Doxy; Apo-Doxy Tabs;
Apprilon; Dom-Doxycycline; Doxycin; Doxytab; Perio-
Respiratory: Epistaxis (ovarian cancer: 1% to 10%),
stat; PHL-Doxycycline; PMS-Doxycycline; Teva-Doxy-
pneumonia (1% to 10%), rhinitis (ovarian cancer: 1%
cycline; Vibramycin
to 10%), sinusitis (ovarian cancer: 1% to 10%), Generic Availability (US) May be product dependent
increased cough (≤10%), cough (Kaposi sarcoma) Pharmacologic Category Antibiotic, Tetracycline
<1%, postmarketing, and/or case reports (Limited to Derivative
important or life-threatening): Abnormal vision, Dental Use Treatment of periodontitis associated with
abscess, acute brain syndrome, albuminuria, alkaline presence of Actinobacillus actinomycetemcomitans
phosphatase increased anaphylactic reaction, anxiety, (AA); adjunct to scaling and root planing to promote
arthralgia, asthma, balanitis, blindness, bone pain, attachment level gain and to reduce pocket depth in
bronchitis, bundle branch block, BUN increased, can- adult periodontitis (systemic levels are subinhibitory
didiasis, cardiac failure (Kaposi sarcoma), cardiome- against bacteria)
galy, cardiomyopathy, cellulitis, colitis, confusion, Use
creatinine increased, cryptococcosis, cryptococcosis, Acne: Adjunctive therapy in severe acne.
Actinomycosis: Treatment of actinomycosis caused
dysuria, edema, emotional lability, erythema multi-
by Actinomyces israelii when penicillin is contraindi-
forme, erythema nodosum, eosinophilia, fecal impac- cated.
tion, flatulence, flu-like syndrome, gastritis, Acute intestinal amebiasis: Adjunct to amebicides in
hemorrhage, hepatitis, hepatosplenomegaly, hyperka- acute intestinal amebiasis.
lemia, muscle spasm, optic neuritis, pain, pallor, pal- Anthrax, including inhalational anthrax (postexpo-
pitations, petechia, pneumothorax, peripheral edema, sure): Treatment of anthrax caused by Bacillus
pleural effusion, pulmonary embolism, secondary anthracis, including inhalational (postexposure) pro-
acute myelocytic leukemia, sepsis, squamous cell phylaxis; to reduce the incidence or progression of
carcinoma, Stevens-Johnson syndrome, thrombo- disease following exposure to aerosolized B.
anthracis.
phlebitis, thromboplastin decreased, thrombosis, toxic
Cholera: Treatment of cholera infections caused by
epidermal necrolysis, vertigo, ventricular arrhythmia
Vibrio cholerae.
Mechanism of Action Doxorubicin inhibits DNA and Clostridium: Treatment of infections caused by Clos-
RNA synthesis by intercalating between DNA base tridium spp. when penicillin is contraindicated.
pairs causing steric obstruction and inhibits topoisomer- Gram-negative infections: Treatment of infections
ase-II at the point of DNA cleavage. Doxorubicin is also caused by Escherichia coli, Enterobacter aerogenes,
a powerful iron chelator. The iron-doxorubicin complex Shigella spp., Acinetobacter spp., Klebsiella spp. (res-
can bind DNA and cell membranes, producing free piratory and urinary infections), and Bacteroides spp.;
hydroxyl (OH) radicals that cleave DNA and cell mem- Neisseria meningitidis (when penicillin is contraindi-
branes. Active throughout entire cell cycle. Doxorubicin cated).
Gram-positive infections: Treatment of infections
liposomal is a pegylated formulation which protects the
caused by Streptococcus spp., when susceptible.
liposomes, and thereby increases blood circulation Listeriosis: Treatment of listeriosis due to Listeria
time. monocytogenes when penicillin is contraindicated.
Pharmacodynamics/Kinetics Malaria prophylaxis: Prophylaxis of malaria due to
Half-life Elimination Terminal: Distribution: ~4.7 to Plasmodium falciparum in short-term travelers (under
5.2 hours, Elimination: ~52 to 55 hours 4 months) to areas with chloroquine and/or pyrimeth-
Pregnancy Considerations Adverse events were amine-sulfadoxine-resistant strains.
observed in animal reproduction studies. May cause Mycoplasma pneumoniae: Treatment of infections
fetal harm if administered during pregnancy. Women caused by Mycoplasma pneumoniae.
and men of reproductive potential should use effective Ophthalmic infections: Treatment of inclusion con-
junctivitis or trachoma caused by Chlamydia tracho-
contraception during therapy and for 6 months after
matis.
treatment. Doxorubicin liposomal may damage sperma- Periodontitis (20 mg tablet and capsule [Periostat
tozoa and testicular tissue in males and may result in (Canadian product)] only): Adjunct to scaling and
oligospermia, azoospermia, and permanent loss of fer- root planing to promote attachment level gain and to
tility. May cause amenorrhea, infertility, and premature reduce pocket depth in patients with adult periodon-
menopause in females. titis.
457
DOXYCYCLINE
Relapsing fever: Treatment of relapsing fever caused Endocrine & metabolic: Increased lactate dehydrogen-
by Borrelia recurrentis. ase (2%), increased serum glucose (1%)
Respiratory tract infections: Treatment of respiratory Gastrointestinal: Diarrhea (5%), upper abdominal pain
infections caused by Haemophilus influenzae, Kleb- (2%), abdominal distention (1%), abdominal pain
siella spp., or Mycoplasma pneumoniae; treatment of (1%), xerostomia (1%)
upper respiratory tract infections caused by Strepto- Hepatic: Increased serum aspartate aminotransfer-
coccus pneumoniae; respiratory infections caused by ase (2%)
Staphylococcus aureus (doxycycline is not the drug of Infection: Fungal infection (2%), influenza (2%)
choice in the treatment of any type of staphylococcal Neuromuscular & skeletal: Back pain (1%)
infection). Respiratory: Nasopharyngitis (5%), sinusitis (3%),
Rickettsial infections: Treatment of Rocky Mountain nasal congestion (2%), sinus headache (1%)
spotted fever, typhus fever and the typhus group, Q Frequency not defined:
fever, rickettsialpox, and tick fevers caused by Rick- Dermatologic: Skin hyperpigmentation
ettsiae. Gastrointestinal: Esophageal ulcer, esophagitis
Rosacea (Oracea, Apprilon [Canadian product] <1%, postmarketing, and/or case reports: Anaphylac-
only): Treatment of only inflammatory lesions (pap- toid reaction, anaphylaxis, angioedema, anorexia,
ules and pustules) of rosacea in adults. bulging fontanel, Clostridioides difficile associated
Sexually transmitted infections: Treatment of lym- diarrhea, Clostridioides difficile colitis, dental discolor-
phogranuloma venereum and uncomplicated urethral, ation, DRESS syndrome, dysphagia, enamel hypopla-
endocervical, or rectal infections caused by Chlamydia sia, enterocolitis, eosinophilia, erythema multiforme,
trachomatis; granuloma inguinale (donovanosis) erythematous rash, exacerbation of systemic lupus
caused by Klebsiella granulomatis; chancroid caused erythematosus, exfoliative dermatitis, glossitis, head-
by Haemophilus ducreyi; nongonococcal urethritis ache, hemolytic anemia, hepatotoxicity, hypersensitiv-
caused by Ureaplasma urealyticum; when penicillin ity reaction, increased blood urea nitrogen, increased
is contraindicated, uncomplicated gonorrhea caused serum alanine aminotransferase, inflammatory ano-
by Neisseria gonorrhea and syphilis caused by Trepo- genital lesion, intracranial hypertension, Jarisch-Herx-
nema pallidum. heimer reaction, maculopapular rash, nausea,
Note: The CDC sexually transmitted disease guide- neutropenia, pancreatitis, pericarditis, serum sick-
lines recommend dual antimicrobial therapy be used ness, skin hyperpigmentation, skin photosensitivity,
for uncomplicated gonorrhea due to N. gonorrhea Stevens-Johnson syndrome, thrombocytopenia, thy-
resistance concerns; ceftriaxone is the preferred roid disease (brown/black discoloration; no dysfunc-
cephalosporin and doxycycline is an alternative tion reported), toxic epidermal necrolysis, urticaria,
option for the second antimicrobial only in cases of vomiting
azithromycin allergy (CDC [Workowski 2015]). Dental Usual Dosage Adults: Oral: Treatment of perio-
Skin and skin structure infections (Avidoxy only): dontitis (refractory): 100-200 mg once daily for 21 days
Treatment of skin and skin structure infections caused (Jolkovsky 2006). Note: A specific formulation (Perio-
by Staphylococcus aureus (doxycycline is not the drug stat [available in Canada]) containing a subantimicrobial
of choice in the treatment of any type of staphylococ- dosage is also available for use as an adjunct to scaling
cal infection). and root planing. In addition, doxycycline gel (Atridox) is
Vincent infection: Treatment of Vincent infection available for subgingival application (see Doxycycline
caused by Fusobacterium fusiforme when penicillin Hyclate Periodontal Extended-Release Liquid mono-
is contraindicated. graph).
Yaws: Treatment of yaws caused by Treponema pal- Dosing
lidum subspecies pertenue when penicillin is contra- Adult & Geriatric Note: Doxycycline is available as
indicated. hyclate, monohydrate, and calcium salts. All doses are
Zoonotic infections: Treatment of psittacosis (ornitho- expressed as doxycycline base.
sis) caused by Chlamydophila psittaci; plague due to Usual dosage range:
Yersinia pestis; tularemia caused by Francisella tular- Oral: Immediate-release and most extended-release
ensis; brucellosis caused by Brucella spp. (in conjunc- formulations: 100 to 200 mg/day in 1 to 2 divided
tion with streptomycin); bartonellosis caused by doses. Note: 120 mg of modified polymer coated
Bartonella bacilliformis; infections caused by Campy- tablet (Doryx MPC) is equivalent to 100 mg con-
lobacter fetus. ventional delayed-release tablet.
Local Anesthetic/Vasoconstrictor Precautions IV: 100 mg every 12 hours. Note: IV form may cause
No information available to require special precautions phlebitis.
Effects on Dental Treatment Key adverse event(s) Acne vulgaris (moderate to severe, inflammatory)
related to dental treatment: Glossitis and tooth discol- (off-label dose): Oral: Note: Use as an adjunct to
oration (children). Opportunistic "superinfection" with topical acne therapy (AAD [Zaenglein 2016]).
Candida albicans; tetracyclines are not recommended Immediate release: 50 to 100 mg twice daily or
for use during pregnancy or in children ≤8 years of age 100 mg once daily (AAD [Zaenglein 2016];
since they have been reported to cause enamel hypo- Graber 2017)
plasia and permanent teeth discoloration. The use of Extended release: 100 mg twice daily on day 1, then
tetracyclines should only be used in these patients if 100 mg once daily (AAD [Zaenglein 2016];
other agents are contraindicated or alternative antimi- Graber 2017)
crobials will not eradicate the organism. Subantimicrobial dosing: 20 mg twice daily (immedi-
Effects on Bleeding Hemolytic anemia and thrombo- ate release) or 40 mg once daily (delayed release)
cytopenia have been reported (Moore 2015; Skidmore 2003)
Adverse Reactions Duration: Use the shortest possible duration to min-
1% to 10%: imize risk of adverse effects and development of
Cardiovascular: Hypertension (3%) bacterial resistance; re-evaluate at 3 to 4 months
Central nervous system: Anxiety (2%), pain (2%) (AAD [Zaenglein 2016]).
458
DOXYCYCLINE
Anaplasmosis and ehrlichiosis (off-label use): (Ariza 2007; Hasanjani Roushan 2006; Skal-
Oral, IV: 100 mg twice daily for 10 days (IDSA sky 2008)
[Wormser 2006]) or at least 3 days after resolution Spondylitis: Oral: 100 mg twice daily for at least 12
of fever (CDC [Biggs 2016]) weeks plus streptomycin for the first 14 to 21 days
Anthrax: Note: Consult public health officials for (Skalsky 2008)
event-specific recommendations. Postexposure prophylaxis (high-risk laboratory expo-
Inhalational exposure (postexposure prophylaxis): sure): Oral: 100 mg twice daily with rifampin for 3
Oral: 100 mg every 12 hours for 60 days (CDC weeks (CDC 2012); for exposure to B. abortus
[Hendricks 2014]) RB51 strains, some experts give doxycycline plus
Cutaneous (without systemic involvement), treat- trimethoprim-sulfamethoxazole (Bosilkovski 2017)
ment: Oral: 100 mg every 12 hours for 7 to 10 days Cellulitis, mild to moderate (outpatient treatment;
after naturally acquired infection; treat for 60 days empiric coverage of MRSA) (off-label use): Oral:
for bioterrorism-related cases (CDC [Hendricks 100 mg twice daily for 5 to 14 days (IDSA [Liu 2011;
2014]). Note: Patients with cutaneous lesions of Stevens 2014]). Note: For empiric therapy of non-
the head or neck or extensive edema should be purulent cellulitis, an additional agent (eg, amoxicil-
treated for systemic involvement. lin, cephalexin) for coverage of beta-hemolytic
Systemic (meningitis excluded; alternative agent), streptococci is needed.
treatment: IV: Initial: 200 mg as a single dose, then Cholera (Vibrio cholerae), treatment (adjunctive
100 mg every 12 hours, in combination with a therapy for severely ill patients): Oral: 300 mg as
bactericidal agent; treat for 2 weeks or until clin- a single dose. Note: Due to resistance concerns,
ically stable, whichever is longer. Note: Following a antimicrobial therapy during an outbreak or epidemic
course of IV combination therapy, patients exposed should be guided by isolate susceptibility (CDC
to aerosolized spores require oral doxycycline 2015; WHO 2010).
monotherapy to complete an antimicrobial course Lyme disease (Borrelia spp. infection) (off-label
of 60 days (CDC [Hendricks 2014]). use): Oral:
Bartonella spp. infection: Prophylaxis: 200 mg as a single dose. Note: Pro-
HIV-infected (off-label use): Note: Duration of ther- phylaxis is used only in patients who meet all of the
apy is at least 3 months; continuation of therapy following criteria: Deer tick attached for ≥36 hours,
depends on relapse occurrence and clinical con- prophylaxis can be given within 72 hours of tick
dition (HHS [OI adult 2017]). removal, local rate of deer tick infection with Borre-
Bacillary angiomatosis, peliosis hepatis, bactere- lia burgdorferi is ≥20%, and there are no contra-
mia, and osteomyelitis: Oral, IV: 100 mg every indications to doxycycline (Hu 2017; IDSA
12 hours [Wormser 2006]).
CNS infections: Oral, IV: 100 mg every 12 hours; Treatment, early localized (eg, erythema migrans):
may add rifampin therapy 100 mg twice daily for 10 to 21 days (IDSA
Endocarditis, confirmed: Oral, IV: 100 mg IV every [Wormser 2006])
12 hours in combination with gentamicin for 2 Treatment, arthritis without neurologic involvement
weeks, then continue with doxycycline 100 mg (early or late disease): 100 mg twice daily for 28
IV or orally every 12 hours days (Hu 2017; IDSA [Wormser 2006])
Other severe infections: Oral, IV: 100 mg every 12 Treatment, early disseminated, mild neurologic
hours in combination with rifampin involvement (isolated facial nerve palsy): 100 mg
HIV-uninfected: twice daily for 14 to 28 days (Hu 2017; IDSA
Bacteremia without endocarditis: Oral: 200 mg [Wormser 2006]). Note: Not recommended for seri-
once daily or 100 mg twice daily for 4 weeks with ous neurologic disease (Hu 2017; IDSA
gentamicin once daily for first 2 weeks (Foucault [Wormser 2006]).
2003; Rolain 2004) Malaria:
Cat-scratch disease, CNS infection, and neuroreti- Chemoprophylaxis in travelers: Oral (immediate
nitis: Oral, IV: 100 mg twice daily in combination release and delayed release): 100 mg daily; initiate
with rifampin (Rolain 2004) 1 to 2 days prior to travel to endemic area; continue
Endocarditis, confirmed: Oral: 100 mg every 12 daily during travel and for 4 weeks after leaving
hours for 6 to 12 weeks with gentamicin for first endemic area.
2 weeks (Rolain 2004; Spach 2017) Uncomplicated malaria, treatment (chloroquine
Bite-wound infection, prophylaxis or treatment resistant or unknown resistance; alternative agent)
(animal and human bites; alternative agent) (off- (off-label use): Oral: 100 mg twice daily for 7 days
label use): Oral, IV: 100 mg twice daily. Duration is 3 in combination with quinine sulfate (plus primaquine
to 5 days for prophylaxis; duration of treatment for for Plasmodium vivax). Note: Quinine sulfate dura-
established infection varies based on patient-specific tion is region specific; consult CDC for current
factors (IDSA [Stevens 2014]). Note: Some experts recommendations (CDC 2013).
use in combination with an appropriate agent for Severe malaria, treatment (alternative agent) (off-
anaerobes (Baddour 2019a; Baddour 2019b). label use): IV, Oral: 100 mg every 12 hours for 7
Brucellosis: days in combination with quinidine gluconate. Note:
Treatment: IV therapy should be administered for at least 24
Endocarditis or neurobrucellosis: Limited data hours or until oral medication tolerated; quinidine
available: IV, Oral: 100 mg twice daily as part of gluconate duration is region specific; consult CDC
a combination regimen (Bosilkovski 2017; Jia for current recommendations (CDC 2013).
2017; Zheng 2017) Periodontitis, chronic: Subantimicrobial dosing:
Uncomplicated (nonfocal): Oral: 100 mg twice daily Oral: 20 mg twice daily (immediate release) for 3 to
plus rifampin for 6 weeks or 100 mg twice daily for 9 months as an adjunct to scaling and root planing
6 weeks plus gentamicin for the first 5 to 14 days (Smiley 2015)
459
DOXYCYCLINE
Plague (Yersinia pestis) (alternative agent): Oral, Sexually transmitted infections:

IV: 200 mg initially then 100 mg twice daily or Cervicitis or urethritis:
200 mg once daily for 10 to 14 days and at least Chlamydia trachomatis: Oral: 100 mg twice daily for
until 2 days after patient has defervesced (CDC 7 days (CDC [Workowski 2015]) or 200 mg
2015; IDSA [Stevens 2014]; Inglesby 2000; Sexton delayed release once daily for 7 days (Geisler
2017a) 2012); consider concurrent treatment for gonor-
Pleurodesis, chemical (sclerosing agent for pleu- rhea with a single dose of ceftriaxone based on
ral effusion) (off-label use): Intrapleural: 500 mg as individual risk factors, if local prevalence is ele-
a single dose in 30 to 100 mL NS (Porcel 2006; vated (>5%), or if intracellular gram-negative dip-
Robinson 1993); may require a repeat dose (Kvale lococci on Gram stain (CDC [Workowski 2015];
2007); some experts combine with or administer Marrazzo 2017). Note: Directly observed single-
following instillation of a local anesthetic (eg, lido- dose azithromycin is preferred for the treatment of
caine, 10 mL [100 mg] of 1% solution [Robinson uncomplicated genital chlamydial infections by
1993] or mepivacaine 20 mL [400 mg] of 2% solution some experts (Marrazzo 2017).
[Porcel 2006]) Neisseria gonorrhea (alternative agent [due to
Pneumonia, community-acquired (alternative resistance]; reserve for patients with azithromycin
agent): Outpatients or inpatients (non-ICU): Oral, intolerance): Oral: 100 mg twice daily for 7 days in
IV: 100 mg twice daily for 5 to 7 days. For empiric combination with a single dose of ceftriaxone
therapy of inpatients, use in combination with (CDC [Workowski 2015])
another appropriate agent (eg, antipneumococcal Epididymitis, acute (off-label use): Empiric or patho-
beta-lactam) (IDSA/ATS [Mandell 2007]). gen-directed therapy for chlamydia and/or gonor-
Prosthetic joint infection (off-label use): Treatment rhea: Oral: 100 mg twice daily for 10 days with
(following pathogen-specific IV therapy in patients single dose of ceftriaxone (CDC [Workowski
undergoing 1-stage exchange or debridement with 2015]). Note: An alternative regimen is recom-
retention of prosthesis): Oral: mended in patients whose sexual practices
Note: Duration ranges from a minimum of 3 months increase risk of infection with enteric pathogens
to indefinitely, depending on patient-specific factors (Eyre 2017; Marrazzo 2017).
(Berbari 2018). Granuloma inguinale (donovanosis) (alternative
Staphylococci: 100 mg twice daily. For the first 3 to 6 agent): Oral: 100 mg twice daily for at least 3 weeks
months of therapy, combine with rifampin (Berbari and until all lesions have healed. Note: If symptoms
2018; IDSA [Osmon 2013]).
do not improve within the first few days of therapy,
Cutibacterium acnes (alternative agent): 100 mg
another agent (eg, aminoglycoside) can be added
twice daily (IDSA [Osmon 2013]; Kanafani 2018).
(CDC [Workowski 2015]).
Q fever: Oral:
Lymphogranuloma venereum (LGV): Oral: 100 mg
Acute: 100 mg every 12 hours for 14 days (CDC
twice daily for 21 days (CDC [Workowski 2015])
[Anderson 2013]). Note: In patients with valvulop-
Pelvic inflammatory disease (off-label use):
athy/cardiomyopathy, some experts recommend
Inpatient (severe PID): IV, Oral: 100 mg every 12
extending treatment to 12 months in combination
hours in combination with cefoxitin or cefotetan;
with hydroxychloroquine to prevent progression to
transition to oral therapy after >24 hours improve-
persistent infection (Million 2013; Raoult 2017).
Persistent localized infection (endocarditis, vascular ment to complete a 14-day total course. If pelvic
infection): Oral: 100 mg every 12 hours in combi- abscess, anaerobic coverage is warranted (CDC
nation with hydroxychloroquine for ≥18 months [Workowski 2015]).
depending on site of infection and serologic Outpatient (mild to moderate PID): Oral: 100 mg
response (CDC [Anderson 2013]) every 12 hours for 14 days in combination with a
Rhinosinusitis, acute bacterial (alternative agent single dose of ceftriaxone (preferred) (Wiesenfeld
for beta-lactam intolerance) (off-label use): Oral: 2017) or single dose of cefoxitin plus oral probe-
200 mg/day in 1 to 2 divided doses for 5 to 7 days necid or other third generation cephalosporin; if
(IDSA [Chow 2012]). Note: In uncomplicated acute Trichomonas vaginalis or recent uterine instru-
bacterial rhinosinusitis, initial observation and symp- mentation, add metronidazole (CDC [Workow-
tom management without antibiotic therapy is appro- ski 2015]).
priate in most patients (ACP/CDC [Harris 2016]). Proctitis, acute or proctocolitis (off-label use):
Rocky Mountain spotted fever: Oral, IV: 100 mg Empiric or pathogen-directed therapy for chlamydia
twice daily for 5 to 7 days or for at least 3 days after and/or gonorrhea: Oral: 100 mg twice daily for 7
fever subsides, whichever is longer; initiate treatment days plus a single dose of ceftriaxone. Note:
as soon as possible. Severe or complicated disease Provide 21 days of doxycycline if polymerase chain
may require longer treatment (CDC [Biggs 2016]). reaction (PCR) for LGV confirmed or as presump-
Note: A loading dose of 200 mg IV is recommended tive therapy for LGV if patient has severe rectal
for critically ill patients (Sexton 2017b). symptoms (eg, bloody discharge, perianal ulcers,
Rosacea, moderate to severe or unresponsive to or mucosal ulcers), and either a positive rectal
topical therapy: Oral: chlamydia NAAT or HIV infection. Additional cover-
Traditional dosing (off-label dose): Initial: 50 to age for herpes simplex virus is warranted in
100 mg twice daily for 4 to 12 weeks; may follow patients with perianal or mucosal ulcers (CDC
with a topical agent and/or subantimicrobial doxy- [Workowski 2015], Zenilman 2017).
cycline dosing for long-term management. Alterna- Syphilis, penicillin-allergic patients: Note: Limited
tively, may initiate therapy with subantimicrobial data support use of alternatives to penicillin and
dosing (Maier 2017) close serologic and clinical follow up is warranted
Subantimicrobial dosing: 40 mg once daily (delayed (CDC [Workowski 2015]; Hicks 2017).
release; Oracea) or 20 mg twice daily (immediate Early syphilis (primary, secondary, and early latent):
release) (Sanchez 2005) Oral: 100 mg twice daily for 14 days
460
DOXYCYCLINE
Late syphilis (late latent): Oral: 100 mg twice daily Infants, Children, and Adolescents:
for 28 days Patient weight <45 kg:
Surgical prophylaxis, uterine evacuation (induced Initial: IV: Loading dose: 4.4 mg/kg once, then
abortion or pregnancy loss) (off-label use): Oral: 2.2 mg/kg/dose every 12 hours; may transi-
200 mg as a single dose 1 hour prior to uterine tion to oral therapy for patients without signs
aspiration (ACOG 2018) of active infection who are able to tolerate oral
Tularemia (Francisella tularensis): therapy and patient/caregiver adherent to
Treatment (mild infection): Oral: 100 mg twice daily therapy.
for ≥14 days (IDSA [Stevens 2014]) Step-down: Oral: 2.2 mg/kg/dose every 12
Postexposure prophylaxis (nonbioterrorism event, hours
high-risk exposure): Oral: 100 mg twice daily for Patient weight ≥45 kg:
14 days (Penn 2017) Initial: IV: Loading dose: 200 mg once, then
Bioterrorism event: Note: Consult public health offi- 100 mg every 12 hours; may transition to oral
cials for event-specific recommendations. therapy for patients without signs of active
Mass casualty management or postexposure pro- infection who are able to tolerate oral therapy
phylaxis (when used as a biological weapon): and patient/caregiver adherent to therapy.
Oral: 100 mg twice daily for 14 days (Den- Step-down: Oral: 100 mg every 12 hours
nis 2001) Brucellosis: Limited data available: Children ≥8 years
Contained casualty management (when used as a and Adolescents: Oral: 1 to 2 mg/kg/dose twice daily
biological weapon): IV (may transition to oral if for 6 weeks; maximum dose: 100 mg/dose; use in
clinically appropriate): 100 mg every 12 hours for combination with rifampin or an aminoglycoside (Red
14 to 21 days (Dennis 2001) Book [AAP 2015])
Renal Impairment: Adult Chlamydial infections, uncomplicated (sexually
No dosage adjustment necessary. transmitted C. trachomatis): Adolescents: Oral:
Dialysis: Poorly dialyzed (0% to 5%); no supplemental 100 mg twice daily for 7 days (CDC [Workow-
dose or dosage adjustment necessary, including ski 2015])
patients on intermittent hemodialysis, peritoneal dial- Lyme disease: Limited data available (IDSA
ysis, or continuous renal replacement therapy (eg, [Wormser 2006]): Children ≥8 years and Adoles-
CVVHD). cents:
Hepatic Impairment: Adult There are no dosage Prophylaxis, postexposure: Oral: 4 mg/kg/dose once
adjustments provided in the manufacturer's labeling. as a single dose; maximum dose: 200 mg/dose;
Pediatric initiate within 72 hours of tick removal
General dosing: Children ≥8 years and Adolescents: Treatment:
Oral, IV: 2.2 mg/kg/dose every 12 hours, maximum Early Lyme disease: Oral: 2 mg/kg/dose twice daily
daily dose: 200 mg/day for 10 to 21 days (usual duration: 14 days);
Anthrax (AAP [Bradley 2014]): maximum dose: 100 mg/dose
Prophylaxis; post-exposure (inhalation or cutane- Lyme arthritis (no neurologic involvement): Oral:
ous); prior to susceptibility testing or penicillin- 2 mg/kg/dose twice daily for 28 days; maximum
resistant strains: Note: Doxycycline is a preferred dose: 100 mg/dose
option or ciprofloxacin: Infants, Children, and Ado- Meningitis, neurologic Lyme disease: Oral: 2 to
lescents: Treatment duration: 60 days 4 mg/kg/dose twice daily for 10 to 28 days; max-
Patient weight <45 kg: Oral: 2.2 mg/kg/dose every imum dose: 200 mg/dose
12 hours Malaria: Children ≥8 years and Adolescents:
Patient weight ≥45 kg: Oral: 100 mg every 12 hours Prophylaxis: Oral: 2.2 mg/kg/dose once daily starting
Treatment; susceptible strains: 1 to 2 days before travel to the area with endemic
Cutaneous infection without systemic involvement: infection, continuing daily during travel and for 4
Note: Doxycycline is an option if first-line therapy weeks after leaving endemic area; maximum daily
(ie, ciprofloxacin) is unavailable or patient unable dose: 100 mg/day
to tolerate; for naturally-occurring infection, usual Treatment: Oral, IV: 2.2 mg/kg/dose twice daily for 7
treatment duration is 7 to 10 days; in the event of days; maximum dose: 100 mg/dose (CDC 2013);
biological weapon exposure, additional therapy for uncomplicated cases, combination therapy with
(as prophylaxis for inhaled spores) is necessary quinine sulfate is recommended; in severe cases,
for a total course of 60 days from onset of illness. combination therapy with quinidine gluconate
Infants, Children, and Adolescents: should be used; Note: Duration of either quinine
Patient weight <45 kg: Oral: 2.2 mg/kg/dose sulfate or quinidine gluconate is region-specific;
every 12 hours consult CDC for current recommendations.
Patient weight ≥45 kg: Oral: 100 mg every 12 Pneumonia, community-acquired; presumed or
hours proven atypical infection (Mycoplasma pneumo-
Systemic anthrax, excluding meningitis: Note: Not niae, Chlamydophila pneumoniae): Children ≥8
recommended for meningitis or disseminated years and Adolescents: Oral: 1 to 2 mg/kg/dose
infection when meningitis cannot be ruled out. twice daily for 10 days (IDSA [Bradley 2011])
Doxycycline is an alternative to clindamycin as Q fever (Coxiella burnetii) (preferred therapy): Chil-
protein synthesis inhibitor and should be used in dren and Adolescents: Oral: 2.2 mg/kg/dose twice
combination with a bactericidal antimicrobial (eg, daily for 14 days; maximum dose: 100 mg/dose; in
fluoroquinolone, carbapenem, or vancomycin). children <8 years with mild or uncomplicated dis-
Duration of therapy at least 14 days or longer until ease, may consider treatment duration of 5 days,
patient clinically stable; additional therapy (as and if longer treatment required, may consider alter-
prophylaxis for inhaled spores) is necessary for nate therapy (trimethoprim/sulfamethoxazole) (CDC
a total course of 60 days from onset of illness. [Anderson 2013])
461
DOXYCYCLINE
Skin/soft tissue infections; MRSA or community- (CDAD) and pseudomembranous colitis; CDAD has
acquired cellulitis (purulent) (IDSA [Liu 2011]): been observed >2 months postantibiotic treatment.
Children ≥8 years and Adolescents: May induce hyperpigmentation in many organs, includ-
≤45 kg: Oral: 2 mg/kg/dose every 12 hours for 5 to ing nails, bone, skin (diffuse pigmentation as well as
10 days over sites of scars and injury), eyes, thyroid, visceral
>45 kg: Oral: 100 mg twice daily for 5 to 10 days tissue, oral cavity (adult teeth, mucosa, alveolar bone),
Tickborne rickettsial disease (Rocky Mountain sclerae, and heart valves independently of time or
spotted fever), ehrlichiosis, or anaplasmosis: amount of drug administration. Safety and effectiveness
Children and Adolescents: Oral, IV: 2.2 mg/kg/dose have not been established for treatment of periodontitis
every 12 hours; maximum dose: 100 mg/dose; treat in patients with coexistent oral candidiasis; use with
for minimum of 5 to 7 days; continue for at least 3 caution in patients with a history or predisposition to
days after defervescence and clinical improvement oral candidiasis. May cause tissue hyperpigmentation,
observed. Severe or complicated disease may tooth enamel hypoplasia, or permanent tooth discolor-
require longer treatment; anaplasmosis should be ation (more common with long-term use, but observed
treated for 10 days (CDC [Biggs 2016]). with repeated, short courses) when used during tooth
Renal Impairment: Pediatric No adjustment neces- development (last half of pregnancy, infancy, and child-
sary; poorly dialyzed (0% to 5%). hood ≤8 years of age); manufacturer states to use in
Hepatic Impairment: Pediatric There are no dos- children ≤8 years of age only when the potential bene-
age adjustments provided in the manufacturer's label- fits outweigh the risks in severe or life threatening
ing. conditions (eg, anthrax, Rocky Mountain spotted fever),
Mechanism of Action particularly when there are no alternative therapies.
Inhibits protein synthesis by binding with the 30S and Limited use between 6 to 7 years of age has minimal
effect on the color of permanent incisors (CDC [Biggs
possibly the 50S ribosomal subunit(s) of susceptible
2016]). Recommended in prevention and treatment of
bacteria; may also cause alterations in the cytoplas-
anthrax (AAP [Bradley 2014]), treatment of tickborne
mic membrane
rickettsial diseases (CDC [Biggs 2016]), and Q fever
20 mg tablets and capsules (Periostat [Canadian prod-
(CDC 2013). When used for malaria prophylaxis, does
uct]): Proposed mechanism: Has been shown to
not completely suppress asexual blood stages of Plas-
inhibit collagenase activity in vitro. Also has been
modium strains. Doxycycline does not suppress P.
noted to reduce elevated collagenase activity in the
falciparum's sexual blood stage gametocytes. Patients
gingival crevicular fluid of patients with periodontal
completing a regimen may still transmit the infection to
disease. Systemic levels do not reach inhibitory con-
mosquitoes outside endemic areas. Potentially signifi-
centrations against bacteria.
cant drug-drug interactions may exist, requiring dose or
Contraindications frequency adjustment, additional monitoring, and/or
Hypersensitivity to doxycycline, other tetracyclines, or selection of alternative therapy.
any component of the formulation
Periostat, Apprilon [Canadian products]: Additional con- Acne: The American Academy of Dermatology acne
traindications: Use in infants and children <8 years of guidelines recommend doxycycline as adjunctive treat-
age or during second or third trimester of pregnancy; ment for moderate and severe acne and forms of
breastfeeding inflammatory acne that are resistant to topical treat-
Warnings/Precautions Photosensitivity reaction may ments. Concomitant topical therapy with benzoyl per-
occur with this drug; discontinue at first sign of skin oxide or a retinoid should be administered with systemic
erythema. Use skin protection and avoid prolonged antibiotic therapy (eg, doxycycline) and continued for
exposure to sunlight and ultraviolet light. May be asso- maintenance after the antibiotic course is completed
ciated with increases in BUN secondary to antianabolic (AAD [Zaenglein 2016]).
effects; this does not occur with use of doxycycline in Oracea or Apprilon (Canadian product): Do not be use
patients with renal impairment. Severe skin reactions for the treatment or prophylaxis of bacterial infections
(eg, exfoliative dermatitis, erythema multiforme, Ste- (dose may be subefficacious and promote resistance).
vens-Johnson syndrome, toxic epidermal necrolysis,
drug reaction with eosinophilia and systemic symptoms Syrup contains sodium metabisulfite, which may cause
[DRESS]) have been reported; discontinue use for allergic reactions in certain individuals (eg, asthmatic
serious hypersensitivity reactions. Hepatotoxicity rarely patients).
occurs; if symptomatic, assess LFTs and discontinue Warnings: Additional Pediatric Considerations
drug. Intracranial hypertension (pseudotumor cerebri) Tooth staining or enamel hypoplasia of developing teeth
has been associated with use; headache, blurred is a known concern with the use of tetracycline-class of
vision, diplopia, vision loss, and/or papilledema may antibiotics in children <8 years of age based on expe-
occur. Women of childbearing age who are overweight rience with older tetracyclines which bind to calcium
or have a history of intracranial hypertension are at more readily than doxycycline. A cohort analysis of 58
greater risk. Intracranial hypertension typically resolves children who were exposed to doxycycline for treatment
after discontinuation of treatment; however, permanent of Rocky Mountain Spotted Fever when <8 years of age
visual loss is possible. If visual symptoms develop reported no visible tetracycline-like tooth staining of
during treatment, prompt ophthalmologic evaluation is permanent teeth and recommended dose and duration
warranted. Intracranial pressure can remain elevated compared to a control group of 213 children not
for weeks after drug discontinuation; monitor patient exposed to doxycycline; the cohort received a total of
until stable. Esophagitis and ulcerations (sometimes 107 courses of doxycycline (multiple courses), mean
severe) may occur; patients with dysphagia and/or duration: 7.3 days (range: 1 to 10 days), and mean
retrosternal pain may require assessment for esopha- dose: 2.3 mg/kg/day (Todd 2015). An analysis of 31
asthmatic children who received doxycycline also
geal lesions.
reported no evidence of tooth staining. A meta-analysis
Prolonged use may result in fungal or bacterial super- of the combined data reported a 0% prevalence rate for
infection, including C. difficile-associated diarrhea tooth staining (CDC [Biggs 2016]; Todd 2015).
462
DOXYCYCLINE
Retrospective data suggests that at standard doses, Periostat [Canadian product]: Manufacturer states to
children <8 years could receive up to 5 courses of take at least 1 hour before morning and evening
doxycycline without detectable evidence of tooth stain- meals. Take with food if gastric irritation occurs.
ing (AAP [Bradley 2014]). Some products may contain sodium.
Administration of tetracycline 25 mg/kg/day was asso-
Half-life Elimination 18 to 22 hours; End-stage renal
ciated with decreased fibular growth rate in premature
disease: 18 to 25 hours
infants (reversible with discontinuation of drug); bulging
fontanels have been reported in infants.
Time to Peak Serum: Oral: Immediate release: 1.5 to
4 hours; delayed-release tablets: 2.8 to 3 hours
Some dosage forms may contain propylene glycol; in Pregnancy Risk Factor D
neonates large amounts of propylene glycol delivered Pregnancy Considerations Tetracyclines cross the
orally, intravenously (eg, >3,000 mg/day), or topically placenta (Mylonas 2011). Therapeutic doses of doxycy-
have been associated with potentially fatal toxicities cline during pregnancy are unlikely to produce substan-
which can include metabolic acidosis, seizures, renal tial teratogenic risk, but data are insufficient to say that
failure, and CNS depression; toxicities have also been there is no risk. In general, reports of exposure have
reported in children and adults including hyperosmolal- been limited to short durations of therapy in the first
ity, lactic acidosis, seizures and respiratory depression; trimester. Tetracyclines accumulate in developing teeth
use caution (AAP 1997; Shehab 2009). and long tubular bones (Mylonas 2011). Permanent
Drug Interactions discoloration of teeth (yellow, gray, brown) can occur
Metabolism/Transport Effects None known. following in utero exposure and is more likely to occur
Avoid Concomitant Use following long-term or repeated exposure.
Avoid concomitant use of Doxycycline with any of the
following: Aminolevulinic Acid (Systemic); BCG (Intra- Doxycycline is the recommended agent for the treat-
vesical); Cholera Vaccine; Mecamylamine; Methoxy- ment of Rocky Mountain spotted fever (RMSF) in
flurane; Retinoic Acid Derivatives; Strontium Ranelate pregnant women (CDC [Biggs 2016]). For other indica-
Increased Effect/Toxicity tions, many guidelines consider use of doxycycline to
be contraindicated during pregnancy, or to be a relative
Doxycycline may increase the levels/effects of: Amino-
contraindication in pregnant women if other agents are
levulinic Acid (Systemic); Aminolevulinic Acid (Top-
available and appropriate for use (Anderson 2013; CDC
ical); Mecamylamine; Methoxyflurane; Mipomersen;
2011; HHS [OI adult 2015]; Stevens 2014; Workowski
Neuromuscular-Blocking Agents; Porfimer; Retinoic
Acid Derivatives; Verteporfin; Vitamin K Antagonists [CDC 2015]; IDSA [Wormser 2006]). Doxycycline
should not be used for the treatment of rosacea in
Decreased Effect
pregnant women. When systemic antibiotics are
Doxycycline may decrease the levels/effects of: BCG
needed for dermatologic conditions, other agents are
(Intravesical); BCG Vaccine (Immunization); Cholera
preferred (Kong 2013; Murase 2014). As a class,
Vaccine; Iron Salts; Lactobacillus and Estriol; Penicil-
tetracyclines are generally considered second-line anti-
lins; Sodium Picosulfate; Typhoid Vaccine
biotics in pregnant women and their use should be
The levels/effects of Doxycycline may be decreased avoided (Mylonas 2011).
by: Antacids; Barbiturates; Bile Acid Sequestrants; Breastfeeding Considerations
Bismuth Subcitrate; Bismuth Subsalicylate; Calcium Doxycycline is present in breast milk.
Salts; CarBAMazepine; Fosphenytoin; Iron Salts; Lan- The relative infant dose (RID) of doxycycline is 6.14%
thanum; Magnesium Salts; Multivitamins/Minerals when calculated using the highest average breast milk
(with ADEK, Folate, Iron); Multivitamins/Minerals (with concentration located and compared to an infant ther-
AE, No Iron); Phenytoin; Proton Pump Inhibitors; apeutic dose of 4.4 mg/kg/day.
Quinapril; RifAMPin; Strontium Ranelate; Sucralfate; In general, breastfeeding is considered acceptable
Sucroferric Oxyhydroxide when the RID is <10%; when an RID is >25% breast-
Food Interactions feeding should generally be avoided (Anderson 2016;
Ethanol: Chronic ethanol ingestion may reduce the Ito 2000).
serum concentration of doxycycline. Using the highest average milk concentration (1.8
Food: Doxycycline serum levels may be slightly mcg/mL), the estimated daily infant dose via breast
decreased if taken with high-fat meal or milk. Admin- milk is 0.27 mg/kg/day. This milk concentration was
istration with iron or calcium may decrease doxycy- obtained following maternal administration of a single
cline absorption. May decrease absorption of calcium, oral dose of doxycycline 200 mg (Tokuda 1969). Con-
iron, magnesium, zinc, and amino acids. Manage- centrations of doxycycline in breast milk may increase
ment: Administer Doryx and Doryx MPC without with duration of therapy (Anderson 1991).
regard to meals. Administer Oracea and doxycycline Oral absorption of doxycycline is not markedly influ-
20 mg tablet on an empty stomach 1 hour before or 2 enced by simultaneous ingestion of milk; therefore,
hours after meals. oral absorption of doxycycline by the breastfeeding
Dietary Considerations infant would not be expected to be diminished by the
Tetracyclines (in general): Take with food if gastric calcium in the maternal milk.
irritation occurs. While administration with food may The therapeutic use of doxycycline should be avoided
decrease GI absorption of doxycycline by up to 20%, during tooth development (children <8 years) unless
administration on an empty stomach is generally not there are no alternative therapies due to the potential
recommended due to GI intolerance. Of currently for tissue hyperpigmentation, tooth enamel hypopla-
available tetracyclines, doxycycline has the least affin- sia, or permanent tooth discoloration. Theoretically,
ity for calcium. this risk is also present in breastfeeding infants
Doxycycline 20 mg tablet, Oracea, Apprilon [Canadian exposed to doxycycline via breast milk. Although
product]: Manufacturer states to take on an empty breastfeeding is not specifically contraindicated, the
stomach 1 hour before or 2 hours after meals. Take effects of long-term exposure via breast milk are not
with food if gastric irritation occurs. known. According to the manufacturer, the decision to
463
DOXYCYCLINE
continue or discontinue breastfeeding during therapy TargaDOX: 50 mg

should take into account the risk of infant exposure, Generic: 20 mg, 50 mg, 75 mg, 100 mg, 150 mg
the benefits of breastfeeding to the infant, and benefits Tablet Delayed Release, Oral:
of treatment to the mother. The World Health Organ- Doryx: 50 mg, 200 mg
ization (WHO) states that maternal use of doxycycline Doryx MPC: 120 mg
should be avoided if possible but that a single dose or Soloxide: 150 mg
the short-term use of doxycycline is probably safe; Generic: 50 mg, 75 mg, 100 mg, 150 mg, 200 mg
there exists a possibility of dental staining and inhib- Dosage Forms: Canada
ition of bone growth in the infant, especially with Capsule, oral:
prolonged use (WHO 2002). In general, antibiotics Apprilon: 40 mg [30 mg (immediate release) and
that are present in breast milk may cause nondose- 10 mg (delayed release)]
related modification of bowel flora. Monitor infants for Periostat: 20 mg
GI disturbances, such as thrush and diarrhea
(WHO 2002).
Current guidelines note that the short-term use of
Doxycycline Hyclate Periodontal
doxycycline for the treatment of RMSF is considered Extended-Release Liquid
compatible with breastfeeding (CDC [Biggs 2016]). (doks i SYE kleen HI klayt per ee oh DON tal ik STEN did ri LES LIK
wid)
However, breastfeeding is a relative contraindication
for the use of doxycycline in the treatment of Lyme Related Information
disease (Wormser 2006). If used for the treatment or Doxycycline on page 457
prophylaxis of malaria, breastfeeding during doxycy- Periodontal Diseases on page 1534
cline therapy is considered compatible; however, the Brand Names: US Atridox
theoretical risk of dental staining and inhibition of long
Brand Names: Canada Atridox
bone growth in the breastfeeding infant should be
considered (WHO 2002).
Generic Availability (US) No
Long-term use of tetracyclines (eg, for the treatment of Pharmacologic Category Antibiotic, Tetracycline
acne) should be avoided in breastfeeding women Derivative
(Pugashetti 2013). Dental Use Treatment of chronic adult periodontitis for
Product Availability LymePak (doxycycline tablets): gain in clinical attachment, reduction in probing depth,
FDA approved June 2018; anticipated availability is and reduction in bleeding upon probing
currently unknown. Information pertaining to this prod- Use Periodontitis: Treatment of chronic adult periodon-
uct within the monograph is pending revision. LymePak titis for a gain in clinical attachment, reduction in probing
is indicated for the treatment of early Lyme disease due depth, and reduction in bleeding on probing.
to Borrelia burgdorferi in adults and pediatric patients Local Anesthetic/Vasoconstrictor Precautions
≥8 years of age weighing ≥45 kg. Consult the prescrib- No information available to require special precautions
ing information for additional information. Effects on Dental Treatment Key adverse event(s)
Dosage Forms Considerations related to dental treatment: Discoloration of teeth (in
Alodox Convenience kits contain doxycycline tablets children), gum discomfort, toothache, periodontal
20 mg, plus eyelid cleanser abscess, tooth sensitivity, broken tooth, tooth mobility,
Morgidox kits contain doxycycline capsules 100 mg, endodontic abscess, and jaw pain
plus AcuWash moisturizing Daily Cleanser Mechanical oral hygiene procedures (ie, tooth brushing,
NizAzel Doxy kits contain doxycycline tablets 100 mg, flossing) should be avoided in any treated area for
plus NicAzel FORTE dietary supplement tablets 7 days.
Ocudox kits contain doxycycline capsules 50 mg, plus Effects reported in clinical trials were similar in inci-
eyelid cleanser and Tears Again Advanced eyelid dence between doxycycline-containing product and
spray vehicle alone; comparable to standard therapies
Dosage Forms: US including scaling and root planing or oral hygiene.
Capsule, Oral: Although there is no known relationship between
Mondoxyne NL: 50 mg, 75 mg, 100 mg doxycycline and hypertension, unspecified primary
Morgidox: 50 mg, 100 mg hypertension was noted in 1.6% of the doxycycline
Okebo: 75 mg gel group, as compared to 0.2% in the vehicle group
Vibramycin: 100 mg (allergic reactions to the vehicle were also reported in
Generic: 50 mg, 75 mg, 100 mg, 150 mg two patients).
Capsule Delayed Release, Oral: Effects on Bleeding No information available to
Oracea: 40 mg require special precautions
Generic: 40 mg Adverse Reactions
Kit, Combination: >10%:
Morgidox: 1 x 50 mg, 1 x 100 mg, 2 x 100 mg Central nervous system: Headache (27%)
Solution Reconstituted, Intravenous [preservative Gastrointestinal: Minor gum irritation (18%), toothache
free]: (14%; pressure sensitivity)
Doxy 100: 100 mg (1 ea) 1% to 10%:
Generic: 100 mg (1 ea) Cardiovascular: Hypertension (<1% to 2%)
Suspension Reconstituted, Oral: Central nervous system: Local discomfort (sensitive
Vibramycin: 25 mg/5 mL (60 mL) teeth: 8%), sore mouth (4%; soft tissue erythema,
Generic: 25 mg/5 mL (60 mL) unspecified pain), insomnia (3%), tension head-
Syrup, Oral: ache (2%)
Vibramycin: 50 mg/5 mL (473 mL) Dermatologic: Dermatitis (1%), skin infection (1%)
Tablet, Oral: Endocrine & metabolic: Premenstrual syndrome (4%)
Acticlate: 75 mg, 150 mg Gastrointestinal: Periodontal abscess (10%), sore
Avidoxy: 100 mg throat (6%), injury of tooth (5%), dyspepsia (4%),
464
DOXYCYCLINE HYCLATE PERIODONTAL EXTENDED-RELEASE LIQUID
gingivitis (4%), diarrhea (3%), nausea (2%), perio- Contraindications

dontal abscess (2%; lesion), vomiting (2%), dental Hypersensitivity to doxycycline, tetracycline or any com-
bleeding (1%) ponent of the formulation; children <8 years of age
Infection: Common cold (26%), influenza (3% to 6%), Canadian labeling: Additional contraindications (not in
tooth abscess (2%; pulpitis) US labeling): Children <12 years of age; pregnancy;
Neuromuscular & skeletal: Myalgia (6%), back pain breastfeeding
(4%), arm pain (2%), leg pain (2%), lower back pain
Warnings/Precautions Photosensitivity reaction may
(2%), muscle tenderness (2%), jaw pain (1%), neck
occur with this drug; avoid prolonged exposure to sun-
pain (1%), shoulder pain (1%)
Respiratory: Sinus congestion (6%), sinus infection light or tanning equipment. Prolonged use may result in
(5%), cough (4%), bronchitis (2%), ENT infection fungal or bacterial superinfection, including C. difficile-
(2%), allergic rhinitis (1%) associated diarrhea (CDAD) and pseudomembranous
Miscellaneous: Fever (1%) colitis; CDAD has been observed >2 months postanti-
<1%, postmarketing, and/or case reports: Aphthous biotic treatment. May cause tissue hyperpigmentation,
stomatitis, enamel hypoplasia, fistula, hypersensitivity enamel hypoplasia, or permanent tooth discoloration;
reaction, permanent dental discoloration, skin photo- use of tetracyclines should be avoided during tooth
sensitivity, tooth loss development (children <8 years of age) unless other
Dental Usual Dosage Oral, subgingival: Dose drugs are not likely to be effective or are contraindi-
depends on size, shape and number of pockets treated. cated. The Canadian labeling contraindicates use in
Application may be repeated four months after initial children <12 years of age.
treatment. The delivery system consists of 2 separate
syringes in a single pouch. Syringe A contains 450 mg Additional specific warnings for doxycycline gel (Atri-
of a bioabsorbable polymer gel; syringe B contains dox) for subgingival application: This product has not
doxycycline hyclate 50 mg. To prepare for instillation, been evaluated or tested in immunocompromised
couple syringe A to syringe B. Inject contents of syringe patients, in patients with oral candidiasis, or in condi-
A (purple stripe) into syringe B, then push contents back tions characterized by severe periodontal defects with
into syringe A. Repeat this mixing cycle at a rate of one little remaining periodontium. May result in overgrowth
cycle per second for 100 cycles. If syringes are stored of nonsusceptible organisms, including fungi. Effects of
prior to use (a maximum of 3 days), repeat mixing cycle treatment >9 months have not been evaluated. Has not
10 times before use. After appropriate mixing, contents been evaluated for use in regeneration of alveolar bone
should be in syringe A. Holding syringes vertically, with Drug Interactions
syringe A at the bottom, pull back on the syringe A Metabolism/Transport Effects None known.
plunger, allowing contents to flow down barrel for Avoid Concomitant Use There are no known inter-
several seconds. Uncouple syringes and attach actions where it is recommended to avoid concomitant
enclosed blunt cannula to syringe A. Local anesthesia
use.
is not required for placement. Cannula tip may be bent
to resemble periodontal probe and used to explore
Increased Effect/Toxicity There are no known sig-
pocket. Express product from syringe until pocket is nificant interactions involving an increase in effect.
filled. To separate tip from formulation, turn tip towards Decreased Effect There are no known significant
the tooth and press against tooth surface to achieve interactions involving a decrease in effect.
separation. An appropriate dental instrument may be Pregnancy Risk Factor D
used to pack gel into the pocket. Pockets may be Pregnancy Considerations Exposure to tetracyclines
covered with either Coe-pak or Octyldentdental adhe- during the second or third trimester may cause perma-
sive. nent discoloration of the teeth. Most reports do not
Dosing show an increase risk for teratogenicity with the excep-
Adult & Geriatric tion of a potential small increased risk for cleft palate or
Periodontitis: Subgingival application: Dose depends esophageal atresia/stenosis. Serum concentrations fol-
on size, shape and number of pockets treated. lowing subgingival use are significantly less than with
Contains 50 mg doxycycline hyclate per 500 mg of oral tablets. The Canadian labeling contraindicates use
formulation in each final blended syringe product.
in pregnant women.
Atridox subgingival controlled-release product: Local Breastfeeding Considerations Tetracyclines, includ-
anesthesia is not required for placement. Cannula tip ing oral doxycycline, are excreted in breast milk and
may be bent to resemble periodontal probe and used therefore, breastfeeding is not recommended. The
to explore pocket. Express product from syringe until Canadian labeling contraindicates use in breastfeeding
pocket is filled. To separate tip from formulation, turn women.
tip towards the tooth and press against tooth surface
to achieve separation. An appropriate dental instru- Doxycycline is less bound to the calcium in maternal
ment may be used to pack gel into the pocket. Pockets milk which may lead to increased absorption compared
may be covered with either Coe-Pak or Octyldent to other tetracyclines. Only minimal amounts of oral
dental adhesive. Application may be repeated 4 doxycycline are excreted in human milk and the relative
months after initial treatment. amount of tooth staining has been reported to be lower
Mechanism of Action Inhibits protein synthesis by when compared to other tetracycline analogs. Non-
binding with the 30S and possibly the 50S ribosomal dose-related effects could include modification of bowel
subunit(s) of susceptible bacteria; may also cause flora. Serum concentrations following subgingival use
alterations in the cytoplasmic membrane are significantly less than with oral tablets.
Doxycycline inhibits collagenase in vitro and has been Dosage Forms: US
shown to inhibit collagenase in the gingival crevicular Liquid, subgingival:
fluid in adults with periodontitis Atridox: 10%
465
DOXYLAMINE

Doxylamine (dox IL a meen) >10%: Central nervous system: Euphoria (antiemetic:
24%; appetite stimulant: 8%)
Brand Names: US Nitetime Sleep-Aid [OTC] [DSC]; 1% to 10%:
Sleep Aid [OTC] Cardiovascular: Facial flushing (>1%), palpitations
Brand Names: Canada Unisom-2 (>1%), tachycardia (>1%), vasodilatation (>1%),
Pharmacologic Category Ethanolamine Derivative; flushing (≤1%), hypotension (≤1%)
Histamine H1 Antagonist; Histamine H1 Antagonist, Central nervous system: Abnormality in thinking (3%
First Generation to 10%), dizziness (3% to 10%), drowsiness (3% to
Use Insomnia: Reduce difficulty falling asleep 10%), paranoia (3% to 10%), amnesia (>1%), anxi-
Local Anesthetic/Vasoconstrictor Precautions ety (>1%), ataxia (>1%), confusion (>1%), deperson-
No information available to require special precautions alization (>1%), hallucination (>1%), nervousness
Effects on Dental Treatment Key adverse event(s) (>1%), chills (≤1%), depression (≤1%), headache
related to dental treatment: Dry mucous membranes (≤1%), malaise (≤1%), nightmares (≤1%), speech
and significant xerostomia (normal salivary flow disturbance (≤1%)
resumes upon discontinuation) Dermatologic: Diaphoresis (≤1%)
Effects on Bleeding No information available to Gastrointestinal: Abdominal pain (3% to 10%), nausea
require special precautions (3% to 10%), vomiting (3% to 10%), anorexia (≤1%),
Adverse Reactions Frequency not defined. diarrhea (≤1%), fecal incontinence (≤1%)
Cardiovascular: Palpitations, tachycardia Hepatic: Increased liver enzymes (≤1%)
Central nervous system: Disorientation, dizziness, Neuromuscular & skeletal: Weakness (>1%), myal-
drowsiness, headache, paradoxical central nervous gia (≤1%)
system stimulation, vertigo Ophthalmic: Conjunctival injection (≤1%), conjunctivi-
Gastrointestinal: Anorexia, constipation, diarrhea, dry tis (≤1%), visual disturbance (≤1%)
mucous membranes, epigastric pain, xerostomia Otic: Tinnitus (≤1%)
Genitourinary: Dysuria, urinary retention Respiratory: Cough (≤1%), rhinitis (≤1%), sinusi-
Ophthalmic: Blurred vision, diplopia tis (≤1%)
Mechanism of Action Doxylamine competes with <1%, postmarketing, and/or case reports: Burning sen-
histamine for H1-receptor sites on effector cells; blocks sation of skin, delirium, disorientation, exacerbation of
chemoreceptor trigger zone, diminishes vestibular stim- depression, falling, fatigue, insomnia, loss of con-
ulation, and depresses labyrinthine function through its sciousness, mental status changes (exacerbation of
central anticholinergic activity. mania or schizophrenia), movement disorder, oral
Pharmacodynamics/Kinetics lesion, panic attack, pharyngeal edema, seizure, skin
Half-life Elimination 10-12 hours (Paton, 1985; rash, swelling of lips, syncope, urticaria, visual dis-
Friedman, 1985); may be increased in the elderly turbance
(Friedman, 1989) Mechanism of Action Dronabinol (synthetic delta-9-
Time to Peak 2-4 hours (Paton, 1985; Friedman, tetrahydrocannabinol [delta-9-THC]), an active canna-
1985; Friedman, 1989) binoid and natural occurring component of Cannabis
Pregnancy Considerations Maternal use of doxyl- sativa L. (marijuana), activates cannabinoid receptors
amine in combination with pyridoxine during pregnancy CB1 and CB2. Activation of the CB1 receptor produces
has not been shown to increase the baseline risk of marijuana-like effects on psyche and circulation,
major malformations. Doxylamine may be used for the whereas activation of the CB2 receptor does not. Dro-
treatment of nausea and vomiting of pregnancy (ACOG nabinol has approximately equal affinity for the CB1 and
189 2018). CB2 receptors; however, efficacy is less at CB2 recep-
tors. Activation of the cannabinoid system with drona-
Dronabinol (droe NAB i nol) binol causes psychological effects that can be divided
into 4 groups: affective (euphoria and easy laughter);
Brand Names: US Marinol; Syndros sensory (increased perception of external stimuli and of
Pharmacologic Category Antiemetic; Appetite Stimu- the person's own body); somatic (feeling of the body
lant; Cannabinoid floating or sinking in the bed); and cognitive (distortion
Use of time perception, memory lapses, difficulty in concen-
Anorexia in patients with AIDS: Treatment of ano- tration). Most effects (eg, analgesia, appetite enhance-
rexia associated with weight loss in patients with ment, muscle relaxation, hormonal actions) are
AIDS. mediated by central cannabinoid receptors (CB1), their
Chemotherapy-induced nausea and vomiting: Treat- distribution reflecting many of the medicinal benefits
ment of nausea and vomiting associated with cancer and adverse effects (Grotenhermen 2003).
chemotherapy in patients who have failed to respond Pharmacodynamics/Kinetics
adequately to conventional antiemetic treatments. Onset of Action ~0.5 to 1 hour; Peak effect: 2 to 4
Local Anesthetic/Vasoconstrictor Precautions hours
No information available to require special precautions Duration of Action 4 to 6 hours (psychoactive
Effects on Dental Treatment Key adverse event(s) effects); ≥24 hours (appetite stimulation)
related to dental treatment: Xerostomia (normal salivary Half-life Elimination Biphasic: Alpha: 4 to 5 hours;
flow resumes upon discontinuation); Patients may Terminal: 25 to 36 hours
experience orthostatic hypotension as they stand up Time to Peak Serum: 0.5 to 4 hours
after treatment; especially if lying in dental chair for Pregnancy Considerations Although information
extended periods of time. Use caution with sudden related to the use of synthetic cannabinoids during
changes in position during and after dental treatment. pregnancy is limited, cannabinoids cross the placenta.
Effects on Bleeding No information available to Maternal use may increase the risk of adverse fetal/
require special precautions neonatal outcomes including growth restriction, low
466
DROPERIDOL
birth weight, preterm birth, and stillbirth. Some dosage conduction and sinus node function through inhibition of
forms also contain a significant amount of alcohol. calcium (ICa-L) channels and beta1-receptor blocking
Controlled Substance Marinol: C-III; Syndros: C-II activity. Similar to amiodarone, dronedarone also inhib-
its alpha1-receptor mediated increases in blood pres-
sure.
Dronedarone (droe NE da rone)
Related Information Half-life Elimination 13 to 19 hours
Cardiovascular Diseases on page 1442 Time to Peak Plasma: 3 to 6 hours
Clinical Risk Related to Drugs Prolonging QT Interval Pregnancy Risk Factor X
on page 1462 Pregnancy Considerations Studies in animals have
Brand Names: US Multaq shown evidence of fetal abnormalities and use is con-
Brand Names: Canada Multaq traindicated in women who are or may become preg-
nant
Pharmacologic Category Antiarrhythmic Agent,
Class III Dental Health Professional Considerations See
Use Paroxysmal or persistent atrial fibrillation: To
reduce the risk of hospitalization for atrial fibrillation
(AF) in patients in sinus rhythm with a history of parox- Droperidol (droe PER i dole)
ysmal or persistent AF
Local Anesthetic/Vasoconstrictor Precautions Related Information
Dronedarone is one of the drugs confirmed to prolong Clinical Risk Related to Drugs Prolonging QT Interval
the QT interval and is accepted as having a risk of on page 1462
causing torsade de pointes. The risk of drug-induced Brand Names: Canada Droperidol Injection, USP
torsade de pointes is extremely low when a single QT Pharmacologic Category Antiemetic; First Genera-
interval prolonging drug is prescribed. In terms of epi- tion (Typical) Antipsychotic
nephrine, it is not known what effect vasoconstrictors in Use Postoperative nausea/vomiting (PONV): Preven-
the local anesthetic regimen will have in patients with a tion and/or treatment of nausea and vomiting from
known history of congenital prolonged QT interval or in surgical and diagnostic procedures
patients taking any medication that prolongs the QT Local Anesthetic/Vasoconstrictor Precautions
interval. Until more information is obtained, it is sug- Droperidol is one of the drugs confirmed to prolong
gested that the clinician consult with the physician prior the QT interval and is accepted as having a risk of
to the use of a vasoconstrictor in suspected patients, causing torsade de pointes. The risk of drug-induced
and that the vasoconstrictor (epinephrine, mepivacaine torsade de pointes is extremely low when a single QT
and levonordefrin [Carbocaine® 2% with Neo-Cobe- interval prolonging drug is prescribed. In terms of epi-
frin®]) be used with caution. nephrine, it is not known what effect vasoconstrictors in
Effects on Dental Treatment No significant effects or the local anesthetic regimen will have in patients with a
complications reported known history of congenital prolonged QT interval or in
Effects on Bleeding No information available to patients taking any medication that prolongs the QT
require special precautions interval. Until more information is obtained, it is sug-
Adverse Reactions gested that the clinician consult with the physician prior
>10%: to the use of a vasoconstrictor in suspected patients,
Cardiovascular: Prolonged Q-T interval on ECG and that the vasoconstrictor (epinephrine, mepivacaine
(Bazett; 28% [placebo: 19%]; defined as >450 msec and levonordefrin [Carbocaine® 2% with Neo-Cobe-
in males or >470 msec in female) frin®]) be used with caution.
Renal: Increased serum creatinine (51%; increased Effects on Dental Treatment See Warnings/Precau-
>10%; occurred 5 days after initiation) tions. Key adverse event(s) related to dental treatment:
1% to 10%: Patients may experience orthostatic hypotension as
Cardiovascular: Bradycardia (3%) they stand up after treatment; especially if lying in
Dermatologic: Allergic dermatitis (≤5%), dermatitis dental chair for extended periods of time. Use caution
(≤5%), eczema (≤5%), pruritus (≤5%), skin rash with sudden changes in position during and after dental
(≤5%; described as generalized, macular, maculo- treatment.
papular, erythematous) Effects on Bleeding No information available to
Gastrointestinal: Diarrhea (9%), nausea (5%), require special precautions
abdominal pain (4%), dyspepsia (2%), vomiting (2%) Adverse Reactions Frequency not defined.
Neuromuscular & skeletal: Weakness (7%) Cardiovascular: Cardiac arrest, hypertension, hypoten-
<1%, postmarketing, and/or case reports: Acute hepatic sion (especially orthostatic), QTc prolongation (dose
failure (requiring transplant), anaphylaxis, angioe- dependent), tachycardia, torsade de pointes, ventric-
dema, atrial flutter (with 1:1 atrioventricular conduc- ular tachycardia
tion), cardiac failure (new or worsened), dysgeusia, Central nervous system: Anxiety, chills, depression
hepatic injury, hyperbilirubinemia, hypersensitivity (postoperative, transient), dizziness, drowsiness
angiitis, increased blood urea nitrogen, increased liver (postoperative) increased, dysphoria, extrapyramidal
enzymes, interstitial pulmonary disease, pneumonitis, symptoms (akathisia, dystonia, oculogyric crisis), hal-
pulmonary fibrosis, skin photosensitivity, vasculitis lucinations (postoperative), hyperactivity, neuroleptic
Mechanism of Action A noniodinated antiarrhythmic malignant syndrome (NMS) (rare), restlessness
agent structurally related to amiodarone exhibiting prop- Respiratory: Bronchospasm, laryngospasm
erties of all 4 antiarrhythmic classes. Dronedarone Miscellaneous: Anaphylaxis, shivering
inhibits sodium (INa) and potassium (Ikr, IkS, Ik1, and Ik- Mechanism of Action Droperidol is a butyrophenone
ACh) channels resulting in prolongation of the action antipsychotic; antiemetic effect is a result of blockade of
potential and refractory period in myocardial tissue dopamine stimulation of the chemoreceptor trigger
without reverse-use dependent effects; decreases AV zone. Other effects include alpha-adrenergic blockade,
467
DROPERIDOL
peripheral vascular dilation, and reduction of the myocardial infarction, pulmonary vascular occlusion,
pressor effect of epinephrine resulting in hypotension pruritus, skin rash, thromboembolism, urticaria,
and decreased peripheral vascular resistance; may also venous obstruction (peripheral deep vein)
reduce pulmonary artery pressure Mechanism of Action
Pharmacodynamics/Kinetics Drospirenone is a synthetic progestin and spironolac-
Onset of Action 3 to 10 minutes; Peak effect: Within tone analog with antimineralocorticoid and antiandro-
30 minutes genic activity. Counteracts estrogen effects causing
Duration of Action 2 to 4 hours, may extend to 12 endometrial thinning.
hours Estrogens are responsible for the development and
Half-life Elimination Children ~1.7 hours; Adults: ~2 maintenance of the female reproductive system and
hours (McKeage 2006) secondary sexual characteristics. Estradiol is the prin-
Pregnancy Risk Factor C cipal intracellular human estrogen and is more potent
Pregnancy Considerations Adverse events were than estrone and estriol at the receptor level; it is the
observed in some animal reproduction studies. Droper- primary estrogen secreted prior to menopause. Fol-
idol has been evaluated for the adjunctive management lowing menopause, estrone and estrone sulfate are
of hyperemesis gravidarum (Ferreira 2003; Nageotte more highly produced. Estrogens modulate the pitui-
1996); however, use for the treatment of persistent tary secretion of gonadotropins, luteinizing hormone,
symptoms of nausea and vomiting in pregnancy is not and follicle-stimulating hormone through a negative
recommended (ACOG 189 2018). feedback system; estrogen replacement reduces ele-
Dental Health Professional Considerations See vated levels of these hormones in postmenopausal
Local Anesthetic/Vasoconstrictor Precautions women.
Half-life Elimination Drospirenone: ~36-42 hours
Drospirenone and Estradiol Time to Peak Plasma: Drospirenone: 1 hour; Estra-
(droh SPYE re none & es tra DYE ole)
diol: ~2 hours (range 0.3-10 hours)
Related Information Pregnancy Considerations Use is contraindicated in
Estradiol (Systemic) on page 521 pregnant women.
Brand Names: US Angeliq
Brand Names: Canada Angeliq Droxidopa (drox i DOE pa)
Pharmacologic Category Estrogen and Progestin
Combination Brand Names: US Northera
Use Pharmacologic Category Alpha/Beta Agonist
Vasomotor symptoms associated with menopause: Use Neurogenic orthostatic hypotension: Treatment
Treatment of moderate to severe vasomotor symp- of orthostatic dizziness, light-headedness, or the "feel-
toms associated with menopause in women with a ing that you are about to black out" in adults with
uterus. symptomatic neurogenic orthostatic hypotension
Vulvar and vaginal atrophy associated with meno- (NOH) caused by primary autonomic failure (Parkinson
pause: Treatment of moderate to severe vulvar and disease [PD], multiple system atrophy [MSA], and pure
vaginal atrophy due to menopause in women with a autonomic failure [PAF]), dopamine beta-hydroxylase
uterus. deficiency, and nondiabetic autonomic neuropathy.
Limitations of use: When used solely for the treatment Local Anesthetic/Vasoconstrictor Precautions
of vulvar and vaginal atrophy, topical vaginal prod- Droxidopa is converted to norepinephrine in tissues to
ucts should be considered. result in possible hypertension; use vasoconstrictor with
Note: The International Society for the Study of Wom- caution since epinephrine or levonordefrin may
en’s Sexual Health and The North American Meno- increase the hypertensive effects of Droxidopa.
pause Society have endorsed the term genitourinary Effects on Dental Treatment Key adverse event(s)
syndrome of menopause (GSM) as new terminology related to dental treatment: Dizziness, syncope, falling
for vulvovaginal atrophy. The term GSM encom- have all been observed; special precautions should be
passes all genital and urinary signs and symptoms taken when patient suddenly arises from the dental
associated with a loss of estrogen due to menopause chair
Portman 2014. Effects on Bleeding No information available to
No information available to require special precautions Adverse Reactions
Effects on Bleeding No information available to >10%: Central nervous system: Headache (6% to 13%)
require special precautions related to hemostasis in 1% to 10%:
dental procedures. Cardiovascular: Hypertension (2% to 7%)
Adverse Reactions Central nervous system: Dizziness (4% to 10%)
>10%: Gastrointestinal: Nausea (9%)
Genitourinary: Mastalgia (6% to 18%), genital bleed- Postmarketing and/or case reports: Abdominal pain,
ing (3% to 14%) agitation, blurred vision, cerebrovascular accident,
1% to 10%: chest pain, confusion, delirium, diarrhea, fatigue, hal-
Central nervous system: Emotional lability (1%), lucination, hyperpyrexia, hypersensitivity reaction
migraine (≤1%) (including anaphylaxis, angioedema, bronchospasm,
Gastrointestinal: Abdominal pain (≤4% to 7%), gastro- skin rash, urticaria), memory impairment, pancreatitis,
intestinal pain (≤4% to 7%) psychosis, vomiting
Genitourinary: Cervical polyp (≤1%) Mechanism of Action A synthetic amino acid analog
<1%, postmarketing, and/or case reports: Cerebral that is directly metabolized to norepinephrine by dop-
infarction, cerebrovascular accident, embolism, hyper- adecarboxylase. Droxidopa is believed to exert its
sensitivity reaction, malignant neoplasm of breast, pharmacological effects through norepinephrine.
468
DULOXETINE
Norepinephrine increases blood pressure by inducing yawning (≥1% to 2%), abnormal dreams (≥1%),
peripheral arterial and venous vasoconstriction. anorgasmia (≥1%), chills (≥1%), hypoesthesia
Pharmacodynamics/Kinetics (≥1%), lethargy (≥1%), paresthesia (≥1%), rigors
Half-life Elimination ~2.5 hours (≥1%), sleep disorder (≥1%), vertigo (≥1%)
Time to Peak Dermatologic: Diaphoresis (6%), pruritus (≥1%)
Plasma: 1 to 4 hours Endocrine & metabolic: Decreased libido (3%),
Pregnancy Considerations Adverse events have orgasm abnormal (≥1% to 2%), hot flash (≥1%),
been observed in some animal reproduction studies. weight gain (≥1%)
Gastrointestinal: Constipation (9% to 10%; dose
related), decreased appetite (6% to 10%; dose
DULoxetine (doo LOX e teen)
related), vomiting (children and adolescents: 9%;
Related Information adults: 3% to 4%), diarrhea (6% to 9%), dyspepsia
Dentin Hypersensitivity, Acid Erosion, High Caries (2%), dysgeusia (≥1%), flatulence (≥1%)
Index, Management of Alveolar Osteitis, and Xerosto- Genitourinary: Erectile dysfunction (4%), ejaculatory
mia on page 1548 disorder (2%), urinary frequency (≥1%)
Vasoconstrictor Interactions With Antidepressants on Hepatic: Increased serum ALT (>3 x ULN: 1%)
page 1606 Neuromuscular & skeletal: Tremor (2% to 3%; dose
Brand Names: US Cymbalta; Irenka [DSC] related), musculoskeletal pain (≥1%)
Brand Names: Canada Cymbalta; Duloxetine DR Ophthalmic: Blurred vision (≥1% to 3%)
Respiratory: Oropharyngeal pain (children and ado-
Pharmacologic Category Antidepressant, Serotonin/
lescents: 4%; adults: ≥1%), cough (children and
Norepinephrine Reuptake Inhibitor
adolescents: 3%)
Use
Fibromyalgia: Management of fibromyalgia
gait, acute pancreatitis, aggressive behavior (particu-
Generalized anxiety disorder: Treatment of general-
larly early in treatment or after treatment discontinua-
ized anxiety disorder (GAD)
tion), akathisia, anaphylaxis, angioedema, angle-
Major depressive disorder (unipolar): Treatment of
closure glaucoma, apathy, bruxism, cardiomyopathy
unipolar major depressive disorder (MDD)
Musculoskeletal pain, chronic: Management of (takotsubo), cholestatic jaundice, cold extremities,
chronic musculoskeletal pain including osteoarthritis confusion, contact dermatitis, dehydration, diplopia,
of the knee and low back pain disorientation, disturbance in attention, dry eye syn-
Neuropathic pain associated with diabetes mellitus: drome, dysarthria, dyskinesia, dyslipidemia, dyspha-
Management of pain associated with diabetic periph- gia, dysuria, ecchymoses, elevated glycosylated
eral neuropathy hemoglobin (diabetic neuropathic pain), emotional
Local Anesthetic/Vasoconstrictor Precautions lability, epistaxis, eructation, erythema, erythema mul-
Although duloxetine is not a tricyclic antidepressant, it tiforme, extrapyramidal reaction, falling, feeling abnor-
does block norepinephrine reuptake within the CNS m a l , g a l a c t o r r h e a , g a s t r i c u l c e r, g a s t r i t i s ,
synapses as part of its mechanism. It has been sug- gastroenteritis, gastrointestinal hemorrhage, gyneco-
gested that vasoconstrictors be administered with cau- logical bleeding, halitosis, hallucination, hematoma,
tion and to monitor vital signs in dental patients taking hepatic failure, hepatitis, hepatomegaly, hostility,
antidepressants that affect norepinephrine in this way. hyperbilirubinemia, hypercholesterolemia, hyperglyce-
Effects on Dental Treatment Key adverse event(s) mia, hyperkalemia, hyperlipidemia, hyperprolactine-
related to dental treatment: Xerostomia and changes in mia, hypersensitivity angiitis, hypersensitivity
salivation (normal salivary flow resumes upon discon- reaction, hypertensive crisis, hypertonia, hypokalemia,
tinuation). See Effects on Bleeding. hypomania, hyponatremia, hypothyroidism, impulsiv-
Effects on Bleeding Platelet dysfunction (ie, impaired ity, increased blood pressure, increased creatine
platelet aggregation) may occur during treatment with phosphokinase, increased diastolic blood pressure,
serotonin norepinephrine reuptake inhibitors (SNRIs) increased serum alkaline phosphatase, increased
such as duloxetine due to platelet serotonin depletion, serum AST, increased serum bicarbonate, increased
possibly increasing the risk of a bleeding complication. serum transaminases, increased thirst, irritability,
Concurrent NSAID use may increase this risk. jaundice, laryngitis, lymphocytic colitis, malaise, mal-
Adverse Reactions odorous urine, mania, menopausal symptoms, men-
>10%: strual disease, myocardial infarction, muscle spasm,
Central nervous system: Headache (13% to 14%), muscle twitching, myoclonus, night sweats, nocturia,
drowsiness (9% to 11%; dose related), fatigue (7% orthostatic hypotension, otalgia, outbursts of anger
to 11%; dose related) (particularly early in treatment or after treatment dis-
Gastrointestinal: Nausea (18% to 23%), xerostomia continuation), panic attack, petechia, pharyngeal
(adults: 11% to 14%; dose related, children and edema, polyuria, restless leg syndrome, seizure, sen-
adolescents: 2%), abdominal pain (children and ado- sation of cold, serotonin syndrome, sexual disorder,
lescents: 13%, adults: 5%) SIADH, skin photosensitivity, skin rash, Stevens-John-
Endocrine & metabolic: Weight loss (children and son syndrome, stomatitis, suicidal ideation, supraven-
adolescents: 14%, adults: ≥1%) tricular cardiac arrhythmia, syncope, tachycardia,
Neuromuscular & skeletal: Weakness (≤7% to ≤11%; testicular pain, tinnitus, trismus, urinary retention, uri-
dose related) nary urgency, urticaria, visual disturbance
1% to 10%: Mechanism of Action Duloxetine is a potent inhibitor
Cardiovascular: Flushing (3%), increased blood pres- of neuronal serotonin and norepinephrine reuptake and
sure (2%), palpitations (≥1% to 2%) a weak inhibitor of dopamine reuptake. Duloxetine has
Central nervous system: Insomnia (7% to 10%; dose no significant activity for muscarinic cholinergic, H1-
related), dizziness (8% to 9%), agitation (3% to 4%), histaminergic, or alpha2-adrenergic receptors. Duloxe-
anxiety (3%), delayed ejaculation (2%; dose related), tine does not possess MAO-inhibitory activity.
469
DULOXETINE
Pharmacodynamics/Kinetics Effects on Dental Treatment No significant effects or

Half-life Elimination ~12 hours (range: 8 to 17 complications reported
hours); ~4 hours longer in elderly women Effects on Bleeding No information available to
Time to Peak 6 hours; 10 hours when ingested with require special precautions
food Adverse Reactions
Pregnancy Risk Factor C >10%: Local: Injection site reaction (10% to 18%)
Pregnancy Considerations 1% to 10%:
Adverse events have been observed in animal repro- Gastrointestinal: Oral herpes simplex infection (4%)
duction studies. Nonteratogenic effects in the newborn Hematologic & oncologic: Eosinophilia (<2%)
following SSRI/SNRI exposure late in the third trimester Immunologic: Antibody development (6% to 9%; neu-
include respiratory distress, cyanosis, apnea, seizures, tralizing: 2% to 4%)
temperature instability, feeding difficulty, vomiting, hypo- Infection: Herpes simplex infection (2%)
glycemia, hyper- or hypotonia, hyper-reflexia, jitteri- Ophthalmic: Conjunctivitis (10%), eye pruritus (1%)
ness, irritability, constant crying, and tremor. Respiratory: Oropharyngeal pain (2%)
Symptoms may be due to the toxicity of the SNRIs/ <1%, postmarketing, and/or case reports: Anaphylaxis,
SSRIs or a discontinuation syndrome and may be eosinophilic granulomatosis with polyangiitis, eosino-
consistent with serotonin syndrome associated with philic pneumonitis, erythema nodosum, hypersensitiv-
SSRI treatment. The long-term effects of in utero ity reaction, keratitis, serum sickness, serum sickness-
SNRI/SSRI exposure on infant development and like reaction, vasculitis, xerophthalmia
behavior are not known. Mechanism of Action Dupilumab is a human mono-
clonal IgG4 antibody that inhibits interleukin-4 (IL-4)
The ACOG recommends that therapy with SSRIs or
and interleukin-13 (IL-13) signaling by binding to the
SNRIs during pregnancy be individualized; treatment of
IL-4Rα subunit. Blocking IL-4Rα with dupilumab inhibits
depression during pregnancy should incorporate the
IL-4 and IL-13 cytokine-induced inflammatory
clinical expertise of the mental health clinician, obste-
responses, including the release of proinflammatory
trician, primary health care provider, and pediatrician.
cytokines, chemokines, nitric oxide and IgE; however,
According to the American Psychiatric Association
the mechanism of dupilumab action in asthma has not
(APA), the risks of medication treatment should be
been definitively established.
weighed against other treatment options and untreated Pharmacodynamics/Kinetics
depression. For women who discontinue antidepres-
Time to Peak ~1 week
sant medications during pregnancy and who may be
at high risk for postpartum depression, the medications
Dupilumab is a monoclonal IgG antibody; IgG mole-
can be restarted following delivery. Treatment algo-
cules are known to cross the placenta therefore expo-
rithms have been developed by the ACOG and the
sure to the fetus during pregnancy may occur.
APA for the management of depression in women prior
Uncontrolled asthma is associated with adverse events
to conception and during pregnancy.
on pregnancy (increased risk of preeclampsia, preterm
Health care providers are encouraged to enroll women birth, low birth weight infants). Asthma should be
exposed to duloxetine during pregnancy in the Cym- closely monitored in pregnant women.
balta Pregnancy Registry (866-814-6975 or http://
Data collection to monitor pregnancy and infant out-
cymbaltapregnancyregistry.com).
comes following exposure to dupilumab is ongoing. For
Pregnant women exposed to antidepressants during additional information or to enroll pregnancies exposed
pregnancy are encouraged to enroll in the National to dupilumab, contact the registry at 1-877-311-8972 or
Pregnancy Registry for Antidepressants (NPRAD). https://mothertobaby.org/ongoing-study/dupixent/.
Women 18 to 45 years of age or their health care
providers may contact the registry by calling
844-405-6185. Enrollment should be done as early in
Durvalumab (dur VAL ue mab)
pregnancy as possible. Brand Names: US Imfinzi

Brand Names: Canada Imfinzi
Dupilumab (doo PIL ue mab) Pharmacologic Category Antineoplastic Agent, Anti-
PD-L1 Monoclonal Antibody; Antineoplastic Agent,
Brand Names: US Dupixent Monoclonal Antibody
Brand Names: Canada Dupixent Use
Pharmacologic Category Interleukin-4 Receptor Non-small cell lung cancer, unresectable: Treatment
Antagonist; Monoclonal Antibody; Monoclonal Antibody, of unresectable stage III non-small cell lung cancer
Anti-Asthmatic which has not progressed following concurrent plati-
Use num-based chemotherapy and radiation therapy.
Asthma: Add-on maintenance treatment of moderate to Urothelial carcinoma, locally advanced or meta-
severe asthma in adults and pediatric patients ≥12 static: Treatment of locally advanced or metastatic
years of age with an eosinophilic phenotype or with urothelial carcinoma in patients who have disease
corticosteroid dependent asthma progression during or following platinum-containing
Limitations of use: Not indicated for the relief of acute chemotherapy, or disease progression within 12
bronchospasm or status asthmaticus. months of neoadjuvant or adjuvant treatment with
Atopic dermatitis: Treatment of moderate to severe platinum-containing chemotherapy.
atopic dermatitis in adults and pediatric patients ≥12 Local Anesthetic/Vasoconstrictor Precautions
years of age whose disease is not adequately con- No information available to require special precautions
trolled with topical prescription therapies or when Effects on Dental Treatment No significant effects or
those therapies are not advisable. complications reported
470
DUTASTERIDE
Adverse Reactions interactions restores antitumor t-cell function (Fehren-

>10%: bacher 2016; Rosenberg 2016).
Cardiovascular: Peripheral edema (15%) Pharmacodynamics/Kinetics
Central nervous system: Fatigue (34% to 39%) Half-life Elimination Terminal half-life: ~18 days
Dermatologic: Dermatitis (≤26%), skin rash (≤26%; Pregnancy Considerations Adverse events were
including immune-mediated rashes), pruritus (12%) observed in animal reproduction studies. Immunoglo-
Endocrine & metabolic: Hyperglycemia (52%), hypo- bulins are known to cross the placenta and fetal expo-
calcemia (46%), hyponatremia (33%), hyperkalemia sure to durvalumab may be expected. Based on the
(32%), increased gamma-glutamyl transferase mechanism of action, durvalumab may cause fetal
(24%), hypothyroidism (11% to 12%) harm if administered to pregnant women. Females of
Gastrointestinal: Constipation (21%), decreased reproductive potential should use effective contracep-
appetite (19%), colitis (≤18%), diarrhea (≤18%), nau- tion during therapy and for at least 3 months after the
sea (16%), abdominal pain (10% to 14%) last durvalumab dose.
Hematologic & oncologic: Lymphocytopenia (43%; Dutasteride (doo TAS teer ide)
grades 3/4: 11%)
Hepatic: Increased serum ALT (39%), increased Brand Names: US Avodart
serum AST (36%), hepatitis (12%) Brand Names: Canada ACT-Dutasteride; Apo-Dutas-
Infection: Infection (38% to 56%) teride; Avodart; Med-Dutasteride; Mint-Dutasteride;
Neuromuscular & skeletal: Musculoskeletal PMS-Dutasteride; Riva-Dutasteride; Sandoz-Dutaster-
pain (24%) ide; Teva-Dutasteride
Respiratory: Cough (≤40%), productive cough (≤40%), Pharmacologic Category 5 Alpha-Reductase Inhib-
pneumonitis (≤34%), radiation pneumonitis (≤34%), itor
upper respiratory tract infection (26%), pneumonia Use
(17%), dyspnea (≤13%), dyspnea on exer- Benign prostatic hyperplasia: Treatment of sympto-
tion (≤13%) matic benign prostatic hyperplasia (BPH) as mono-
Miscellaneous: Fever (≤15%; including tumor-associ- therapy (to improve symptoms, reduce the risk of
ated fever) acute urinary retention, and to reduce the risk of need
1% to 10%: for BPH-related surgery) or combination therapy with
Central nervous system: Voice disorder (<10%) tamsulosin
Dermatologic: Night sweats (<10%) Limitations of use: Not approved for the prevention of
Endocrine & metabolic: Hyperthyroidism (7%), hyper- prostate cancer.
magnesemia (grades 3/4: 4%), dehydration (grades Local Anesthetic/Vasoconstrictor Precautions
3/4: ≥3%), hypercalcemia (grades 3/4: 3%), hypo- No information available to require special precautions
albuminemia (grades 3/4: 1%), hypokalemia (grades Effects on Dental Treatment No significant effects or
3/4: 1%) complications reported
Genitourinary: Dysuria (<10%) Effects on Bleeding No information available to
Hematologic & oncologic: Anemia (grades 3/4: 8%), require special precautions
neutropenia (grades 3/4: 1%) Adverse Reactions Frequency of most adverse
Hepatic: Increased serum alkaline phosphatase events (except prostate cancer high grade) tends to
(grades 3/4: 4%), hyperbilirubinemia (grades decrease with continued use (>6 months). Frequency
3/4: 1%) not always defined.
Immunologic: Antibody development (3%) 1% to 10%:
Infection: Increased susceptibility to infection (<10%) Endocrine & metabolic: Decreased libido (≤3%; inci-
Renal: Nephritis (6%; immune-mediated), increased dence highest during first 6 months of therapy),
serum creatinine (grades 3/4: 1%) gynecomastia (including breast tenderness, breast
Miscellaneous: Infusion-related reaction (2%) enlargement; ≤1%), increased luteinizing hormone,
Frequency not defined: increased testosterone level, increased thyroid stim-
Endocrine & metabolic: Hypophysitis ulating hormone level
Hepatic: Hepatic injury Genitourinary: Impotence (≤5%; incidence highest
Infection: Sepsis during first 6 months of therapy), ejaculatory disorder
Renal: Acute renal failure (≤2%)
<1%, postmarketing, and/or case reports: Adrenocort- Hematologic & oncologic: Prostate cancer high
ical insufficiency, aseptic meningitis (immune-medi- grade (≤1%)
ated), hemolytic anemia (immune-mediated), <1%, postmarketing, and/or case reports: Angioedema,
immune thrombocytopenia, myocarditis (immune- cardiac failure, depressed mood, dermatological reac-
mediated), myositis (immune-mediated), ocular toxic- tion (serious), dizziness, hypersensitivity, localized
ity (immune-mediated; including uveitis and keratitis), edema, malignant neoplasm of breast (males), pruri-
pituitary insufficiency, thyroiditis, type 1 diabetes mel- tus, skin rash, testicular pain, testicular swelling, urti-
litus, vitiligo caria
Mechanism of Action Durvalumab is a human immu- Mechanism of Action Dutasteride is a 4-azo analog of
noglobulin G1 kappa monoclonal antibody which blocks testosterone and is a competitive, selective inhibitor of
programmed cell death ligand 1 (PD-L1) binding to PD- both reproductive tissues (type 2) and skin and hepatic
1 and CD80 (B7.1); PD-L1 blockade leads to increased (type 1) 5α-reductase. This results in inhibition of the
T-cell activation, allowing T-cells to kill tumor cells conversion of testosterone to dihydrotestosterone and
(Massard 2016). PD-L1 is an immune check point markedly suppresses serum dihydrotestosterone lev-
protein expressed on tumor cells and tumor infiltrating els.
cells and down regulates anti-tumor t-cell function by Pharmacodynamics/Kinetics
binding to PD-1 and B7.1; blocking PD-1 and B7.1 Half-life Elimination Terminal: ~5 weeks
471
DUTASTERIDE
Time to Peak 2-3 hours

Pregnancy Risk Factor X Duvelisib (DOO ve LIS ib)
Pregnancy Considerations Abnormalities of external Brand Names: US Copiktra
male genitalia were reported in animal reproduction
studies. Use is not indicated in women. Pregnant
Phosphatidylinositol 3-Kinase Inhibitor
women are advised to avoid contact with crushed or
Use
broken tablets and the semen from a male partner
Chronic lymphocytic leukemia/small lymphocytic
exposed to dutasteride.
lymphoma, relapsed or refractory: Treatment of
relapsed or refractory chronic lymphocytic leukemia
Dutasteride and Tamsulosin (CLL) or small lymphocytic lymphoma (SLL) in adult
(doo TAS teer ide & tam SOO loe sin) patients after at least 2 prior therapies.
Follicular lymphoma, relapsed or refractory: Treat-
Related Information ment of relapsed or refractory follicular lymphoma (FL)
Dutasteride on page 471 in adult patients after at least 2 prior systemic
Tamsulosin on page 1228 therapies.
Brand Names: US Jalyn Local Anesthetic/Vasoconstrictor Precautions
Brand Names: Canada Jalyn No information available to require special precautions
Pharmacologic Category 5 Alpha-Reductase Inhib- Effects on Dental Treatment Key adverse event(s)
itor; Alpha1 Blocker related to dental treatment: Frequent occurrence of
Use mucositis
Benign prostatic hyperplasia: Treatment of sympto- Effects on Bleeding Chemotherapy may result in
matic benign prostatic hyperplasia (BPH) in men with significant myelosuppression; leukopenia, neutropenia,
an enlarged prostate. and thrombocytopenia are significant (see adverse
Limitations of use: Dutasteride-containing products are reactions); in patients under active treatment with duve-
not approved for the prevention of prostate cancer. lisib, medical consult is suggested.
Effects on Dental Treatment Key adverse event(s) Cardiovascular: Edema (11% to 14%)
related to dental treatment: Tamsulosin: Patients may Central nervous system: Fatigue (25% to 29%), head-
experience orthostatic hypotension as they stand up ache (12%)
after treatment; especially if lying in dental chair for Dermatologic: Skin rash (27% to 31%)
extended periods of time. Use caution with sudden Endocrine & metabolic: Hypophosphatemia (31%),
changes in position during and after dental treatment. hyponatremia (27% to 31%), hyperkalemia (26% to
Effects on Bleeding No information available to 31%), hypoalbuminemia (25% to 31%), hypocalce-
mia (23% to 25%), hypokalemia (10% to 20%),
weight loss (11%)
Adverse Reactions Frequencies reported for when
Gastrointestinal: Colitis (≤57%), diarrhea (≤57%),
products used in combination. Also see individual
increased serum lipase (36% to 37%), increased
agents. serum amylase (28% to 31%), nausea (23% to
1% to 10%: 24%), abdominal pain (16% to 18%), constipation
Central nervous system: Dizziness (2%) (13% to 17%), vomiting (15% to 16%), mucositis
Endocrine & metabolic: Decreased libido (5% to 6%), (14%), decreased appetite (13% to 14%)
breast changes (3% to 5%, including breast hyper- Hematologic & oncologic: Neutropenia (34% to 67%;
trophy, breast swelling, breast tenderness, gyneco- grade ≥3: 30% to 49%; grade 4: 18% to 32%),
mastia, mastalgia, nipple pain, nipple swelling) anemia (20% to 55%; grade ≥3: 11% to 20%),
Genitourinary: Ejaculatory disorder (10% to 11%), thrombocytopenia (17% to 43%; grade ≥3: 10% to
impotence (8% to 10%) 16%; grade 4: 6% to 7%), lymphocytosis (30%;
<1%, postmarketing, and/or case reports: Malignant grade ≥3: 21% to 22%), leukopenia (29%; grade
neoplasm of prostate (high-grade) ≥3: 8%; grade 4: 2%), lymphocytopenia (21%; grade
Mechanism of Action ≥3: 9%; grade 4: 3%)
Dutasteride is a 4-azo analog of testosterone and is a Hepatic: Increased serum alanine aminotransferase
competitive, selective inhibitor of both reproductive (40% to 42%), increased serum aspartate amino-
tissues (type 2) and skin and hepatic (type 1) 5α- transferase (36% to 37%), decreased serum alkaline
reductase. This results in inhibition of the conversion phosphatase (34%), increased serum alkaline phos-
of testosterone to dihydrotestosterone and markedly phatase (27% to 29%), increased serum transami-
suppresses serum dihydrotestosterone levels. nases (11% to 15%)
Infection: Sepsis (≤58%), serious infection (31%)
Tamsulosin is an antagonist of alpha1A-adrenoreceptors Neuromuscular & skeletal: Musculoskeletal pain (17%
in the prostate. Smooth muscle tone in the prostate is to 20%)
mediated by alpha1A-adrenoreceptors; blocking them Renal: Renal insufficiency (≤58%), increased serum
leads to relaxation of smooth muscle in the bladder creatinine (24% to 29%)
neck and prostate, causing an improvement of urine Respiratory: Upper respiratory tract infection (21% to
flow and decreased symptoms of BPH. Approximately 28%), pneumonia (21% to 27%), cough (23% to
75% of the alpha1-receptors in the prostate are of the 25%), lower respiratory tract infection (10% to
alpha1Asubtype. 18%), dyspnea (12%)
Pregnancy Risk Factor X Miscellaneous: Fever (26% to 29%)
Pregnancy Considerations Use contraindicated in 1% to 10%:
pregnancy. Not indicated for use in women. See indi- Dermatologic: Dermatological reaction (5%)
vidual agents. Infection: Cytomegalovirus disease (1%)
472
EDOXABAN
Neuromuscular & skeletal: Arthralgia (10%) manufacturer recommends avoiding use during preg-
Respiratory: Pneumonitis (5%), pneumonia due to nancy, especially during the first trimester.
Pneumocystis jiroveci (1%)
Mechanism of Action Duvelisib is an oral PI3K inhib- Edaravone (e DAR a vone)
itor with dual inhibitory activity primarily against PI3K-δ
and PI3K-γ which are expressed in hematologic malig- Brand Names: US Radicava
nancies. Inhibition of PI3K-δ reduced tumor cell prolif- Pharmacologic Category Free Radical Scavenger
eration while allowing survival of normal cells. Inhibition Use Amyotrophic lateral sclerosis: Treatment of
of PI3K-γ reduces differentiation and migration of tumor amyotrophic lateral sclerosis (ALS)
microenvironment support cells (Flinn 2018). Duvelisib Local Anesthetic/Vasoconstrictor Precautions
resulted in reduced viability of cell lines derived from No information available to require special precautions
malignant B-cells and CLL cells. Additionally, duvelisib Effects on Dental Treatment No significant effects or
inhibits B-cell receptor signaling pathways and complications reported
CXCR12-mediated chemotaxis of malignant B-cells as Effects on Bleeding No information available to
well as CXCL12-induced T cell migration and M-CSF require special precautions
and IL-4 driven M2 macrophage polarization. Adverse Reactions
Pharmacodynamics/Kinetics >10%:
Half-life Elimination 4.7 hours Central nervous system: Abnormal gait (13%)
Time to Peak 1 to 2 hours Hematologic & oncologic: Bruise (15%)
Pregnancy Considerations 1% to 10%:
Based on the mechanism of action and adverse events Central nervous system: Headache (10%)
observed in animal reproduction studies, fetal harm Dermatologic: Dermatitis (8%), eczema (7%),
may occur if administered to a pregnant female. tinea (4%)
Pregnancy status should be evaluated prior to treat- Endocrine & metabolic: Glycosuria (4%)
ment. Females of reproductive potential, and males Respiratory: Dyspnea (≤6%), hypoxia (≤6%), respira-
with female partners of reproductive potential, should tory failure (≤6%)
use effective contraception during therapy and for at
hypersensitivity reaction
least 1 month after the last duvelisib dose. Male fertility
may be impaired by duvelisib treatment (based in Mechanism of Action The mechanism by which edar-
animal studies). avone slows the decline of physical function in patients
with ALS is unknown. Edaravone is a free radical and
peroxynitrite scavenger that prevents oxidative damage
Econazole (e KONE a zole) to cell membranes and may contribute to inhibiting the
progression of ALS (Nagase 2016).
Brand Names: US Ecoza Pharmacodynamics/Kinetics
Pharmacologic Category Antifungal Agent, Imida- Half-life Elimination 4.5 to 6 hours
zole Derivative; Antifungal Agent, Topical Time to Peak 1 hour
Use Fungal infection: Pregnancy Considerations Adverse events were
Cream: Treatment of tinea pedis, tinea cruris, and tinea observed in some animal reproduction studies.
corporis caused by Trichophyton rubrum, Trichophy-
ton mentagrophytes, Trichophyton tonsurans, Micro-
sporum canis, Microsporum audouini, Microsporum Edoxaban (e DOX a ban)
gypseum, and Epidermophyton floccosum in the treat-
Related Information
ment of cutaneous candidiasis, and in the treatment of
tinea versicolor.
tistry on page 1454
Foam: Treatment of interdigital tinea pedis caused by
Brand Names: US Savaysa
Trichophyton rubrum, Trichophyton mentagrophytes,
and Epidermophyton floccosum in patients 12 years Brand Names: Canada Lixiana
and older Pharmacologic Category Anticoagulant; Anticoagu-
Local Anesthetic/Vasoconstrictor Precautions lant, Factor Xa Inhibitor; Direct Oral Anticoagulant
No information available to require special precautions (DOAC)
Effects on Dental Treatment No significant effects or Use
Nonvalvular atrial fibrillation: To reduce the risk of
stroke and systemic embolism in patients with non-
valvular atrial fibrillation (AF)
Limitations of use: Do not use in nonvalvular AF
Adverse Reactions patients with CrCl >95 mL/minute because of an
1% to 10%: Dermatologic: Burning sensation of skin increased risk of ischemic stroke compared to war-
(3%), erythema (3%), pruritus (3%), stinging of the farin.
skin (3%) Venous thromboembolism (deep vein thrombosis
<1%, postmarketing, and/or case reports: Application and pulmonary embolism): Treatment of deep vein
site reaction, pruritic rash thrombosis (DVT) and pulmonary embolism (PE) fol-
Mechanism of Action Alters fungal cell wall mem- lowing 5 to 10 days of initial therapy with a parenteral
brane permeability; may interfere with RNA and protein anticoagulant
synthesis, and lipid metabolism Note: A recent open-label randomized trial in cancer
Pharmacodynamics/Kinetics patients with VTE comparing edoxaban (initiated
Time to Peak Foam: 6.8 ± 5.1 hours after at least 5 days of treatment with a low-molec-
Pregnancy Risk Factor C ular-weight heparin [LMWH]) to dalteparin showed
Pregnancy Considerations Adverse events were noninferiority for VTE recurrence. Although there
observed in some animal reproduction studies. The was an increased rate of major bleeding with
473
EDOXABAN
edoxaban, this was mostly observed in patients with

gastrointestinal cancer (Raskob 2017). With the Efavirenz (e FAV e renz)
exception of gastrointestinal cancer, either LMWH
or edoxaban is preferred first-line long-term antico- Related Information
agulant therapy for treatment of VTE in cancer HIV Infection and AIDS on page 1477
patients (Bauer 2018). Brand Names: US Sustiva
Local Anesthetic/Vasoconstrictor Precautions Brand Names: Canada Sustiva
No information available to require special precautions Pharmacologic Category Antiretroviral, Reverse
Effects on Dental Treatment Key adverse event(s) Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)
related to dental treatment: Surgical site bleeding may Use HIV-1 infection: Treatment of HIV-1 infection in
occur. See effects on bleeding. combination with other antiretroviral agents in adults
Effects on Bleeding Edoxaban inhibits platelet activa- and pediatric patients at least 3 months old and weigh-
tion and fibrin clot formation via direct, selective, and ing at least 3.5 kg
reversible inhibition of factor Xa. As with all anticoagu- Local Anesthetic/Vasoconstrictor Precautions
lants, bleeding is the major adverse effect of edoxaban. No information available to require special precautions
Hemorrhage may occur at virtually any site; risk is Effects on Dental Treatment Key adverse event(s)
dependent on multiple variables including the intensity related to dental treatment: Abnormal taste
of anticoagulation and patient susceptibility. Medical Effects on Bleeding No information available to
consult is suggested. require special precautions related to hemostasis.
Adverse Reactions Adverse Reactions Unless otherwise noted, fre-
>10%: quency of adverse events is as reported for patients
Hematologic and oncologic: Hemorrhage (22%) receiving combination antiretroviral therapy.
1% to 10%: >10%:
Dermatologic: Dermal hemorrhage (6%), skin Central nervous system: Dizziness (2% to 28%),
rash (4%) depression (≤19%; severe: 2%), insomnia (≤16%),
Gastrointestinal: Gastrointestinal hemorrhage (4%), anxiety (2% to 13%), pain (1% to 13%), headache
lower GI bleeding (3%) (2% to 8%)
Genitourinary: Vaginal hemorrhage (9%), gross hem- Dermatologic: Skin rash (5% to 32%)
aturia (≤2%), urethral bleeding (≤2%) Endocrine & metabolic: Increased serum cholesterol
Hematologic and oncologic: Major hemorrhage, non- (20% to 40%), increased HDL cholesterol (25% to
life-threatening (7% to 9%; noncritical organ: 1%; 35%), increased serum triglycerides (≥751 mg/dL:
critical organ: <1%), major hemorrhage (1%), oral 6% to 11%)
hemorrhage (≤3%), anemia (2%), decreased hemo- Gastrointestinal: Diarrhea (3% to 14%), nausea (2% to
globin (≥ 2 g/dL: 1%), puncture site bleeding (1%) 10%), vomiting (3% to 6%)
Hepatic: Abnormal hepatic function tests (5% to 8%) 1% to 10%:
Respiratory: Epistaxis (5%), pharyngeal bleed- Central nervous system: Fatigue (≤8%), lack of con-
ing (≤3%) centration (≤8%), drowsiness (≤7%), nervousness
<1%, postmarketing, and/or case reports: Hemorrha- (≤7%), abnormal dreams (1% to 6%), hallucina-
gic stroke, interstitial pulmonary disease (con- tion (1%)
founded by concomitant amiodarone therapy and Dermatologic: Pruritus (≤9%), erythema multi-
infectious pneumonia), intracranial hemorrhage forme (≤2%)
(includes epidural hematoma, nonhemorrhagic Endocrine & metabolic: Increased gamma-glutamyl
stroke with major hemorrhagic conversion, primary transferase (≤8%), increased amylase (grades 3/4:
hemorrhagic stroke, subarachnoid hemorrhage, sub- ≤6%), hyperglycemia (>250 mg/dL: 2% to 5%)
dural hematoma) Gastrointestinal: Dyspepsia (≤4%), abdominal pain
Mechanism of Action Edoxaban, a selective factor Xa (2% to 3%), anorexia (≤2%)
inhibitor, inhibits free factor Xa and prothrombinase Hematologic & oncologic: Neutropenia (grades 3/4:
activity and inhibits thrombin-induced platelet aggrega- 2% to 10%)
tion. Inhibition of factor Xa in the coagulation cascade Hepatic: Increased serum AST (grades 3/4: 5% to 8%;
reduces thrombin generation and thrombus formation. incidence higher with hepatitis B and/or C coinfec-
Pharmacodynamics/Kinetics tion), increased serum ALT (grades 3/4: 2% to 8%;
Half-life Elimination 10 to 14 hours incidence higher with hepatitis B and/or C coin-
Time to Peak 1 to 2 hours fection)
Pregnancy Considerations Ten pregnancies were <1%, postmarketing, and/or case reports: Aggressive
reported in a study using edoxaban for the treatment behavior, agitation, arthralgia, ataxia, catatonia, cer-
of DVT or PE. Estimated exposure occurred during the ebellar ataxia, constipation, delusions, dyspnea, emo-
first trimester with duration of exposure ~6 weeks; out- t i o na l l a bi l i t y, f l u s h in g , f u l m i n a n t h e p a ti t i s ,
comes included six live births (two preterm), one first gynecomastia, hepatic failure, hepatitis, hypersensitiv-
trimester spontaneous abortion, and three elective ter- ity reaction, hypoesthesia, immune reconstitution syn-
minations of pregnancy (Burnett 2016). Data are insuf- drome, lipotrophy, loss of balance, malabsorption,
ficient to evaluate the safety of oral factor Xa inhibitors mania, myalgia, myopathy, neuropathy, palpitations,
during pregnancy; use in pregnant women should be pancreatitis, paranoia, paresthesia, photodermatitis,
avoided (Bates 2012; Burnett 2016). psychoneurosis, psychosis, redistribution of body fat,
Dental Health Professional Considerations Rou- seizure, Stevens-Johnson syndrome, suicidal idea-
tine coagulation testing (INR) is not required, or neces- tion, tinnitus, tremor, vertigo, visual disturbance,
sary, for Direct-Acting Oral Anticoagulants (DOAC). weakness
474
EFAVIRENZ, EMTRICITABINE, AND TENOFOVIR DISOPROXIL FUMARATE
Mechanism of Action As a non-nucleoside reverse postpartum for all females living with HIV and can be
transcriptase inhibitor, efavirenz has activity against modified after delivery.
HIV-1 by binding to reverse transcriptase. It conse- The manufacturer recommends women of reproductive
quently blocks the RNA-dependent and DNA-depend- potential undergo pregnancy testing prior to initiation of
ent DNA polymerase activities including HIV-1 efavirenz. Barrier contraception should be used in
replication. It does not require intracellular phosphor- combination with other (hormonal) methods of contra-
ylation for antiviral activity. ception during therapy and for 12 weeks after efavirenz
Pharmacodynamics/Kinetics is discontinued. However, current HHS Perinatal HIV
Half-life Elimination Single dose: 52 to 76 hours; Guidelines do not restrict use in females planning a
Multiple doses: 40 to 55 hours pregnancy.
Pregnancy Considerations Health care providers are encouraged to enroll preg-
Efavirenz has a moderate level of transfer across the nant females exposed to antiretroviral medications as
human placenta. early in pregnancy as possible in the Antiretroviral
Based on data from the Antiretroviral Pregnancy Regis- APRegistry.com). Health care providers caring for
try, an increased risk of overall birth defects has not HIV-infected females and their infants may contact the
been observed following first trimester exposure to National Perinatal HIV Hotline (888-448-8765) for clin-
efavirenz. Neural tube and other CNS defects have ical consultation (HHS [perinatal] 2018).
been reported; however, a meta-analysis has shown Prescribing and Access Restrictions Efavirenz oral
that the risk for neural tube defects after efavirenz solution is available only through an expanded access
exposure in the first trimester are not greater than those (compassionate use) program. Enrollment information
in the general population. Maternal antiretroviral ther- may be obtained by calling 877-372-7097.
apy (ART) may increase the risk of preterm delivery,
due to variability of maternal factors (disease severity; Efavirenz, Emtricitabine, and Tenofovir
gestational age at initiation of therapy). An increased Disoproxil Fumarate
risk of stillbirth, low birth weight, and small for gesta- (e FAV e renz, em trye SYE ta been, & ten OF oh vir dye soe PROX il
FUE ma rate)
tional age infants has been observed in some but not all
studies. Because there is clear benefit to appropriate Related Information
treatment, maternal ART should not be withheld due to Efavirenz on page 474
concerns for adverse neonatal outcomes. Long-term Emtricitabine on page 484
follow-up is recommended for all infants exposed to
antiretroviral medications; children who develop signifi-
Tenofovir Disoproxil Fumarate on page 1238
cant organ system abnormalities of unknown etiology
(particularly of the CNS or heart) should be evaluated
Brand Names: US Atripla
for potential mitochondrial dysfunction. Hypersensitivity Brand Names: Canada Atripla
reactions (including hepatic toxicity and rash) are more Pharmacologic Category Antiretroviral, Reverse
common in women on NNRTI therapy; it is not known if Transcriptase Inhibitor, Non-nucleoside (Anti-HIV); Anti-
pregnancy increases this risk. retroviral, Reverse Transcriptase Inhibitor, Nucleoside
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhib-
The Health and Human Services (HHS) Perinatal HIV itor, Nucleotide (Anti-HIV)
Guidelines consider efavirenz an alternative ART for Use HIV-1 infection: Treatment of HIV-1 infection in
HIV-infected pregnant females who are antiretroviral- adult and pediatric patients weighing ≥40 kg (may be
naive, who have had ART therapy in the past but are used alone or in combination with other antiretroviral
restarting, who require a new ART regimen (due to poor agents)
tolerance or poor virologic response of current regi- Local Anesthetic/Vasoconstrictor Precautions
men), and who are not yet pregnant but are trying to No information available to require special precautions
conceive. Females who become pregnant while taking Effects on Dental Treatment Key adverse event(s)
efavirenz may continue if viral suppression is effective related to dental treatment: Efavirenz alone has caused
and the regimen is well tolerated. Pharmacokinetic data xerostomia (normal salivary flow resumes upon discon-
from available studies do not suggest dose alterations tinuation) and abnormal taste (see individual mono-
are needed during pregnancy. graph). No significant effects or complications
Use may be considered for females having drug inter- reported with combination drug.
actions with other medications or who require the Effects on Bleeding No information available to
convenience of once daily dosing (and are not eligible require special precautions related to hemostasis.
for dolutegravir or rilpivirine); screening for antenatal Adverse Reactions Frequency not always defined.
and postpartum depression is recommended. Although The complete adverse reaction profile of combination
not recommended by the manufacturer, HHS guidelines therapy has not been established. See individual
do not restrict the use of efavirenz in the first trimester. If agents. The following adverse effects were noted in
an efavirenz-containing regimen must be discontinued clinical trials with combination therapy.
for more than a few days due to toxicity, consider >10%: Endocrine & metabolic: Hypercholesterole-
evaluating for rebound viremia and drug resistance; mia (22%)
consult current guidelines. 1% to 10%:
Central nervous system: Depression (9%), fatigue
In general, ART is recommended for all pregnant (9%), dizziness (8%), headache (6%), anxiety (5%),
females with HIV to keep the viral load below the limit insomnia (5%), drowsiness (4%), abnormal dreams
of detection and reduce the risk of perinatal trans- Dermatologic: Skin rash (7%)
mission. Monitoring during pregnancy is more frequent Endocrine & metabolic: Increased serum triglycerides
than in non-pregnant adults. ART should be continued (4%), hyperglycemia (2%)
475
EFAVIRENZ, EMTRICITABINE, AND TENOFOVIR DISOPROXIL FUMARATE
Gastrointestinal: Diarrhea (9%), nausea (9%), Effects on Bleeding No information available to

increased serum amylase (8%), vomiting (2%) require special precautions
Genitourinary: Hematuria (3%) Adverse Reactions Also see individual agents.
Hematologic & oncologic: Neutropenia (3%) >10%:
Hepatic: Increased serum AST (3%), increased serum Central nervous system: Headache (14%), pain
ALT (2%), increased serum alkaline phospha- (13%), depression (11%)
tase (1%) Dermatologic: Skin rash (18%)
Neuromuscular & skeletal: Increased creatine phos- Endocrine & metabolic: Increased serum cholesterol
phokinase (9%) (grades 3/4: 19%)
Respiratory: Sinusitis (8%), upper respiratory tract Gastrointestinal: Diarrhea (11%)
infection (8%), nasopharyngitis (5%) Neuromuscular & skeletal: Decreased bone mineral
<1%, postmarketing, and/or case reports: Glycosuria density (28%), increased creatine phosphokinase
Mechanism of Action (grades 3/4: 12%)
Efavirenz: Non-nucleoside reverse transcriptase inhib- 1% to 10%:
itor of HIV-1. It consequently blocks the RNA-depend- Central nervous system: Anxiety (6%), insomnia (5%),
ent and DNA-dependent DNA polymerase activities dizziness (3%), peripheral neuropathy (1%)
including HIV-1 replication. Endocrine & metabolic: Increased amylase (grades
Emtricitabine: Nucleoside reverse transcriptase inhibi- 3/4: 9%), increased serum triglycerides (grades 3/4:
tor; cytosine analogue that is phosphorylated intra- 1%), lipodystrophy (1%)
cellularly to emtricitabine 5'-triphosphate which Gastrointestinal: Nausea (8%), abdominal pain (7%),
interferes with HIV viral RNA dependent DNA poly- vomiting (5%), dyspepsia (4%)
merase resulting in inhibition of viral replication. Genitourinary: Hematuria (grades 3/4: 7%)
Tenofovir disoproxil fumarate: Nucleotide reverse tran- Hematologic & oncologic: Decreased neutrophils
scriptase inhibitor; analog of adenosine 5'-monophos- (grades 3/4: 3%)
phate that interferes with the HIV viral RNA dependent Hepatic: Increased serum AST (grades 3/4: 5%),
DNA polymerase resulting in inhibition of viral repli- increased serum ALT (grades 3/4: 4%)
cation. TDF is first converted intracellularly by hydrol- Neuromuscular & skeletal: Back pain (9%), weakness
ysis to tenofovir and subsequently phosphorylated to (6%), arthralgia (5%), myalgia (3%)
the active tenofovir diphosphate. Tenofovir inhibits Respiratory: Pneumonia (5%)
replication of HBV by inhibiting HBV polymerase. Miscellaneous: Fever (8%)
Pregnancy Considerations Mechanism of Action
The Health and Human Services (HHS) Perinatal HIV Efavirenz: Non-nucleoside reverse transcriptase inhib-
Guidelines consider this fixed-dose combination an itor of HIV-1. It consequently blocks the RNA-depend-
alternative regimen for HIV-infected pregnant females ent and DNA-dependent DNA polymerase activities
who are antiretroviral-naive, who have had antiretroviral including HIV-1 replication.
therapy (ART) in the past but are restarting, who require Lamivudine: Cytosine analog that is phosphorylated
a new ART regimen (due to poor tolerance or poor intracellularly to its active 5"-triphosphate metabolite.
virologic response of current regimen), and who are The principle mode of action is inhibition of HIV
not yet pregnant but are trying to conceive. In addition, reverse transcription via viral DNA chain termination;
females who become pregnant while taking this fixed- inhibits RNA- and DNA-dependent DNA polymerase
dose combination may continue if viral suppression is activities of reverse transcriptase.
effective and the regimen is well tolerated (HHS [peri- Tenofovir disoproxil fumarate: Nucleotide reverse tran-
natal] 2018). scriptase inhibitor; analog of adenosine 5' monophos-
The manufacturer's labeling recommends pregnancy phate that interferes with the HIV viral RNA dependent
testing prior to therapy, and effective contraception in DNA polymerase resulting in inhibition of viral repli-
females of reproductive potential during treatment and cation. TDF is first converted intracellularly by hydrol-
for 12 weeks after therapy is discontinued. ysis to tenofovir and subsequently phosphorylated to
the active tenofovir diphosphate. Tenofovir inhibits
Refer to individual monographs for additional infor- replication of HBV by inhibiting HBV polymerase.
mation. Pregnancy Considerations
Efavirenz, Lamivudine, and Tenofovir Guidelines consider this fixed-dose combination an
alternative regimen for HIV-infected pregnant females
Disoproxil Fumarate who are antiretroviral-naive, who have had antiretroviral
(e FAV e renz la MI vyoo deen & ten OF oh vir dye soe PROX il FUE
ma rate) therapy (ART) in the past but are restarting, who require
a new ART regimen (due to poor tolerance or poor
Brand Names: US Symfi; Symfi Lo virologic response of current regimen), and who are
Pharmacologic Category Antiretroviral, Reverse not yet pregnant but are trying to conceive. In addition,
Transcriptase Inhibitor, Non-nucleoside (Anti-HIV); Anti- females who become pregnant while taking this fixed-
retroviral, Reverse Transcriptase Inhibitor, Nucleoside dose combination may continue if viral suppression is
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhib- effective and the regimen is well tolerated (HHS [peri-
itor, Nucleotide (Anti-HIV) natal] 2018).
Use HIV-1 infection: Treatment of HIV-1 infection in
The manufacturer's labeling recommends pregnancy
adult and pediatric patients weighing ≥40 kg (Symfi)
or ≥35 kg (Symfi Lo) testing prior to therapy and effective contraception in
females of reproductive potential during treatment and
for 12 weeks after therapy is discontinued.
Effects on Dental Treatment No significant effects or Refer to individual monographs for additional infor-
complications reported mation.
476
ELBASVIR AND GRAZOPREVIR

Efinaconazole (ef in a KON a zole) Endocrine & metabolic: Increased HDL cholesterol,
increased LDL cholesterol, increased serum choles-
Brand Names: US Jublia terol, increased triglycerides
Brand Names: Canada Jublia Genitourinary: Menstrual flow (reduction in the
Pharmacologic Category Antifungal Agent, Topical amount, intensity, or duration of menstrual bleeding)
Use Onychomycosis: Topical treatment of onychomy- <1%, postmarketing, and/or case reports: Appendicitis,
cosis of the toenail(s) due to Trichophyton rubrum and back pain, suicidal ideation
Trichophyton mentagrophytes Mechanism of Action Elagolix is a short-acting, non-
Local Anesthetic/Vasoconstrictor Precautions peptide, gonadotropin-releasing hormone antagonist
No information available to require special precautions that suppresses pituitary and ovarian hormone function
Effects on Dental Treatment No significant effects or in a dose-dependent manner. Concentrations of LH,
complications reported FSH, and estradiol are decreased during therapy and
Effects on Bleeding No information available to rapidly return to previous levels once treatment is
require special precautions discontinued. In patients with endometriosis, these
Adverse Reactions 1% to 10%: actions reduce dysmenorrhea and nonmenstrual pelvic
Dermatologic: Ingrown nail (2%) pain (Ng 2017; Struthers 2009; Taylor 2017).
Local: Application site dermatitis (2%), application site Pharmacodynamics/Kinetics
vesicles (2%), application site pain (1%) Onset of Action FSH, LH, and estradiol suppression:
Mechanism of Action An azole antifungal; inhibits Within hours of day 1 (initial) administration (Ng 2017)
fungal lanosterol 14alpha-demethylase involved in the Duration of Action FSH, LH, and estradiol concen-
biosynthesis of ergosterol, a constituent of fungal cell trations return to baseline or higher within 24 to 48
membranes, resulting in fungal cell death. hours after discontinuation (Ng 2017)
Pharmacodynamics/Kinetics Half-life Elimination 4 to 6 hours
Half-life Elimination 29.9 hours. Time to Peak 1 hour
Pregnancy Risk Factor C Pregnancy Considerations
Pregnancy Considerations Adverse events were Use is contraindicated during pregnancy.
observed in some animal reproduction studies following Information related to inadvertent exposure in preg-
SubQ administration. Small amounts of efinaconazole nancy is limited. Elagolix may increase the risk of early
are absorbed systemically following topical administra- pregnancy loss. Pregnancy should be ruled out prior to
tion. treatment and if suspected during elagolix therapy;
discontinue elagolix if pregnancy occurs.
Elagolix (EL a GOE lix) Ovulation is not fully suppressed during elagolix therapy
(Taylor 2017). Nonhormonal contraceptives should be
Brand Names: US Orilissa used during therapy and for 1 week after elagolix treat-
Brand Names: Canada Orilissa ment is discontinued.
Pharmacologic Category Gonadotropin Releasing
Hormone Antagonist
Use Endometriosis: Management of moderate to Elbasvir and Grazoprevir
(ELB as vir & graz OH pre vir)
severe pain associated with endometriosis.
Local Anesthetic/Vasoconstrictor Precautions Brand Names: US Zepatier
No information available to require special precautions Brand Names: Canada Zepatier
Effects on Dental Treatment No significant effects or Pharmacologic Category Antihepaciviral, NS3/4A
complications reported Protease Inhibitor (Anti-HCV); Antihepaciviral, NS5A
Effects on Bleeding No information available to Inhibitor; NS3/4A Inhibitor; NS5A Inhibitor
require special precautions Use Chronic hepatitis C: Treatment of chronic hepatitis
Adverse Reactions C virus (HCV) genotype 1 or 4 infection in adults; used
>10%: with ribavirin in certain patient populations.
Central nervous system: Headache (17% to 20%) Local Anesthetic/Vasoconstrictor Precautions
Dermatologic: Night sweats (≤46%) No information available to require special precautions
Endocrine & metabolic: Amenorrhea (4% to 57%), hot Effects on Dental Treatment Key adverse event(s)
flash (≤46%) related to dental treatment: Xerostomia; normal salivary
Gastrointestinal: Nausea (16%) flow resumes upon discontinuation
Neuromuscular & skeletal: Decreased bone mineral Effects on Bleeding No information available to
density (≤21%) require special precautions
1% to 10%: Adverse Reactions
Central nervous system: Insomnia (6% to 9%), >10%:
depressed mood (≤6%), depression (≤6%), emo- Central nervous system: Fatigue (11%), headache
tional lability (≤6%), lacrimation (≤6%; including tear- (10% to 11%)
fulness), mood changes (≤6%), anxiety (5%), Gastrointestinal: Nausea (11%)
dizziness (≥3% to <5%), irritability (≥3% to <5%) 1% to 10%: Hepatic: Increased serum alanine amino-
Endocrine & metabolic: Decreased libido (≥3% to transferase (1% to 2%)
<5%), weight gain (≥3% to <5%) <1%, postmarketing, and/or case reports: Angioedema,
Gastrointestinal: Abdominal pain (≥3% to <5%), con- decreased hemoglobin, increased serum bilirubin,
stipation (≥3% to <5%), diarrhea (≥3% to <5%) reactivation of HBV
Hepatic: Increased serum alanine aminotransferase Mechanism of Action
(≥3 x ULN: 1%) Elbasvir is an inhibitor of HCV NS5A, which is essential
Neuromuscular & skeletal: Arthralgia (5%) for viral replication and virion assembly.
477
ELBASVIR AND GRAZOPREVIR
Grazoprevir is an inhibitor of HCV NS3/4A protease, anemia, angina pectoris, angioedema, aphasia,
necessary for the proteolytic cleavage of the HCV- ataxia, cardiac arrhythmia, confusion, constipation,
encoded polyprotein (into mature forms of the NS3, depersonalization, depression, diarrhea, diplopia, dys-
NS4A, NS4B, NS5A, and NS5B proteins) and is geusia, dyspnea, dystonia, edema, emotional lability,
essential for viral replication. esophagitis, euphoria, gingivitis, hallucination, hyper-
Pharmacodynamics/Kinetics esthesia, hyperglycemia, hyperkinesia, hypersensitiv-
Half-life Elimination Elbasvir: ~24 hours; Grazopre- ity reaction, hypertension, impotence, increased
vir: ~31 hours creatine phosphokinase, insomnia, ischemic colitis,
Time to Peak Elbasvir: Median: 3 hours (range: 3 to 6 lacrimation, manic behavior, myalgia, myasthenia,
hours); Grazoprevir: Median: 2 hours (range: 30 myocardial infarction, nervousness, paralysis, periph-
minutes to 3 hours) eral edema, peripheral vascular disorder, photopho-
Pregnancy Considerations bia, polyuria, Prinzmetal angina, pruritus, purpura,
Adverse events have not been observed in animal seizure, sensation of pressure (chest/neck/throat/
reproduction studies. jaw), shock, sialorrhea, skin discoloration, skin rash,
Treatment of hepatitis C is not currently recommended speech disturbance, stupor, syncope, tachycardia,
to treat maternal infection or to decrease the risk of thrombophlebitis, tinnitus, tongue edema, tremor,
mother-to-child transmission during pregnancy (Tran twitching, urinary frequency, urticaria, vasospasm,
2016). HCV-infected females of childbearing potential ventricular fibrillation, visual disturbance, vomiting
should consider postponing pregnancy until therapy is Mechanism of Action Selective agonist for serotonin
complete to reduce the risk of HCV transmission (5-HT1B, 5-HT1D, and 5-HT1F receptors) in cranial
(AASLD/IDSA 2017). When HCV infection is detected arteries; causes vasoconstriction and reduces sterile
during pregnancy, treatment should be deferred until inflammation associated with antidromic neuronal trans-
after delivery. Direct-acting antiviral medications should mission correlating with relief of migraine
not be used in pregnant females outside of clinical trials Pharmacodynamics/Kinetics
until safety and efficacy information is available (SMFM Half-life Elimination ~4 hours (Elderly: 4.4 to 5.7
[Hughes 2017]). hours); Metabolite: ~13 hours
Time to Peak Plasma: 1.5 to 2 hours
If used in combination with ribavirin, all warnings related Pregnancy Risk Factor C
to the use of ribavirin and pregnancy and/or contra-
ception should be followed. Refer to the ribavirin mono-
observed in animal reproduction studies. Information
graph for additional information.
related to eletriptan use in pregnancy is limited (Källén
2011; Nezvalová-Henriksen, 2010; Nezvalová-Henrik-
Eletriptan (el e TRIP tan) sen 2012). Until additional information is available,
other agents are preferred for the initial treatment of
Related Information migraine in pregnancy (Da Silva 2012; MacGregor
Temporomandibular Dysfunction (TMD), Chronic Pain, 2012; Williams 2012).
Brand Names: US Relpax
Brand Names: Canada Relpax® Eliglustat (el i GLOO stat)
Pharmacologic Category Antimigraine Agent; Sero- Brand Names: US Cerdelga
tonin 5-HT1B, 1D Receptor Agonist
Brand Names: Canada Cerdelga
Use Migraines: Acute treatment of migraine, with or
Pharmacologic Category Enzyme Inhibitor; Gluco-
without aura in adults
sylceramide Synthase Inhibitor
Use
Gaucher disease: Treatment of adult patients with
Gaucher disease type 1 (GD1) who are CYP2D6
extensive metabolizers (EMs), intermediate metabo-
lizers (IMs), or poor metabolizers (PMs).
Limitations of use: Patients who are CYP2D6 ultra-rapid
metabolizers (URMs) may not achieve adequate con-
Adverse Reactions
centrations of eliglustat to achieve a therapeutic effect.
1% to 10%:
A specific dosage cannot be recommended for those
Cardiovascular: Chest pain (2% to 4%; chest tight-
patients whose CYP2D6 genotype cannot be deter-
ness, pain, and pressure), palpitations
mined (indeterminate metabolizers).
Central nervous system: Dizziness (6% to 7%), drows-
iness (6% to 7%), headache (4%), paresthesia (3% Local Anesthetic/Vasoconstrictor Precautions
to 4%), chills, hypertonia, hypoesthesia, pain, vertigo No information available to require special precautions
Dermatologic: Diaphoresis Effects on Dental Treatment Key adverse event(s)
Gastrointestinal: Nausea (8%), xerostomia (3% to related to dental treatment: Oropharyngeal pain has
4%), abdominal pain (2%; pain, discomfort, stomach been reported in up to 10% of patients receiving the
pain, cramps, and pressure), dyspepsia (2%), dys- drug
phagia (1% to 2%) Effects on Bleeding No information available to
Neuromuscular & skeletal: Weakness (4% to 10%), require special precautions
back pain Adverse Reactions
Respiratory: Pharyngitis >10%:
<1%, postmarketing, and/or case reports (limited to Central nervous system: Headache (13% to 40%),
important or life-threatening): Abnormal dreams, fatigue (14%)
abnormal hepatic function tests, agitation, alopecia, Gastrointestinal: Diarrhea (12%), nausea (10%
amnesia, anaphylactoid reaction, anaphylaxis, to 12%)
478
ELOTUZUMAB
Neuromuscular & skeletal: Arthralgia (45%), back pain Pharmacodynamics/Kinetics

(12%), limb pain (11%) Half-life Elimination Week 0: ~8 minutes; Week 22:
1% to 10%: ~36 minutes
Cardiovascular: Palpitations (5%) Time to Peak Week 0: 172 minutes; Week 22: 202
Central nervous system: Migraine (10%), dizzi- minutes
ness (8%) Pregnancy Risk Factor C
Dermatologic: Skin rash (5%) Pregnancy Considerations Adverse events were
Gastrointestinal: Flatulence (10%), upper abdominal observed in some animal reproduction studies. Muco-
pain (10%), dyspepsia (7%), gastroesophageal polysaccharidosis type IVA (MPS IVA) has the potential
reflux disease (7%), constipation (5%) to cause adverse events in both the mother and fetus. A
Neuromuscular & skeletal: Weakness (8%) pregnancy registry is available for women who may be
Respiratory: Oropharyngeal pain (10%), cough (7%) exposed to elosulfase alfa for the treatment of MPS IVA
Mechanism of Action Eliglustat inhibits the enzyme during pregnancy (MARS@bmrn.com or
needed to produce glycosphingolipids and decreases 1-800-983-4587).
the rate of glycosphingolipid glucosylceramide forma-
tion. Glucosylceramide accumulates in type 1 Gaucher Elotuzumab (el oh TOOZ ue mab)
disease, causing complications specific to this disease.
Pharmacodynamics/Kinetics Brand Names: US Empliciti
Half-life Elimination EMs: 6.5 hours; PMs: 8.9 hours. Brand Names: Canada Empliciti
Time to Peak EMs: 1.5 to 2 hours; PMs: 3 hours Pharmacologic Category Antineoplastic Agent, Anti-
Pregnancy Considerations SLAMF7; Antineoplastic Agent, Monoclonal Antibody
Adverse events were observed in some animal repro- Use Multiple myeloma, relapsed/refractory: Treat-
duction studies. ment of multiple myeloma (in combination with lenali-
Uncontrolled type 1 Gaucher disease is associated with domide and dexamethasone) in patients who have
an increased risk of spontaneous abortion; maternal received 1 to 3 prior therapies; treatment of multiple
hepatosplenomegaly and thrombocytopenia may also myeloma (in combination with pomalidomide and dex-
occur and lead to adverse pregnancy outcomes. amethasone) in patients who have received at least 2
prior therapies, including lenalidomide and a protea-
some inhibitor
Elosulfase Alfa (el oh SUL fase AL fa)
Brand Names: US Vimizim No information available to require special precautions
Brand Names: Canada Vimizim Effects on Dental Treatment No significant effects or
Pharmacologic Category Enzyme complications reported
Use Mucopolysaccharidosis type IVA: Treatment of Effects on Bleeding Cytopenias including thrombocy-
mucopolysaccharidosis type IVA (MPS IVA; Morquio A topenia (grades 3/4, 19%) has been reported. Medical
syndrome) consult is recommended.
Local Anesthetic/Vasoconstrictor Precautions Adverse Reactions All incidences reported with com-
No information available to require special precautions bination therapy.
Effects on Dental Treatment No significant effects or >10%:
Cardiovascular: Decreased heart rate (43% to 66%;
<60 bpm), increased heart rate (23% to 48%; ≥100
bpm), altered blood pressure (systolic ≥160 mmHg:
18% to 33%; systolic <90 mmHg: 7% to 29%; dia-
Adverse Reactions stolic ≥100 mmHg: 8% to 17%), peripheral
>10%: edema (13%)
Central nervous system: Headache (26%) Central nervous system: Fatigue (62%), peripheral
Gastrointestinal: Vomiting (31%), nausea (24%), neuropathy (27%; grades 3/4: 4%), headache (15%)
abdominal pain (21%) Endocrine & metabolic: Hyperglycemia (20% to 89%),
Hypersensitivity: Hypersensitivity reaction (19%) hypocalcemia (58% to 78%), hypoalbuminemia (65%
Miscellaneous: Fever (33%) to 73%), decreased serum bicarbonate (63%), hypo-
1% to 10%: natremia (40%), hyperkalemia (32%), hypokalemia
Central nervous system: Chills (10%), fatigue (10%) (23%), weight loss (14%)
Hypersensitivity: Anaphylaxis (8%; presenting as Gastrointestinal: Diarrhea (18% to 47%), constipation
cough, erythema, throat tightness, urticaria, flushing, (22% to 36%), decreased appetite (21%), vomit-
cyanosis, hypotension, rash, dyspnea, chest discom- ing (14%)
fort, and gastrointestinal symptoms) Hematologic & oncologic: Lymphocytopenia (10% to
Immunologic: Immunogenicity 99%; grades 3/4: 8% to 77%), leukopenia (80% to
Mechanism of Action Elosulfase alfa is a recombinant 91%; grades 3/4: 32% to 52%), thrombocytopenia
form of N-acetylgalactosamine-6-sulfatase, produced in (78% to 84%; grades 3/4: 17% to 19%)
Chinese hamster cells. A deficiency of this enzyme Hepatic: Increased serum alkaline phosphatase (39%)
leads to accumulation of the glycosaminoglycan Immunologic: Antibody development (19% to 36%;
(GAG) substrates (keratan sulfate and chondroitin-6- neutralizing: 4% to 6%)
sulfate) in tissues, causing cellular, tissue and organ Infection: Infection (65% to 81%), opportunistic infec-
dysfunction. Elosulfase alfa provides the exogenous tion (10% to 22%), herpes zoster infection (5% to
enzyme (N-acetylgalactosamine-6-sulfatase) that is 14%), fungal infection (10%)
taken into lysosomes and thereby increases the catab- Neuromuscular & skeletal: Limb pain (16%), ostealgia
olism of the GAG substrates (eg, keratan sulfate and (15%), muscle spasm (13%)
chondroitin-6-sulfate). Ophthalmic: Cataract (12%)
479
ELOTUZUMAB
Respiratory: Cough (34%), nasopharyngitis (25%), Chronic immune thrombocytopenia: Treatment of

upper respiratory tract infection (23%), pneumonia thrombocytopenia in adult and pediatric patients ≥1
(13% to 20%), respiratory tract infection (3% to year of age with chronic immune thrombocytopenia
17%), dyspnea (15%), oropharyngeal pain (10%) (ITP) who have had insufficient response to cortico-
Miscellaneous: Fever (7% to 37%), infusion related steroids, immunoglobulins, or splenectomy.
reaction (3% to 10%) Limitations of use: For ITP, eltrombopag should only be
1% to 10%: used if the degree of thrombocytopenia and clinical
Cardiovascular: Chest pain (≥5%), pulmonary embo- condition increase the risk for bleeding. For CHC,
lism (3%) eltrombopag should only be used if the degree of
Central nervous system: Hypoesthesia (≥5%), mood thrombocytopenia prevents initiation of or limits the
changes (≥5%) ability to maintain interferon-based therapy. Safety
Dermatologic: Night sweats (≥5%) and efficacy have not been established when used
Hematologic & oncologic: Second primary malignant in combination with direct-acting antiviral agents with-
neoplasm (9%), malignant neoplasm of skin (4%), out interferon for treatment of CHC infection. Eltrom-
malignant solid tumor (4%), anemia (3%), malignant bopag is not indicated for the treatment of
neoplasm (hematologic: 2%) myelodysplastic syndromes (MDS).
Hepatic: Hepatotoxicity (3%) Local Anesthetic/Vasoconstrictor Precautions
Hypersensitivity: Hypersensitivity reaction (≥5%) No information available to require special precautions
Renal: Acute renal failure (3%) Effects on Dental Treatment Key adverse event(s)
Mechanism of Action Elotuzumab is a humanized related to dental treatment: Risk of bleeding in soft
IgG1 immunostimulatory monoclonal antibody directed tissues upon discontinuation of therapy due to rebound
against signaling lymphocytic activation molecule family thrombocytopenia; monitor for at least 4 weeks after
member 7 (SLAMF7, also called CS1 [cell surface discontinuation of treatment.
glycoprotein CD2 subset 1). SLAMF7 is expressed on Effects on Bleeding Eltrombopag is used in the
most myeloma and natural killer cells, but not on normal management of severe thrombocytopenia. Medical con-
tissues; more than 95% of bone marrow myeloma cells sultation is warranted.
express SLAMF7 (Lonial 2015). Elotuzumab directly Adverse Reactions
activates natural killer cells through both the SLAMF7 >10%:
pathway and Fc receptors. It also targets SLAMF7 on Hepatic: Abnormal hepatic function tests (adults: 11%)
myeloma cells and mediates antibody-dependent cel- Respiratory: Upper respiratory tract infection (children
lular cytotoxicity (ADCC) through the CD16 pathway and adolescents: 17%; adults: 7%), nasopharyngitis
(Lonial 2015). This immunostimulatory activity, through (children and adolescents: 12%)
the increased activation of natural killer cells, increases 1% to 10%:
anti-tumor activity. Cardiovascular: Thromboembolic disease (adults:
Pharmacodynamics/Kinetics 6%), thrombosis (adults: 3%), portal vein thrombosis
Half-life Elimination ~97% of the maximum steady- (adults: 2%)
state concentration is expected to be eliminated with a Dermatologic: Skin rash (3% to 5%), alopecia
geometric mean (CV%) of 78 to 82.4 days. (adults: 2%)
Pregnancy Considerations Animal reproduction Gastrointestinal: Diarrhea (9%), nausea (adults: 9%),
studies have not been conducted. Elotuzumab is indi- abdominal pain (children and adolescents: 8%),
cated for use in combination with lenalidomide or toothache (children and adolescents: 6%), vomiting
pomalidomide. Due to its potential to cause fetal harm, (adults: 6%), xerostomia (adults: 2%)
lenalidomide/pomalidomide is only available through a Genitourinary: Urinary tract infection (adults: 5%)
REMS program. Males and females of reproductive Hepatic: Increased serum alanine aminotransferase
potential using these combinations must be able to (5% to 6%), increased serum aspartate aminotrans-
comply with pregnancy testing and contraception ferase (4%), increased serum alkaline phosphatase
requirements for lenalidomide or pomalidomide. Refer (adults: 2%), hepatotoxicity (≤1%)
to the lenalidomide or pomalidomide monograph for Infection: Influenza (adults: 3%)
additional information. Neuromuscular & skeletal: Myalgia (adults: 5%), back
pain (adults: 3%), paresthesia (adults: 3%), muscu-
Eltrombopag (el TROM boe pag) loskeletal pain (adults: 2%)
Ophthalmic: Cataract (children and adolescents: 1%)
Brand Names: US Promacta Respiratory: Cough (children and adolescents: 9%),
Brand Names: Canada Revolade oropharyngeal pain (4% to 8%), pharyngitis (adults:
Pharmacologic Category Colony Stimulating Factor; 4%), rhinorrhea (children and adolescents: 4%)
Hematopoietic Agent; Thrombopoietic Agent; Thrombo- Miscellaneous: Fever (children and adolescents: 9%)
poietin Receptor Agonist Frequency not defined: Hematologic & oncologic: Hem-
Use orrhage
Aplastic anemia, severe: First-line treatment (in com- <1%, postmarketing, and/or case reports: Skin discol-
bination with standard immunosuppressive therapy) of oration (including hyperpigmentation and skin yellow-
severe aplastic anemia in patients ≥2 years of age; ing), thrombotic microangiopathy (with acute renal
treatment of severe (refractory) aplastic anemia in failure)
patients who have had an insufficient response to Mechanism of Action Eltrombopag is a thrombopoie-
immunosuppressive therapy tin (TPO) nonpeptide agonist which increases platelet
Chronic hepatitis C infection-associated thrombo- counts by binding to and activating the human TPO
cytopenia: Treatment of thrombocytopenia in patients receptor. Activates intracellular signal transduction
with chronic hepatitis C (CHC) to allow the initiation pathways to increase proliferation and differentiation
and maintenance of interferon-based therapy. of marrow progenitor cells.
480
ELVITEGRAVIR, COBICISTAT, EMTRICITABINE, AND TENOFOVIR ALAFENAMIDE
Pharmacodynamics/Kinetics therapy). An increased risk of stillbirth, low birth weight,

Onset of Action Platelet count increase: Within 1 to 2 and small for gestational age infants has been observed
weeks in some but not all studies. Because there is clear
Duration of Action Platelets return to baseline: 1 to 2 benefit to appropriate treatment, maternal ART should
weeks after last dose not be withheld due to concerns for adverse neonatal
Half-life Elimination ~21 to 32 hours in healthy outcomes. Long-term follow-up is recommended for all
individuals; ~26 to 35 hours in patients with ITP infants exposed to antiretroviral medications; children
Time to Peak 2 to 6 hours who develop significant organ system abnormalities of
Pregnancy Considerations unknown etiology (particularly of the CNS or heart)
Adverse effects were observed in animal reproduction should be evaluated for potential mitochondrial dys-
studies. function.
Information related to the use of eltrombopag for the The Health and Human Services (HHS) Perinatal HIV
treatment of thrombocytopenia in pregnancy is limited Guidelines do not recommend an elvitegravir-contain-
(Favier 2018; Purushothaman 2016; Suzuki 2018). ing regimen in pregnant females with HIV due to inad-
equate serum concentrations observed during
Females of reproductive potential should use effective pregnancy. Pharmacokinetic data are insufficient to
contraception during eltrombopag therapy and for at make dosing recommendations during pregnancy. If
least 7 days after the last eltrombopag dose. pregnancy occurs during therapy, consideration should
If used in combination with ribavirin, all warnings related be given to changing to a more effective regimen. If
to the use of ribavirin and pregnancy and/or contra- continued, close monitoring, including therapeutic drug
ception should be followed. Refer to the ribavirin mono- monitoring if available, is recommended. Do not admin-
graph for additional information. ister within 2 hours of iron or calcium containing prep-
arations, including prenatal vitamins.
Elvitegravir (el vi TEG ra vir) In general, ART is recommended for all pregnant
females with HIV to keep the viral load below the limit
Brand Names: US Vitekta [DSC] of detection and reduce the risk of perinatal trans-
Pharmacologic Category Antiretroviral, Integrase mission. Monitoring during pregnancy is more frequent
Inhibitor (Anti-HIV) than in non-pregnant adults. ART should be continued
Use HIV-1 infection: In combination with an HIV pro- postpartum for all females living with HIV and can be
tease inhibitor coadministered with ritonavir and with modified after delivery.
other antiretroviral drug(s) for the treatment of HIV-1 Health care providers are encouraged to enroll preg-
infection in antiretroviral treatment-experienced adults nant females exposed to antiretroviral medications as
Local Anesthetic/Vasoconstrictor Precautions early in pregnancy as possible in the Antiretroviral
No information available to require special precautions Pregnancy Registry (1-800-258-4263 or http://www.-
Effects on Dental Treatment No significant effects or APRegistry.com). Health care providers caring for
complications reported HIV-infected females and their infants may contact the
Effects on Bleeding No information available to National Perinatal HIV Hotline (888-448-8765) for clin-
require special precautions ical consultation (HHS [perinatal] 2018).
Adverse Reactions Percentages are reported for anti- Product Availability Vitekta has been discontinued in
retroviral treatment experienced adults. the US for more than 1 year.
1% to 10%:
Central nervous system: Headache (3%), depression
(<2%), fatigue (<2%), insomnia (<2%), suicidal idea- Elvitegravir, Cobicistat, Emtricitabine,
tion (<2%) and Tenofovir Alafenamide
Dermatologic: Skin rash (<2%) (el vi TEG ra vir, koe BIK i stat, em trye SYE ta been, & ten OF oh vir
Gastrointestinal: Diarrhea (7%), nausea (4%), al a FEN a mide)
abdominal pain (<2%), dyspepsia (<2%), vomit-
Brand Names: US Genvoya
ing (<2%)
Brand Names: Canada Genvoya
Immunologic: Immune reconstitution syndrome
Mechanism of Action Integrase is an HIV-1 encoded Pharmacologic Category Antiretroviral, Integrase
Inhibitor (Anti-HIV); Antiretroviral, Reverse Transcrip-
enzyme that is required for viral replication. Inhibition of
tase Inhibitor, Nucleoside (Anti-HIV); Antiretroviral,
integrase prevents the integration of HIV-1 DNA into
Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV);
host genomic DNA, blocking the formation of the HIV-1
Cytochrome P-450 Inhibitor
provirus and propagation of the viral infection. Elvite-
gravir does not inhibit human topoisomerases I or II. Use HIV-1 infection: Treatment of HIV-1 infection in
Pharmacodynamics/Kinetics adult and pediatric patients weighing ≥25 kg who have
Half-life Elimination Terminal: ~9 hours no antiretroviral treatment history or to replace the
current antiretroviral regimen in those who are virolog-
Time to Peak Plasma: ~4 hours
ically-suppressed (HIV-1 RNA <50 copies per mL) on a
Pregnancy Risk Factor B stable antiretroviral regimen for ≥6 months with no
Pregnancy Considerations history of treatment failure and no known substitutions
Elvitegravir has a high level of transfer across the associated with resistance to elvitegravir, cobicistat,
placenta. emtricitabine, or tenofovir alafenamide.
Data collected by the antiretroviral pregnancy registry Local Anesthetic/Vasoconstrictor Precautions
are insufficient to evaluate teratogenic risk. Maternal No information available to require special precautions
antiretroviral therapy (ART) may increase the risk of Effects on Dental Treatment No significant effects or
preterm delivery, although available information is con- complications reported
flicting possibly due to variability of maternal factors Effects on Bleeding No information available to
(disease severity; gestational age at initiation of require special precautions
481
ELVITEGRAVIR, COBICISTAT, EMTRICITABINE, AND TENOFOVIR ALAFENAMIDE
Adverse Reactions Includes data from both treat-

ment-naive and treatment-experienced patients. Also Elvitegravir, Cobicistat, Emtricitabine,
see individual agents. and Tenofovir Disoproxil Fumarate
>10%: (el vi TEG ra vir, koe BIK i stat, em trye SYE ta been, & ten OF oh vir
Endocrine & metabolic: Increased LDL cholesterol dye soe PROX il FUE ma rate)
(grades 3/4: 11%)
Related Information
Gastrointestinal: Nausea (11%)
Brand Names: US Stribild
density (≥5% decrease at lumbar spine: 12%; ≥7%
decrease at femoral neck: 11%), increased serum
Brand Names: Canada Stribild
creatine kinase (grades 3/4: 11%) Pharmacologic Category Antiretroviral, Integrase
1% to 10%: Inhibitor (Anti-HIV); Antiretroviral, Reverse Transcrip-
tase Inhibitor, Nucleoside (Anti-HIV); Antiretroviral,
Central nervous system: Headache (6%), fatigue (5%)
Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV);
Endocrine & metabolic: Increased serum cholesterol
Cytochrome P-450 Inhibitor
(grades 3/4: 4%)
Gastrointestinal: Diarrhea (7%)
Use HIV-1 infection: Treatment of HIV-1 infection in
adults and pediatric patients ≥12 years weighing ≥35
Genitourinary: Hematuria (grades 3/4: 3%)
kg who are antiretroviral treatment-naïve; as a replace-
ment for the current antiretroviral regimen in patients
(grades 3/4: 3%), increased serum amylase (grades
who are virologically-suppressed (HIV-1 RNA <50 cop-
3/4: 3%), increased serum aspartate aminotransfer-
ies/mL) on a stable antiretroviral regimen for ≥6 months
ase (grades 3/4: 3%)
with no history of treatment failure and no known
Frequency not defined: substitutions associated with resistance to elvitegravir,
Endocrine & metabolic: Increased HDL cholesterol, cobicistat, emtricitabine, or tenofovir disoproxil fuma-
increased serum triglycerides rate.
Hepatic: Exacerbation of hepatitis B Local Anesthetic/Vasoconstrictor Precautions
Renal: Increased serum creatinine (mean increase No information available to require special precautions
0.1 mg/dL) Effects on Dental Treatment No significant effects or
<1%, postmarketing, and/or case reports: Angioedema, complications reported
skin rash, urticaria Effects on Bleeding No information available to
Mechanism of Action Integrase strand transfer inhib- require special precautions
itor, CYP3A enzyme inhibitor plus nucleoside and Adverse Reactions
nucleotide reverse transcriptase inhibitor combination; >10%:
the viral cDNA strand produced by reverse transcrip- Gastrointestinal: Nausea (4% to 16%), diarrhea (12%)
tase is processed and inserted into the human genome Genitourinary: Proteinuria (52%)
by the enzyme HIV-1 integrase. Elvitegravir inhibits the Renal: Increased serum creatinine (12%)
catalytic activity of integrase, thus preventing integra- 1% to 10%:
tion of the proviral gene into human DNA. Cobicistat Central nervous system: Abnormal dreams (9%),
inhibits enzymes of the CYP3A subfamily and enhan- headache (2% to 7%), fatigue (4%), dizziness
ces systemic exposure to elvitegravir. Emtricitabine is a (3%), insomnia (3%), drowsiness (1%)
cytosine analogue and tenofovir alafenamide is con- Dermatologic: Skin rash (4%)
verted to tenofovir in vivo; tenofovir is an analog of Endocrine & metabolic: Increased amylase (3%)
adenosine 5'-monophosphate. Emtricitabine and teno- Gastrointestinal: Flatulence (2%)
fovir interfere with HIV viral RNA dependent DNA Genitourinary: Hematuria (4%)
polymerase activities resulting in inhibition of viral rep- Hepatic: Increased serum AST (3%), increased serum
lication. ALT (2%)
Pharmacodynamics/Kinetics Neuromuscular & skeletal: Increased creatine phos-
Half-life Elimination Elvitegravir: 12.9 hours; Cobici- phokinase (8%), bone fracture (4%)
stat: 3.5 hours; Emtricitabine: 10 hours; Tenofovir Frequency not defined:
alafenamide: 0.51 hours Endocrine & metabolic: Increased serum cholesterol,
Time to Peak Elvitegravir: 4 hours; Cobicistat: 3 increased serum triglycerides
hours; Emtricitabine: 3 hours; Tenofovir alafenamide: Gastrointestinal: Increased serum lipase
1 hour <1%, postmarketing, and/or case reports: Acute renal
Pregnancy Considerations failure, Fanconi syndrome, immune reconstitution syn-
The Health and Human Services (HHS) Perinatal HIV drome, renal failure, renal tubular disease (proximal),
Guidelines do not recommend this fixed dose combina- scleral icterus, suicidal ideation
tion for HIV-infected pregnant females who are antire- Mechanism of Action Integrase strand transfer inhib-
troviral-naïve, who have had antiretroviral therapy itor, CYP3A enzyme inhibitor plus nucleoside and
(ART) in the past but are restarting, who require a nucleotide reverse transcriptase inhibitor combination;
new ART regimen (due to poor tolerance or poor the viral cDNA strand produced by reverse transcrip-
virologic response of current regimen), and who are tase is processed and inserted into the human genome
not yet pregnant but are trying to conceive. For females by the enzyme HIV-1 integrase. Elvitegravir inhibits the
who become pregnant while taking this combination, catalytic activity of integrase, thus preventing integra-
consider altering the regimen, or continue with frequent tion of the proviral gene into human DNA. Cobicistat
monitoring if viral suppression is effective and the inhibits enzymes of the CYP3A subfamily and enhan-
ces systemic exposure to elvitegravir. Emtricitabine is a
regimen is well tolerated (HHS [perinatal] 2018).
cytosine analogue and tenofovir disoproxil fumarate
Refer to individual monographs for additional infor- (TDF) is an analog of adenosine 5'-monophosphate.
mation. Emtricitabine and tenofovir interfere with HIV viral
482
EMPAGLIFLOZIN
RNA dependent DNA polymerase activities resulting in Mechanism of Action Emapalumab-lzsg is an inter-
inhibition of viral replication. feron gamma (IFNγ) blocking monoclonal antibody.
Pharmacodynamics/Kinetics IFNγ is hypersecreted in hemophagocytic lymphohistio-
Half-life Elimination Elvitegravir: 12.9 hours; Cobici- cytosis (HLH); emapalumab-lzsg binds to IFNγ and
stat: 3.5 hours; Emtricitabine: 10 hours; Tenofovir: 12 neutralizes it.
to 18 hours Pharmacodynamics/Kinetics
Time to Peak Plasma: Elvitegravir: 4 hours; Cobici- Half-life Elimination Healthy subjects: ~22 days;
stat: 3 hours; Emtricitabine: 3 hours; Tenofovir: 2 Patients with hemophagocytic lymphohistiocytosis
hours (HLH): 2.5 to 18.9 days
Pregnancy Considerations Pregnancy Considerations Adverse events were not
The Health and Human Services (HHS) Perinatal HIV observed in animal reproduction studies.
Guidelines do not recommend this fixed-dose combina-
tion for HIV-infected pregnant females who are antire-
troviral-naive, who have had antiretroviral therapy
Empagliflozin (em pa gli FLOE zin)
(ART) in the past but are restarting, who require a Brand Names: US Jardiance
new ART regimen (due to poor tolerance or poor Brand Names: Canada Jardiance
virologic response of current regimen), and who are Pharmacologic Category Antidiabetic Agent,
not yet pregnant but are trying to conceive. For females Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor;
who become pregnant while taking this combination, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
consider altering the regimen, or continue with frequent
Use
monitoring if viral suppression is effective and the
Diabetes mellitus, type 2: Treatment of type 2 diabe-
regimen is well tolerated (HHS [perinatal] 2018).
tes mellitus as an adjunct to diet and exercise to
Refer to individual monographs for additional infor- improve glycemic control; risk reduction of cardiovas-
mation. cular mortality in adults with type 2 diabetes mellitus
and established cardiovascular disease
Guideline recommendation: In patients with established
Emapalumab-lzsg (EM a PAL ue mab lzsg)
atherosclerotic cardiovascular disease (ASCVD) on
Brand Names: US Gamifant metformin, empagliflozin is a preferred add-on agent
Pharmacologic Category Monoclonal Antibody to reduce major adverse cardiovascular events (ADA
2018d)
Use Primary hemophagocytic lymphohistiocytosis:
Treatment of primary hemophagocytic lymphohistiocy- Local Anesthetic/Vasoconstrictor Precautions
tosis (HLH) in adult and pediatric (newborn and older) No information available to require special precautions
patients with refractory, recurrent or progressive dis- Effects on Dental Treatment Key adverse event(s)
ease or intolerance to conventional HLH therapy. related to dental treatment: Dizziness and syncope
have been reported; patients may experience ortho-
No information available to require special precautions static hypotension as they stand up after treatment;
especially if lying in dental chair for extended periods
of time. Use caution with sudden changes in position
during and after dental treatment.
require special precautions Empagliflozin-dependent patients with diabetes (non-
Adverse Reactions insulin dependent, type 2) should be questioned by
>10%: the dental professional at each dental visit to assess
Cardiovascular: Hypertension (41%), tachycar- their risk for stress-induced hypoglycemia. The dental
dia (12%) professional should inquire about the patient’s routine
Central nervous system: Irritability (12%) (ie, work, sleep schedule, eating patterns), history of
Dermatologic: Skin rash (12%) hypoglycemia, time of last medication dose, last meal,
Endocrine & metabolic: Hypokalemia (15%) and most recent blood sugar assessment. Keep a
Gastrointestinal: Appendicitis (≤32%), constipation supply of glucose tablets and other carbohydrates in
(15%), abdominal pain (12%), diarrhea (12%) the office to prepare for a hypoglycemic event. Seek
Hematologic & oncologic: Lymphocytosis (12%) medical attention when necessary (American Diabetes
Infection: Infection (56%), viral infection (32% to 41%), Association 2016).
bacterial infection (35%), bacteremia (≤32%), histo- Effects on Bleeding No information available to
plasmosis (≤32%), necrotizing fasciitis (≤32%), sep- require special precautions
sis (≤32%), cytomegalovirus disease (12%) Adverse Reactions
Respiratory: Pneumonia (≤32%), cough (12%), >10%: Genitourinary: Urinary tract infection (9%;
tachypnea (12%) females: 18%; males: 4%)
Miscellaneous: Infusion related reaction (27%), 1% to 10%:
fever (24%) Endocrine & metabolic: Dyslipidemia (4%), increased
1% to 10%: thirst (2%)
Cardiovascular: Bradycardia (<10%), peripheral Gastrointestinal: Nausea (2%)
edema (<10%) Genitourinary: Increased urine output (3%)
Gastrointestinal: Gastrointestinal hemorrhage (<10%), Hematologic & oncologic: Increased hematocrit (3%
vomiting (<10%) to 4%)
Immunologic: Antibody development (3% to 5%) Infection: Genitourinary fungal infection (2% to 6%)
Infection: Fungal infection (9%) Frequency not defined: Endocrine & metabolic:
Neuromuscular & skeletal: Asthenia (<10%) Increased LDL cholesterol
Renal: Acute renal failure (<10%) <1%, postmarketing, and/or case reports: Acute renal
Respiratory: Dyspnea (<10%), epistaxis (<10%) failure, angioedema, decreased estimated GFR
Miscellaneous: Multi-organ failure (≥3%) (eGFR), hypersensitivity reaction, hypovolemia,
483
EMPAGLIFLOZIN
increased serum creatinine, ketoacidosis, necrotizing Gastrointestinal: Diarrhea (children: 20%; adults: 9%
fasciitis (perineum), phimosis, pyelonephritis, skin to 23%), vomiting (children: 23%; adults: 9%), nau-
rash, urinary tract infection with sepsis, urticaria sea (13% to 18%), abdominal pain (8% to 14%),
Mechanism of Action By inhibiting sodium-glucose gastroenteritis (children: 11%)
cotransporter 2 (SGLT2) in the proximal renal tubules, Infection: Infection (children: 44%)
empagliflozin reduces reabsorption of filtered glucose Neuromuscular & skeletal: Weakness (12% to 16%),
from the tubular lumen and lowers the renal threshold increased creatine phosphokinase (grades 3/4: 11%
for glucose (RTG). SGLT2 is the main site of filtered to 12%)
glucose reabsorption; reduction of filtered glucose reab- Otic: Otitis media (children: 23%)
sorption and lowering of RTG result in increased urinary Respiratory: Cough (children: 28%; adults; 14%), rhi-
excretion of glucose, thereby reducing plasma glucose nitis (children: 20%; adults: 12% to 18%), pneumonia
concentrations. (children: 15%)
Pharmacodynamics/Kinetics Miscellaneous: Fever (children: 18%)
Half-life Elimination 12.4 hours 1% to 10%:
Central nervous system: Depression (6% to 9%),
Time to Peak 1.5 hours
paresthesia (5% to 6%), neuritis (≤4%), neuropa-
Pregnancy Considerations thy (≤4%)
Use is not recommended during the second and third Endocrine & metabolic: Increased serum triglycerides
trimesters. (grades 3/4: 4% to 10%), increased amylase (grades
In women with diabetes, maternal hyperglycemia can 3/4: children: 9%; adults: 2% to 5%), hyperglycemia
be associated with congenital malformations as well as (grades 3/4: 2% to 3%)
adverse effects in the fetus, neonate, and the mother Gastrointestinal: Dyspepsia (4% to 8%), increased
(ACOG 2005; ADA 2018c; Metzger 2007). To prevent serum lipase (grades 3/4: ≤1%)
adverse outcomes prior to conception and throughout Genitourinary: Hematuria (grades 3/4: 3%)
pregnancy, maternal blood glucose and HbA1c should Hematologic & oncologic: Anemia (children: 7%), neu-
be kept as close to target goals as possible but without tropenia (grades 3/4: children: 2%; adults: 5%)
causing significant hypoglycemia (ADA 2018c; Blumer Hepatic: Increased serum transaminases (grades 3/4:
2013). Agents other than empagliflozin are currently 2% to 6%), increased serum alkaline phosphatase
recommended to treat diabetes in pregnant women (>550 units/L: 1%), increased serum bilirubin (grades
3/4: 1%)
(ADA 2018c).
Neuromuscular & skeletal: Myalgia (4% to 6%),
arthralgia (3% to 5%)
Emtricitabine (em trye SYE ta been) Respiratory: Sinusitis (8%), upper respiratory tract
infection (8%), pharyngitis (5%)
Related Information <1%, postmarketing, and/or case reports: Immune
HIV Infection and AIDS on page 1477 reconstitution syndrome
Brand Names: US Emtriva Mechanism of Action Nucleoside reverse transcrip-
Brand Names: Canada Emtriva tase inhibitor; emtricitabine is a cytosine analogue
Pharmacologic Category Antiretroviral, Reverse which is phosphorylated intracellularly to emtricitabine
Transcriptase Inhibitor, Nucleoside (Anti-HIV) 5'-triphosphate which interferes with HIV viral RNA
Use HIV-1 infection, treatment: Treatment of HIV-1 dependent DNA polymerase resulting in inhibition of
infection in combination with other antiretroviral agents. viral replication.
No information available to require special precautions Half-life Elimination Normal renal function:
Effects on Dental Treatment No significant effects or Infants, Children, and Adolescents: Elimination half-
complications reported life (emtricitabine):
Single dose: 11 hours
Multiple dose: 7.9 to 9.5 hours
require special precautions related to hemostasis.
Infants 0 to 3 months (n=20; median age: 26 days):
Adverse Reactions Clinical trials were conducted in 12.1 ± 3.1 hours
patients receiving other antiretroviral agents, and it is Infants 3 to 24 months (n=14): 8.9 ± 3.2 hours
not possible to correlate frequency of adverse events Children 25 months to 6 years (n=19): 11.3 ± 6.4
with emtricitabine alone. The range of frequencies of hours
adverse events is generally comparable to comparator Children 7 to 12 years (n=17): 8.2 ± 3.2 hours
groups, with the exception of hyperpigmentation, which Adolescents 13 to 17 years (n=27): 8.9 ± 3.3 hours
occurred more frequently in patients receiving emtrici- Adults: Emtricitabine: 10 hours; Intracellular half-life
tabine. Unless otherwise noted, percentages are as (emtricitabine 5'-triphosphate): 39 hours
reported in adults. Time to Peak Plasma: 1 to 2 hours
>10%: Pregnancy Considerations Emtricitabine has a high
Central nervous system: Dizziness (4% to 25%), level of transfer across the human placenta.
headache (6% to 22%), insomnia (5% to 16%), No increased risk of overall birth defects has been
abnormal dreams (2% to 11%) observed according to data collected by the antiretro-
Dermatologic: Hyperpigmentation (children: 32%; viral pregnancy registry. Maternal antiretroviral therapy
adults: 2% to 4%; primarily of palms and/or soles (ART) may increase the risk of preterm delivery,
but may include tongue, arms, lip and nails; generally although available information is conflicting possibly
mild and nonprogressive without associated local due to variability of maternal factors (disease severity;
reactions such as pruritus or rash), skin rash (17% gestational age at initiation of therapy). An increased
to 30%; includes hypersensitivity reaction, maculo- risk of stillbirth, low birth weight, and small for gesta-
papular rash, pruritus, pustular rash, vesiculobul- tional age infants has been observed in some but not all
lous rash) studies. Because there is clear benefit to appropriate
484
EMTRICITABINE AND TENOFOVIR ALAFENAMIDE
treatment, maternal ART should not be withheld due to Antiretroviral, Reverse Transcriptase Inhibitor, Nucleo-
concerns for adverse neonatal outcomes. Long-term tide (Anti-HIV)
follow-up is recommended for all infants exposed to Use
antiretroviral medications; children who develop signifi-
HIV-1 infection: Treatment of HIV-1 infection in combi-
cant organ system abnormalities of unknown etiology
(particularly of the CNS or heart) should be evaluated nation with other antiretroviral agents in adults and
for potential mitochondrial dysfunction. Cases of lactic pediatric patients weighing ≥35 kg; in combination with
acidosis and hepatic steatosis related to mitochondrial other antiretroviral agents (other than protease inhib-
toxicity have been reported with use of NRTIs. These itors that require a CYP3A inhibitor) in pediatric
adverse events are similar to other rare but life-threat- patients weighing ≥25 kg and <35 kg.
ening syndromes that occur during pregnancy (eg, Limitations of use: Not indicated for use as preexposure
HELLP syndrome). In general NRTIs are well tolerated prophylaxis (PrEP) to reduce the risk of sexually
and the benefits of use generally outweigh poten-
acquired HIV-1 in adults at high risk.
tial risk.
The Health and Human Services (HHS) Perinatal HIV No information available to require special precautions
Guidelines consider emtricitabine a preferred NRTI for
HIV-infected pregnant females who are antiretroviral-
naive, who have had ART therapy in the past but are related to dental treatment: Nausea reported in 10% of
restarting, who require a new ART regimen (due to poor patients
tolerance or poor virologic response of current regi- Effects on Bleeding No information available to
men), and who are not yet pregnant but are trying to require special precautions
conceive. In addition, females who become pregnant Adverse Reactions All adverse drug reactions are
while taking emtricitabine may continue if viral suppres- from combination therapy with cobistat plus elvitegravir
sion is effective and the regimen is well tolerated. The
in treatment-naïve and treatment-experienced patients.
pharmacokinetics of emtricitabine are not significantly
altered during pregnancy and dosing adjustments are Also see individual agents.
not needed. 1% to 10%:
Gastrointestinal: Nausea (10%)
The HHS Perinatal HIV Guidelines consider emtricita-
bine with tenofovir disoproxil fumarate to be a preferred
NRTI backbone for initial therapy in antiretroviral-naive density (≥5% decrease at lumbar spine: 1% to 10%;
pregnant females. The guidelines also consider emtri- ≥7% decrease at femoral neck: 1% to 7%), bone
citabine plus tenofovir disoproxil fumarate a recom- fracture (≤1%; excluding fingers and toes)
mended dual NRTI backbone in regimens for HIV/ Frequency not defined:
hepatitis B virus-coinfected pregnant females. Use cau- Endocrine & metabolic: Increased HDL cholesterol,
tion with hepatitis B coinfection; hepatitis B flare may increased LDL cholesterol, increased serum choles-
occur if emtricitabine is discontinued. Emtricitabine is terol, increased serum triglycerides
also a recommended component of an initial regimen
Hepatic: Exacerbation of hepatitis B
when acute HIV infection is detected during pregnancy.
Renal: Increased serum creatinine (mean increase
In general, ART is recommended for all pregnant 0.1 mg/dL)
females with HIV to keep the viral load below the limit <1%, postmarketing, and/or case reports: Acute renal
of detection and reduce the risk of perinatal trans-
failure, renal disease
mission. Monitoring during pregnancy is more frequent
than in nonpregnant adults. ART should be continued Mechanism of Action Nucleoside and nucleotide
postpartum for all females living with HIV and can be reverse transcriptase inhibitor combination; emtricita-
modified after delivery. bine is a cytosine analogue while tenofovir alafenamide
fumarate (TAF) is an analog of adenosine 5'-mono-
Emtricitabine is one of the agents recommended for
pre-exposure prophylaxis in couples with discordant phosphate. Each drug interferes with HIV viral RNA
HIV status who are planning a pregnancy. The partner dependent DNA polymerase activities resulting in inhib-
without HIV should begin therapy 1 month prior to ition of viral replication.
attempting conception and continue therapy for 1 month Pharmacodynamics/Kinetics
after attempting conception. Half-life Elimination Emtricitabine: 10 hours; TAF:
Health care providers are encouraged to enroll preg- 0.51 hours
nant females exposed to antiretroviral medications as Pregnancy Considerations
early in pregnancy as possible in the Antiretroviral The Health and Human Services (HHS) Perinatal HIV
Pregnancy Registry (1-800-258-4263 or http://www.- Guidelines note there are insufficient data to recom-
APRegistry.com). Health care providers caring for mend use of this combination product as an initial
HIV-infected females and their infants may contact the regimen in antiretroviral-naive pregnant females.
ical consultation (HHS [perinatal] 2018). In general, females who become pregnant on a stable
antiretroviral therapy (ART) regimen may continue that
Emtricitabine and Tenofovir regimen if viral suppression is effective, appropriate
drug exposure can be achieved, contraindications for
Alafenamide
(em trye SYE ta been & ten OF oh vir al a FEN a mide) use in pregnancy are not present, and the regimen is
well tolerated (HHS [perinatal] 2018).
Brand Names: US Descovy
Pharmacologic Category Antiretroviral, Reverse Refer to individual monographs for additional infor-
Transcriptase Inhibitor, Nucleoside (Anti-HIV); mation.
485
EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE
In addition, this combination is recommended for pre-

Emtricitabine and Tenofovir Disoproxil exposure prophylaxis in couples with discordant HIV
Fumarate status who are planning a pregnancy. The partner with-
(em trye SYE ta been & ten OF oh vir dye soe PROX il FUE ma rate) out HIV should begin therapy 1 month prior to and
continue for 1 month after conception is attempted
Related Information (HHS [perinatal] 2018).
Emtricitabine on page 484
Refer to individual monographs for additional infor-
mation.
Tenofovir Disoproxil Fumarate on page 1238
Brand Names: US Truvada
Brand Names: Canada Truvada Emtricitabine, Rilpivirine, and
Pharmacologic Category Antiretroviral, Reverse Tenofovir Alafenamide
Transcriptase Inhibitor, Nucleoside (Anti-HIV); Antiretro- (em trye SYE ta been, ril pi VIR een, & ten OF oh vir al a FEN a
viral, Reverse Transcriptase Inhibitor, Nucleotide (Anti- mide)
HIV)
Brand Names: US Odefsey
Use
Brand Names: Canada Odefsey
HIV-1 infection, treatment: Treatment of HIV-1 infec-
tion in combination with other antiretroviral agents in
Pharmacologic Category Antiretroviral, Reverse
Transcriptase Inhibitor, Non-nucleoside (Anti-HIV); Anti-
adults and pediatric patients weighing ≥17 kg
retroviral, Reverse Transcriptase Inhibitor, Nucleoside
HIV-1 infection, preexposure prophylaxis: Preexpo-
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhib-
sure prophylaxis (PrEP) to reduce the risk of sexually
itor, Nucleotide (Anti-HIV)
acquired HIV-1 infection in at-risk adults and adoles-
cents weighing ≥35 kg, in combination with safer sex Use
practices. HIV-1 infection: Treatment of HIV-1 infection (as a
complete regimen) in patients ≥12 years of age as
initial therapy in those with no antiretroviral treatment
history with HIV-1 RNA ≤100,000 copies/mL; or to
replace a stable antiretroviral regimen in those who
are virologically suppressed (HIV-1 RNA <50 copies/
Effects on Bleeding No information available to mL) for ≥6 months with no history of treatment failure
require special precautions related to hemostasis. and no known substitutions associated with resistance
Adverse Reactions Also see individual agents. to the individual components.
>10%: Neuromuscular & skeletal: Decreased bone Limitations of use: More rilpivirine-treated patients with
mineral density (13%) no history of antiretroviral treatment with HIV-1 RNA
1% to 10%: >100,000 copies/mL at therapy initiation experienced
Central nervous system: Headache (7%) virologic failure (HIV-1 RNA ≥50 copies/mL) compared
Endocrine & metabolic: Weight loss (3%) to rilpivirine-treated patients with HIV-1 RNA ≤100,000
Gastrointestinal: Abdominal pain (4%) copies/mL.
Hematologic & oncologic: Abnormal phosphorus lev- Local Anesthetic/Vasoconstrictor Precautions
els (<2.0 mg/dL: 10%), decreased neutrophils (5%) No information available to require special precautions
Neuromuscular & skeletal: Bone fracture (2%)
<1%, postmarketing, and/or case reports: Glycosuria,
immune reconstitution syndrome, proteinuria
Mechanism of Action Nucleoside and nucleotide require special precautions
reverse transcriptase inhibitor combination; emtricita-
Adverse Reactions Also see individual agents.
bine is a cytosine analogue while tenofovir is an analog
1% to 10%:
of adenosine 5'-monophosphate. Each drug interferes
Central nervous system: Headache (2%), sleep dis-
with HIV viral RNA dependent DNA polymerase result-
order (2%), abnormal dreams (1%)
ing in inhibition of viral replication.
Gastrointestinal: Diarrhea (1%), nausea (1%), flatu-
Pregnancy Considerations lence (≤1%)
Guidelines consider emtricitabine with tenofovir diso- density (1% to 2%)
proxil fumarate to be a preferred NRTI backbone for Frequency not defined: Endocrine: Decreased HDL
initial therapy in antiretroviral-naive pregnant females. cholesterol, decreased LDL cholesterol, decreased
Emtricitabine with tenofovir disoproxil fumarate may serum cholesterol, decreased serum triglycerides,
also be recommended as part of a regimen when acute increased HDL cholesterol, increased LDL choles-
HIV infection is detected during pregnancy. In addition, terol, increased serum cholesterol, increased serum
this combination is preferred for use in HIV-infected triglycerides
females who have had antiretroviral therapy (ART) in
Mechanism of Action Non-nucleoside, nucleoside,
the past but are restarting, who require a new ART
and nucleotide reverse transcriptase inhibitor combina-
regimen (due to poor tolerance or poor virologic
tion; rilpivirine binds to reverse transcriptase and does
response of current regimen), and who are not yet
not require intracellular phosphorylation for antiviral
pregnant but are trying to conceive. Females who
activity; emtricitabine is a cytosine analogue while
become pregnant while taking this combination may
tenofovir alafenamide fumarate (TAF) is an analog of
continue if viral suppression is effective and the regi-
adenosine 5'-monophosphate. Each drug interferes
men is well tolerated.
with HIV viral RNA dependent DNA polymerase activ-
The HHS perinatal guidelines also recommend emtrici- ities resulting in inhibition of viral replication.
tabine plus tenofovir disoproxil fumarate as a compo- Pregnancy Considerations
nent of regimens for HIV/hepatitis B virus-coinfected The Health and Human Services (HHS) Perinatal HIV
pregnant females. Guidelines note data are insufficient to recommend this
486
ENALAPRIL
fixed-dose combination for initiation in HIV-infected Gastrointestinal: Abdominal distress, abdominal pain,
pregnant females who are antiretroviral-naive, who cholecystitis, cholelithiasis, decreased appetite, diar-
have had antiretroviral therapy (ART) in the past but rhea, vomiting
are restarting, who require a new ART regimen (due to Renal: Glomerulonephritis (membranous and mesan-
poor tolerance or poor virologic response of current gioproliferative), nephrolithiasis
regimen), and who are not yet pregnant but are trying <1%, postmarketing, and/or case reports: DRESS syn-
to conceive. Females who become pregnant while drome, hypersensitivity reaction, immune reconstitu-
taking this combination may continue if viral suppres- tion syndrome, severe dermatological reaction,
sion is effective and the regimen is well tolerated; suicidal ideation, suicidal tendencies, weight gain
however, more frequent monitoring is recommended Mechanism of Action Non-nucleoside, nucleoside,
(HHS [perinatal] 2018). and nucleotide reverse transcriptase inhibitor combina-
tion; rilpivirine binds to reverse transcriptase and does
Refer to individual monographs for additional infor- not require intracellular phosphorylation for antiviral
mation. activity; emtricitabine is a cytosine analogue while
Product Availability Odefsey: FDA approved March tenofovir disoproxil fumarate (TDF) is an analog of
2016; anticipated availability is currently undetermined adenosine 5'-monophosphate. Each drug interferes
with HIV viral RNA dependent DNA polymerase activ-
Emtricitabine, Rilpivirine, and ities resulting in inhibition of viral replication.
Tenofovir Disoproxil Fumarate The Health and Human Services (HHS) Perinatal HIV
(em trye SYE ta been, ril pi VIR een, & ten OF oh vir dye soe PROX
il FUE ma rate) Guidelines recommend this fixed-dose combination an
alternative regimen for initial use in HIV-infected preg-
Related Information nant females who are antiretroviral-naive, who have
HIV Infection and AIDS on page 1477 had antiretroviral therapy (ART) in the past but are
Brand Names: US Complera restarting, who require a new ART regimen (due to poor
Brand Names: Canada Complera tolerance or poor virologic response of current regi-
Pharmacologic Category Antiretroviral, Reverse men), and who are not yet pregnant but are trying to
Transcriptase Inhibitor, Non-nucleoside (Anti-HIV); Anti- conceive. Females who become pregnant while taking
retroviral, Reverse Transcriptase Inhibitor, Nucleoside this combination may continue if viral suppression is
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhib- effective and the regimen is well tolerated; however,
itor, Nucleotide (Anti-HIV) more frequent monitoring is recommended. This combi-
Use HIV-1 infection: Treatment of HIV-1 infection (as a nation should not be used in pregnant females with a
complete regimen) in adult and pediatric patients >35 pretreatment HIV RNA ≤100,000 copies/mL or CD4 cell
kg as initial therapy in antiretroviral treatment-naive count ≥200 cells/mm3.
patients with HIV-1 RNA ≤100,000 copies/mL at the Refer to individual monographs for additional infor-
start of therapy, and in certain virologically suppressed mation.
(HIV-1 RNA <50 copies/mL) patients on a stable anti-
retroviral regimen for ≥6 months with no treatment
failure or substitutions due to resistance to emtricita-
Enalapril (e NAL a pril)
bine, rilpivirine, or tenofovir disoproxil fumarate in order Related Information
to replace their current antiretroviral treatment regimen. Cardiovascular Diseases on page 1442
Local Anesthetic/Vasoconstrictor Precautions Brand Names: US Epaned; Vasotec
No information available to require special precautions Brand Names: Canada Vasotec
Effects on Dental Treatment No significant effects or Pharmacologic Category Angiotensin-Converting
complications reported Enzyme (ACE) Inhibitor; Antihypertensive
require special precautions Asymptomatic left ventricular dysfunction: To
Adverse Reactions Observed in patients receiving the decrease the rate of development of overt heart failure
same doses of emtricitabine, rilpivirine, and tenofovir as (HF) and decrease the incidence of hospitalization for
the combination product; also see individual agents. HF in clinically stable asymptomatic left ventricular
>10%: dysfunction (ejection fraction ≤35%)
Endocrine & metabolic: Increased serum cholesterol Heart Failure: Treatment of symptomatic HF
(≤14%), increased LDL cholesterol (1% to 13%) Guideline recommendations: The American College
Hepatic: Increased serum alanine aminotransferase of Cardiology/American Heart Association (ACC/
(1% to 19%), increased serum aspartate aminotrans- AHA) 2013 Heart Failure Guidelines recommend
ferase (1% to 16%) the use of ACE inhibitors, along with other guide-
1% to 10%: line-directed medical therapies, to prevent progres-
Central nervous system: Depression (2% to 9%), sion of heart failure (HF) and reduced ejection
headache (2%), insomnia (2%), abnormal dreams fraction in asymptomatic patients with or without a
(1%), dizziness (1%) history of myocardial infarction (Stage B HF), or to
Dermatologic: Skin rash (1%) treat those with symptomatic heart failure and
Endocrine & metabolic: Adrenocortical insufficiency reduced ejection fraction to reduce morbidity and
(7%), increased serum triglycerides (1%) mortality (Stage C HFrEF).
Gastrointestinal: Nausea (1%) Hypertension: Management of hypertension
Hepatic: Increased serum bilirubin (1% to 6%) Guideline recommendations: The 2017 Guideline
Renal: Increased serum creatinine (≤6%) for the Prevention, Detection, Evaluation, and Man-
Frequency not defined: agement of High Blood Pressure in Adults recom-
Central nervous system: Anxiety, drowsiness, fatigue, mends if monotherapy is warranted, in the absence
sleep disorder of comorbidities (eg, cerebrovascular disease,
487
ENALAPRIL
chronic kidney disease, diabetes, heart failure, ische- pulmonary embolism, pulmonary infarct, pulmonary
mic heart disease, etc.), that thiazide-like diuretics or infiltrates, Raynaud's phenomenon, rhinorrhea, seros-
dihydropyridine calcium channel blockers may be itis, Sjogren's syndrome, skin photosensitivity, sore
preferred options due to improved cardiovascular throat, Stevens-Johnson syndrome, stomatitis, sys-
endpoints (eg, prevention of heart failure and stroke). temic lupus erythematosus, thrombocytopenia, tinni-
ACE inhibitors and ARBs are also acceptable for tus, toxic epidermal necrolysis, upper respiratory tract
monotherapy. Combination therapy may be required infection, urticaria, vasculitis, vertigo, visual hallucina-
to achieve blood pressure goals and is initially pre- tion (Doane, 2013), xerostomia
ferred in patients at high risk (stage 2 hypertension or Mechanism of Action Competitive inhibitor of angio-
atherosclerotic cardiovascular disease [ASCVD] risk tensin-converting enzyme (ACE); prevents conversion
≥10%) (ACC/AHA [Whelton 2017]). of angiotensin I to angiotensin II, a potent vasoconstric-
Local Anesthetic/Vasoconstrictor Precautions tor; results in lower levels of angiotensin II which causes
No information available to require special precautions an increase in plasma renin activity and a reduction in
Effects on Dental Treatment Key adverse event(s) aldosterone secretion
related to dental treatment: Abnormal taste; Patients Pharmacodynamics/Kinetics
may experience orthostatic hypotension as they stand Onset of Action ~1 hour; Peak effect: 4 to 6 hours
up after treatment; especially if lying in dental chair for Duration of Action 12 to 24 hours
extended periods of time. Use caution with sudden Half-life Elimination
changes in position during and after dental treatment. Enalapril: CHF: Neonates (n=3, PNA: 10 to 19 days):
10.3 hours (range: 4.2 to 13.4 hours) (Nakamura
An angiotensin-converting enzyme (ACE) Inhibitor
1994); CHF: Infants and Children ≤6.5 years of age
cough is a dry, hacking, nonproductive cough that can
(n=11): 2.7 hours (range: 1.3 to 6.3 hours) (Naka-
potentially interfere with longer dental procedures if
mura 1994); Adults: Healthy: 2 hours; CHF: 3.4 to 5.8
patient has this side effect.
hours
Enalaprilat: CHF: Neonates (n=3, PNA: 10 to 19
days): 11.9 hours (range: 5.9 to 15.6 hours) (Naka-
Adverse Reactions Note: Frequency ranges include mura 1994); CHF: Infants and Children ≤6.5 years of
data from hypertension and heart failure trials. Higher age (n=11): 11.1 hours (range: 5.1 to 20.8 hours)
rates of adverse reactions have generally been noted in (Nakamura 1994); Infants 6 weeks to 8 months of
patients with CHF. However, the frequency of adverse age: 6 to 10 hours (Lloyd 1989); Adults: ~35 hours
effects associated with placebo is also increased in this (Till 1984; Ulm 1982)
population.
Time to Peak Serum: Oral: Enalapril: 0.5 to 1.5 hours;
>10%: Renal: Increased serum creatinine (≤20%) Enalaprilat (active metabolite): 3 to 4.5 hours
1% to 10%: Pregnancy Considerations
Cardiovascular: Hypotension (1% to 7%), chest pain [US Boxed Warning]: Drugs that act on the renin-
(2%), orthostatic effect (1% to 2%), orthostatic hypo- angiotensin system can cause injury and death to
tension (2%), syncope (≤2%) the developing fetus. Discontinue as soon as pos-
Central nervous system: Dizziness (4% to 8%), head- sible once pregnancy is detected. Enalapril crosses
ache (2% to 5%), fatigue (2% to 3%) the placenta; the active metabolite enalaprilat can be
Dermatologic: Skin rash (1% to 2%) detected in the newborn (Schubiger 1988).
Gastrointestinal: Abdominal pain, anorexia, constipa-
Drugs that act on the renin-angiotensin system are
tion, diarrhea, dysgeusia, nausea, vomiting
associated with oligohydramnios. Oligohydramnios,
Neuromuscular & skeletal: Weakness
due to decreased fetal renal function, may lead to fetal
Renal: Renal insufficiency (in patients with bilateral
lung hypoplasia and skeletal malformations. The use of
renal artery stenosis or hypovolemia)
these drugs in pregnancy is also associated with anuria,
Respiratory: Bronchitis (1% to 2%), cough (1% to 2%),
hypotension, renal failure, skull hypoplasia, and death
dyspnea (1% to 2%)
in the fetus/neonate. Teratogenic effects may occur
following maternal use of an ACE inhibitor during the
dreams, acute generalized exanthematous pustulosis,
first trimester, although this finding may be confounded
agranulocytosis, alopecia, anaphylactoid reaction,
by maternal disease. Because adverse fetal events are
angina pectoris, angioedema, anosmia, arthralgia,
well documented with exposure later in pregnancy, ACE
arthritis, asthma, ataxia, atrial fibrillation, atrial tachy-
inhibitor use in pregnant women is not recommended
cardia, blurred vision, bone marrow depression, bra-
(Seely 2014; Weber 2014). Infants exposed to an ACE
dycardia, bronchospasm, cardiac arrest, cardiac
inhibitor in utero should be monitored for hyperkalemia,
arrhythmia, cerebrovascular accident, cholestatic
hypotension, and oliguria. Oligohydramnios may not
jaundice, confusion, conjunctivitis, depression, dia-
appear until after irreversible fetal injury has occurred.
phoresis, drowsiness, dry eye syndrome, dyspepsia,
Exchange transfusions or dialysis may be required to
eosinophilia, eosinophilic pneumonitis, erythema mul-
reverse hypotension or improve renal function, although
tiforme, exfoliative dermatitis, fever, flank pain, flush-
data related to the effectiveness in neonates is limited.
ing, giant-cell arteritis, glossitis, gynecomastia,
hallucination, hemolysis (with G6PD), hepatitis, her- Chronic maternal hypertension itself is also associated
pes zoster, hoarseness, IgA vasculitis, increased with adverse events in the fetus/infant and mother. ACE
erythrocyte sedimentation rate, intestinal obstruction, inhibitors are not recommended for the treatment of
impotence, insomnia, interstitial nephritis, jaundice, uncomplicated hypertension in pregnancy (ACOG
lacrimation, leukocytosis, lichenoid eruption, melena, 2013) and they are specifically contraindicated for the
muscle cramps, myocardial infarction, myalgia, myo- treatment of hypertension and chronic heart failure
sitis, nervousness, neutropenia, ototoxicity, palpita- during pregnancy by some guidelines (Regitz-Zagrosek
tions, pancreatitis, paresthesia, pemphigus, [ESC 2018]). In addition, ACE inhibitors should gener-
pemphigus foliaceus, peripheral neuropathy, positive ally be avoided in women of reproductive age (ACOG
ANA titer, pruritus, psychosis, pulmonary edema, 2013). If treatment for hypertension or chronic heart
488
ENASIDENIB
failure in pregnancy is needed, other agents should be due to decreased fetal renal function, may lead to fetal
used (ACOG 2013; Regitz-Zagrosek [ESC 2018]). lung hypoplasia and skeletal malformations. The use of
these drugs in pregnancy is also associated with anuria,
hypotension, renal failure, skull hypoplasia, and death
Enalaprilat (en AL a pril at)
in the fetus/neonate. Teratogenic effects may occur
Brand Names: Canada Vasotec IV following maternal use of an ACE inhibitor during the
Pharmacologic Category Angiotensin-Converting first trimester, although this finding may be confounded
Enzyme (ACE) Inhibitor; Antihypertensive by maternal disease. Because adverse fetal events are
Use Hypertension: Management of hypertension when well documented with exposure later in pregnancy, ACE
oral therapy is not practical inhibitor use in pregnant women is not recommended
(Seely 2014; Weber 2014). Infants exposed to an ACE
hypotension, and oliguria. Oligohydramnios may not
Effects on Dental Treatment Key adverse event(s) appear until after irreversible fetal injury has occurred.
related to dental treatment: Abnormal taste; Patients
Exchange transfusions or dialysis may be required to
may experience orthostatic hypotension as they stand
reverse hypotension or improve renal function, although
up after treatment; especially if lying in dental chair for
data related to the effectiveness in neonates is limited
extended periods of time. Use caution with sudden
changes in position during and after dental treatment. Chronic maternal hypertension itself is also associated
with adverse events in the fetus/infant and mother. ACE
An angiotensin-converting enzyme (ACE) Inhibitor inhibitors are not recommended for the treatment of
cough is a dry, hacking, nonproductive cough that can uncomplicated hypertension in pregnancy (ACOG
potentially interfere with longer dental procedures if 2013) and they are specifically contraindicated for the
patient has this side effect. treatment of hypertension and chronic heart failure
Effects on Bleeding No information available to during pregnancy by some guidelines (Regitz-Zagrosek
require special precautions 2011). In addition, ACE inhibitors should generally be
Adverse Reactions Since enalapril is converted to avoided in women of reproductive age (ACOG 2013). If
enalaprilat, adverse reactions associated with enalapril treatment for hypertension in pregnancy is needed,
may also occur with enalaprilat (also refer to Enalapril other agents should be used (ACOG 2013; Regitz-
monograph). Frequency ranges include data from Zagrosek 2011).
hypertension and cardiac failure trials. Higher rates of
adverse reactions have generally been noted in
patients with cardiac failure. However, the frequency Enasidenib (en a SID a nib)
of adverse effects associated with placebo is also
Brand Names: US IDHIFA
increased in this population.
1% to 10%: Pharmacologic Category Antineoplastic Agent, IDH2
Cardiovascular: Hypotension (2% to 5%) Inhibitor
Central nervous system: Headache (3%) Use Acute myeloid leukemia (relapsed/refractory):
Gastrointestinal: Nausea (1%) Treatment of relapsed or refractory acute myeloid leu-
<1%, postmarketing, and/or case reports: Angioedema, kemia (AML) in patients with an isocitrate dehydrogen-
constipation, cough, dizziness, fatigue, fever, myocar- ase-2 (IDH2) mutation as detected by an approved test
dial infarction, skin rash Local Anesthetic/Vasoconstrictor Precautions
Mechanism of Action Competitive inhibitor of angio- No information available to require special precautions
tensin-converting enzyme (ACE); prevents conversion Effects on Dental Treatment No significant effects or
of angiotensin I to angiotensin II, a potent vasoconstric- complications reported
tor; results in lower levels of angiotensin II which causes Effects on Bleeding No information available to
an increase in plasma renin activity and a reduction in require special precautions
aldosterone secretion Adverse Reactions
Onset of Action IV: ≤15 minutes; Peak effect: IV: 1-4 Endocrine & metabolic: Decreased serum calcium
hours (74%), decreased serum potassium (41%)
Duration of Action IV: ~6 hours (dose-dependent) Gastrointestinal: Nausea (50%), diarrhea (43%),
Half-life Elimination CHF: Neonates (n=3; PNA: decreased appetite (34%), vomiting (34%), dysgeu-
10-19 days): 11.9 hours (range: 5.9-15.6 hours) sia (12%)
(Nakamura, 1994); CHF: Infants and Children ≤6.5 Hematologic & oncologic: Abnormal phosphorus lev-
years of age (n=11): 11.1 hours (range: 5.1-20.8 els (27%; ≥3 grade: 8%; decreased), differentiation
hours) (Nakamura, 1994); Infants 6 weeks to 8 months syndrome (14%), leukocytosis (12%; ≥3 grade: 6%;
of age: 6-10 hours (Lloyd, 1989); Adults: ~35 hours noninfectious)
(Till, 1984; Ulm, 1982) Hepatic: Increased serum bilirubin (81%)
Pregnancy Risk Factor C (1st trimester); D (2nd and 1% to 10%:
Hematologic & oncologic: Tumor lysis syndrome (6%)
3rd trimesters)
Respiratory: Acute respiratory distress (≤10%), pulmo-
Pregnancy Considerations [US Boxed Warning]:
nary edema (≤10%)
Drugs that act on the renin-angiotensin system
can cause injury and death to the developing fetus.
Mechanism of Action Enasidenib is a small molecule
inhibitor of the enzyme isocitrate dehydrogenase 2
Discontinue as soon as possible once pregnancy is
(IDH2); it targets the mutant IDH2 variants R140Q,
detected. Enalapril crosses the placenta; the active
R172S, and R172K at ~40-fold lower concentrations
metabolite enalaprilat can be detected in the newborn
than the wild-type enzyme. Mutant IDH2 inhibition
(Schubiger 1988).
results in decreased 2-hydroxyglutarate (2-HG) levels,
Drugs that act on the renin-angiotensin system are reduced abnormal histone hypermethylation, and
associated with oligohydramnios. Oligohydramnios, restored myeloid differentiation (Stein 2017).
489
ENASIDENIB
Additionally, enasidenib reduces blast counts and (16% to 38%), pruritus (13% to 31%), dermatological
increases percentages of mature myeloid cells. reaction (2% to 21%), erythema (7% to 16%)
Pharmacodynamics/Kinetics Endocrine & metabolic: Increased gamma-glutamyl
Half-life Elimination 137 hours transferase (45%), hyperglycemia (28%), hyponatre-
Time to Peak 4 hours mia (18%)
Pregnancy Considerations Based on the mecha- Gastrointestinal: Nausea (41%), vomiting (30%),
nism of action and data from animal reproduction abdominal pain (28%), constipation (22%), dysgeu-
studies, the use of enasidenib in pregnancy may cause sia (6% to 13%)
fetal harm. Women of reproductive potential should Hematologic & oncologic: Anemia (36%; grades 3/4:
have a pregnancy test prior to treatment initiation; 4%), hemorrhage (19%; grades 3/4: 3%), leukopenia
effective contraception should be used during therapy (13%), lymphocytopenia (13%; grades 3/4: 2%),
and for at least 1 month after the last dose. Male neutropenia (13%; grades 3/4: 3%)
patients with female partners of reproductive potential Hepatic: Increased serum alanine aminotransferase
should also use effective contraception during therapy (29%), increased serum aspartate aminotransferase
and for at least 1 month after the last dose. Based on (27%), increased serum alkaline phosphatase (21%)
animal data, treatment with enasidenib may impair Neuromuscular & skeletal: Arthralgia (26% to 44%),
fertility in females and males. myopathy (23% to 33%), back pain (9% to 15%),
Prescribing and Access Restrictions Enasidenib is limb pain (11%)
available through select specialty pharmacies and Renal: Increased serum creatinine (93%)
authorized distributors. Refer to http://www.idhifa.com Miscellaneous: Fever (18%)
for further information. 1% to 10%:
Central nervous system: Facial paresis (<10%)
Encorafenib (en koe RAF e nib) Dermatologic: Acneiform eruption (3% to 8%)
Endocrine & metabolic: Hypermagnesemia (10%)
Brand Names: US Braftovi Gastrointestinal: Pancreatitis (<10%), hematochezia
Pharmacologic Category Antineoplastic Agent, (3%), hemorrhoidal bleeding (1%)
BRAF Kinase Inhibitor Hypersensitivity: Hypersensitivity (<10%)
Use Hematologic & oncologic: Squamous cell carcinoma of
Melanoma, unresectable or metastatic: Treatment of skin (3% to 8%), malignant melanoma (5%), rectal
unresectable or metastatic melanoma with a BRAF hemorrhage (4%), keratoacanthoma (3%), basal cell
V600E or V600K mutation (in combination with bini- carcinoma (1% to 2%)
metinib) as detected by an approved test. Neuromuscular & skeletal: Panniculitis (<10%)
Limitations of use: Encorafenib is not indicated for Ophthalmic: Uveitis (4%)
treatment of wild-type BRAF melanoma.
<1%, postmarketing, and/or case reports: Prolonged
Local Anesthetic/Vasoconstrictor Precautions QT interval on ECG
BRAF kinase inhibitors, including encorafinib, are asso-
Mechanism of Action Encorafenib is an ATP-compet-
ciated with prolonging the QT interval. Encorafenib is
itive inhibitor of protein kinase B-raf (BRAF) which
one of the drugs confirmed to prolong the QT interval
suppresses the MAPK pathway (Dummer 2018). Encor-
and is accepted as having a risk of causing torsade de
pointes. The risk of drug-induced torsade de pointes is afenib targets BRAF V600E, V600 D, and V600 K, and
extremely low when a single QT interval-prolonging has a longer dissociation half-life than other BRAF
drug is prescribed. In terms of epinephrine, it is not inhibitors, allowing for sustained inhibition (Dummer
known what effect vasoconstrictors in the local anes- 2018). BRAF V600 mutations result in constitutive
thetic regimen will have in patients with a known history activation of the BRAF pathway (which may stimulate
of congenital prolonged QT interval or in patients taking tumor growth); BRAF inhibition inhibits tumor cell
any medication that prolongs the QT interval. Until more growth. The combination of encorafenib and binimetinib
information is obtained, it is suggested that the clinician allows for greater antitumor activity in BRAF V600
consult with the physician prior to the use of a vaso- mutant cell lines; in animal studies, the combination
constrictor in suspected patients, and that the vaso- also delayed the emergence of resistance in BRAF
constrictor (epinephrine, mepivacaine, and V600E mutant cells compared to either drug alone.
levonordefrin [Carbocaine 2% with Neo-Cobefrin]) be Pharmacodynamics/Kinetics
used with caution. Half-life Elimination 3.5 hours
Effects on Dental Treatment Key adverse event(s) Time to Peak 2 hours
related to dental treatment: Facial paresis has been Pregnancy Considerations
reported Based on its mechanism of action and on findings in
Effects on Bleeding Hemorrhage has been reported; animal reproduction studies, encorafenib may cause
none involving the oral cavity fetal harm if administered during pregnancy.
Adverse Reactions Incidences of adverse reactions
include those defined during combination therapy with Verify pregnancy status in females of reproductive
binimetinib. Encorafenib when used as a single agent is potential prior to initiating encorafenib therapy. Females
associated with an increased risk of certain adverse of reproductive potential should use a highly effective
reactions. nonhormonal contraceptive during therapy and for at
>10%: least 2 weeks after the last encorafenib dose; hormonal
Central nervous system: Fatigue (43%), headache contraceptives may not be effective. Fertility may be
(22%), dizziness (15%), peripheral neuropa- impaired in males.
thy (12%) Prescribing and Access Restrictions Encorafenib
Dermatologic: Hyperkeratosis (23% to 57%), alopecia is available through a network of select specialty phar-
(14% to 56%), palmar-plantar erythrodysesthesia macies. Refer to https://www.braftovimektovi.com/hcp/
(7% to 51%), skin rash (22% to 41%), xeroderma for more information.
490
ENOXAPARIN
Time to Peak SubQ: Single dose: Median: 8 hours

Enfuvirtide (en FYOO vir tide) (range: 3 to 12 hours); Multiple dosing: Median: 4
hours (range: 4 to 8 hours)
Related Information Pregnancy Considerations
HIV Infection and AIDS on page 1477 Enfuvirtide has minimal to low transfer across the
Brand Names: US Fuzeon human placenta.
Brand Names: Canada Fuzeon
Pharmacologic Category Antiretroviral, Fusion Pro- Data collected by the antiretroviral pregnancy registry
tein Inhibitor (Anti-HIV) are insufficient to evaluate human teratogenic risk.
Use HIV-1 infection: Treatment of HIV-1 infection in Maternal antiretroviral therapy (ART) may increase the
combination with other antiretroviral agents in treat- risk of preterm delivery, although available information
ment-experienced patients with evidence of HIV-1 rep- is conflicting possibly due to variability of maternal
lication despite ongoing antiretroviral therapy factors (disease severity; gestational age at initiation
Local Anesthetic/Vasoconstrictor Precautions of therapy). An increased risk of stillbirth, low birth
No information available to require special precautions weight, and small for gestational age infants has been
Effects on Dental Treatment Key adverse event(s) observed in some but not all studies. Because there is
related to dental treatment: Xerostomia (normal salivary clear benefit to appropriate treatment, maternal ART
flow resumes upon discontinuation) and taste disturb- should not be withheld due to concerns for adverse
ance neonatal outcomes. Long-term follow-up is recom-
Effects on Bleeding No information available to mended for all infants exposed to antiretroviral medi-
require special precautions related to hemostasis. cations; children who develop significant organ system
abnormalities of unknown etiology (particularly of the
Adverse Reactions
CNS or heart) should be evaluated for potential mito-
>10%:
chondrial dysfunction.
Central nervous system: Fatigue (20%), insom-
nia (11%) The Health and Human Services (HHS) Perinatal HIV
Gastrointestinal: Diarrhea (32%), nausea (23%) Guidelines do not recommend enfuvirtide for HIV-
Local: Injection site reaction (98%; may include cyst at infected pregnant females who are antiretroviral-naive
injection site, erythema at injection site, induration at (due to insufficient data); enfuvirtide is not recom-
injection site, injection site ecchymosis, injection site mended (except in special circumstances) in pregnant
nodule, injection site pruritus, pain at injection site), females who have had ART therapy in the past but are
injection site infection (children: 11%, adults: 2%) restarting, who require a new ART regimen (due to poor
1% to 10%: tolerance or poor virologic response of current regi-
Dermatologic: Folliculitis (2%) men), and who are not yet pregnant but are trying to
Endocrine & metabolic: Weight loss (7%) conceive. Females who become pregnant while taking
Gastrointestinal: Abdominal pain (4%), decreased enfuvirtide may continue if viral suppression is effective
appetite (3%), pancreatitis (3%), anorexia (2%), and the regimen is well tolerated. Pharmacokinetic data
xerostomia (2%) are insufficient to make dosing recommendations dur-
Hematologic & oncologic: Eosinophilia (2% to 9%) ing pregnancy.
Hepatic: Increased serum transaminases (4%, grade
4: 1%) In general, ART is recommended for all pregnant
Infection: Infection (4% to 6%), herpes simplex infec- females with HIV to keep the viral load below the limit
tion (4%) of detection and reduce the risk of perinatal trans-
Neuromuscular & skeletal: Increased creatine phos- mission. Monitoring during pregnancy is more frequent
phokinase (3% to 7%), limb pain (3%), myalgia (3%) than in non-pregnant adults. ART should be continued
Ophthalmic: Conjunctivitis (2%) postpartum for all females living with HIV and can be
Respiratory: Sinusitis (6%), cough (4%), bacterial modified after delivery.
pneumonia (3%), flu-like symptoms (2%) Health care providers are encouraged to enroll preg-
<1%, postmarketing, and/or case reports: Amyloidosis nant females exposed to antiretroviral medications as
(cutaneous; at the injection site), angina pectoris, early in pregnancy as possible in the Antiretroviral
anxiety, constipation, depression, dysgeusia, glomer- Pregnancy Registry (1-800-258-4263 or http://www.-
ulonephritis, Guillain-Barré syndrome, hyperglycemia; APRegistry.com). Health care providers caring for
hypersensitivity exacerbation (to abacavir), hypersen- HIV-infected females and their infants may contact the
sitivity reaction (symptoms may include fever, hypo- National Perinatal HIV Hotline (888-448-8765) for clin-
tension, increased serum transaminases, nausea, ical consultation (HHS [perinatal] 2018).
skin rash, vomiting); increased amylase, increased
gamma-glutamyl transferase, insomnia, increased
serum lipase, increased serum triglycerides, liver stea- Enoxaparin (ee noks a PA rin)
tosis, lymphadenopathy, neutropenia, peripheral neu-
ropathy, pulmonary disease, renal failure, renal Related Information
insufficiency, renal tubular necrosis, respiratory dis- Cardiovascular Diseases on page 1442
tress, sepsis, sixth nerve palsy, suicidal tendencies, Brand Names: US Lovenox
thrombocytopenia, toxic hepatitis, weakness Brand Names: Canada Lovenox; Lovenox HP; Love-
Mechanism of Action Binds to the first heptad-repeat nox With Preservative
(HR1) in the gp41 subunit of the viral envelope glyco- Pharmacologic Category Anticoagulant; Anticoagu-
protein. Inhibits the fusion of HIV-1 virus with CD4 cells lant, Low Molecular Weight Heparin
by blocking the conformational change in gp41 required Use
for membrane fusion and entry into CD4 cells Acute coronary syndromes: Unstable angina (UA),
Pharmacodynamics/Kinetics non-ST elevation myocardial infarction (NSTEMI), and
Half-life Elimination 3.8 ± 0.6 hours ST elevation myocardial infarction (STEMI)
491
ENOXAPARIN
VTE prophylaxis: Following hip or knee replacement (following long-term therapy), pneumonia, pruritus,
surgery, abdominal surgery, or in medical patients with pulmonary edema, purpura, shock, skin necrosis,
severely restricted mobility during acute illness who thrombocythemia, thrombosis in heparin-induced
are at risk for thromboembolic complications. Note: thrombocytopenia, thrombosis (prosthetic value [in
Patients at risk of thromboembolic complications who pregnant females] or associated with enoxaparin-
undergo abdominal surgery include those with one or induced thrombocytopenia; can cause limb ischemia
more of the following risk factors: age >40 years, or organ infarction), urticaria, vesicobullous rash
obesity, general anesthesia lasting >30 minutes, Mechanism of Action Standard heparin consists of
malignancy, history of DVT or PE.
components with molecular weights ranging from 4000
DVT treatment (acute): Inpatient treatment (patients
to 30,000 daltons with a mean of 16,000 daltons.
with or without PE) and outpatient treatment (patients
without PE). Note: In patients with VTE (ie, DVT or Heparin acts as an anticoagulant by enhancing the
PE) and without cancer, oral anticoagulants are pre- inhibition rate of clotting proteases by antithrombin III
ferred over low-molecular-weight heparin (LMWH) impairing normal hemostasis and inhibition of factor Xa.
(unless LMWH is used as initial parenteral anticoagu- Low molecular weight heparins have a small effect on
lation prior to dabigatran, edoxaban, or while initiating the activated partial thromboplastin time and strongly
warfarin). In patients with VTE (ie, DVT or PE) and inhibit factor Xa. Enoxaparin is derived from porcine
cancer, ACCP recommends LMWH over oral antico- heparin that undergoes benzylation followed by alkaline
agulants for initial and long-term treatment (ACCP depolymerization. The average molecular weight of
[Kearon 2012]; ACCP [Kearon 2016]). enoxaparin is 4500 daltons which is distributed as
Local Anesthetic/Vasoconstrictor Precautions (≤20%) 2000 daltons (≥68%) 2000 to 8000 daltons,
No information available to require special precautions and (≤18%) >8000 daltons. Enoxaparin has a higher
Effects on Dental Treatment Key adverse event(s) ratio of antifactor Xa to antifactor IIa activity than
related to dental treatment: Bleeding is the major unfractionated heparin.
adverse effect of enoxaparin. See Effects on Bleeding. Pharmacodynamics/Kinetics
Effects on Bleeding As with all anticoagulants, bleed- Onset of Action Peak effect: SubQ: Antifactor Xa and
ing is the major adverse effect of enoxaparin. Hemor- antithrombin (antifactor IIa): 3 to 5 hours
rhage may occur at virtually any site. Routine Duration of Action 40 mg dose: Antifactor Xa activ-
coagulation tests, such as prothrombin time (PT) and ity: ~12 hours
aPTT, are relatively insensitive measures of enoxaparin
Half-life Elimination Plasma: 2 to 4 times longer than
injection activity and, therefore, unsuitable for monitor-
standard heparin, independent of dose; based on anti-
ing. Moderate thrombocytopenia occurred at a rate of
Xa activity: 4.5 to 7 hours
~1%. Medical consult is suggested.
Adverse Reactions As with all anticoagulants, bleed- Pregnancy Considerations
ing is the major adverse effect of enoxaparin. Hemor- Low molecular weight heparin (LMWH) does not cross
rhage may occur at virtually any site. Risk is dependent the placenta; increased risks of fetal bleeding or terato-
on multiple variables. At the recommended doses, genic effects have not been reported (Bates 2012).
single injections of enoxaparin do not significantly influ- LMWH is recommended over unfractionated heparin for
ence platelet aggregation or affect global clotting time the treatment of acute VTE in pregnant women. LMWH
(ie, PT or aPTT).
is also recommended over unfractionated heparin for
>10%: Hematologic & oncologic: Anemia (≤16%), hem-
VTE prophylaxis in pregnant women with certain risk
orrhage (4% to 13%)
1% to 10%: factors (eg, homozygous factor V Leiden, antiphospho-
Cardiovascular: Peripheral edema (6%) lipid antibody syndrome with ≥3 previous pregnancy
Central nervous system: Confusion (2%) losses). Prophylaxis is not routinely recommended for
Gastrointestinal: Nausea (3%) women undergoing assisted reproduction therapy; how-
Hematologic & oncologic: Major hemorrhage (<1% to ever, LMWH therapy is recommended for women who
4%; includes cases of intracranial [up to 0.8%], develop severe ovarian hyperstimulation syndrome. For
retroperitoneal, or intraocular hemorrhage; incidence women undergoing cesarean section and who have
varies with indication/population), ecchymoses (3%), additional risk factors for developing VTE, the prophy-
thrombocytopenia (1% to 2%) lactic use of LMWH may be considered (Bates 2012).
Hepatic: Increased serum ALT (>3 x ULN: 6%), Consult current recommendations for appropriate use in
increased serum AST (>3 x ULN: 6%) pregnant women.
Local: Hematoma at injection site (9%), bleeding at
injection site (3% to 5%), pain at injection site (2%) LMWH may also be used in women with mechanical
Renal: Hematuria (≤2%) heart valves (consult current guidelines for details)
Miscellaneous: Fever (≤8%) (Bates 2012; Nishimura 2014). Women who require
<1%, postmarketing, and/or case reports: Acute post- long-term anticoagulation with warfarin and who are
hemorrhagic anemia, alopecia, anaphylactoid reac- considering pregnancy, LMWH substitution should be
tion, anaphylaxis, atrial fibrillation, bruising at done prior to conception when possible. When choos-
injection site, eosinophilia, epidural hematoma (spinal; ing therapy, fetal outcomes (ie, pregnancy loss, malfor-
after neuroaxial anesthesia or spinal puncture; risk mations), maternal outcomes (ie, VTE, hemorrhage),
may be increased with indwelling epidural catheter burden of therapy, and maternal preference should be
or concomitant use of other drugs affecting hemo- considered (Bates 2012). Monitoring antifactor Xa lev-
stasis), erythema at injection site, headache, hepatic els is recommended (Bates 2012; Nishimura 2014).
injury (hepatocellular and cholestatic), hyperkalemia,
hyperlipidemia (very rare), hypersensitivity angiitis, Multiple-dose vials contain benzyl alcohol (avoid in
hypersensitivity reaction, hypertriglyceridemia, injec- pregnant women due to association with gasping syn-
tion site reactions (including nodules, inflammation, drome in premature infants); use of preservative-free
oozing), irritation at injection site, osteoporosis formulations is recommended.
492
ENTECAVIR
Half-life Elimination Beta phase: 0.4 to 0.7 hours;

Entacapone (en TA ka pone) gamma phase: 2.4 hours
Time to Peak Serum: 1 hour
Brand Names: US Comtan Pregnancy Considerations Adverse events were
Brand Names: Canada Comtan; Mylan-Entacapone; observed in some animal reproduction studies. The
Sandoz-Entacapone; Teva-Entacapone incidence of Parkinson disease in pregnancy is rela-
Pharmacologic Category Anti-Parkinson Agent, tively rare and information related to the use of entaca-
COMT Inhibitor pone in pregnant women is very limited (Kranick, 2010).
Use Parkinson disease: Adjunct to levodopa/carbidopa
therapy in patients with idiopathic Parkinson disease
who experience "wearing-off" symptoms at the end of a Entecavir (en TE ka veer)
dosing interval Related Information
Local Anesthetic/Vasoconstrictor Precautions HIV Infection and AIDS on page 1477
Brand Names: US Baraclude
related to dental treatment: Abnormal taste; Dopami-
nergic therapy in Parkinson's disease (ie, treatment with
Brand Names: Canada Apo-Entecavir; Auro-Enteca-
vir; Baraclude; PMS-Entecavir
levodopa) is associated with orthostatic hypotension.
Entacapone enhances levodopa bioavailability and may Pharmacologic Category Antihepadnaviral, Reverse
Transcriptase Inhibitor, Nucleoside (Anti-HBV)
increase the occurrence of hypotension/syncope in the
dental patient. Patients may experience orthostatic Use Chronic hepatitis B: Treatment of chronic hepatitis
hypotension as they stand up after treatment; especially B virus (HBV) infection in adults and pediatric patients 2
years and older with evidence of active viral replication
if lying in dental chair for extended periods of time. Use
and either evidence of persistent transaminase eleva-
caution with sudden changes in position during and
tions or histologically-active disease. Note: In adults,
after dental treatment.
indication is based on data in patients with compen-
Effects on Bleeding No information available to sated and decompensated liver disease; in children,
indication is based on data in patients with compen-
Adverse Reactions sated liver disease.
Gastrointestinal: Nausea (14%) No information available to require special precautions
Neuromuscular & skeletal: Dyskinesia (25%) Effects on Dental Treatment No significant effects or
1% to 10%: complications reported
Cardiovascular: Syncope (1%)
Central nervous system: Dizziness (8%), fatigue (6%),
require special precautions related to hemostasis.
anxiety (2%), drowsiness (2%), agitation (1%), hallu-
Adverse Reactions As reported with adult patients,
cination (≤1%)
unless otherwise noted.
Dermatologic: Diaphoresis (increased; 2%)
>10%: Hepatic: Increased serum alanine aminotrans-
Gastrointestinal: Diarrhea (10%), abdominal pain
ferase (>5 x ULN: 11% to 12%; >10 x ULN and >2 x
(8%), constipation (6%), vomiting (4%), xerostomia baseline: 2%)
(3%), dyspepsia (2%), flatulence (2%), dysgeusia 1% to 10%:
(1%), gastritis (1%), gastrointestinal disease (1%) Central nervous system: Headache (2% to 4%),
Genitourinary: Urine discoloration (brown- fatigue (1% to 3%)
orange; 10%) Dermatologic: Skin rash (>1%)
Hematologic & oncologic: Purpura (2%) Endocrine & metabolic: Glycosuria (4%), hyperglyce-
Infection: Bacterial infection (1%) mia (2% to 3%)
Neuromuscular & skeletal: Hyperkinesia (10%), hypo- Gastrointestinal: Increased serum lipase (7%),
kinesia (9%), back pain (2% to 4%), weakness (2%) abdominal pain (children and adolescents: >1%),
Respiratory: Dyspnea (3%) diarrhea (children and adolescents: >1%; adults:
<1%, postmarketing, and/or case reports: Behavioral ≤1%), nausea (children and adolescents: >1%;
changes (including psychotic-like behavior), hepatitis adults: <1%), unpleasant taste (children and adoles-
(mainly cholestatic features), impulse control disorder cents: >1%), vomiting (children and adolescents:
(eg, pathological gambling, hypersexuality, spending >1%; adults: <1%), dyspepsia (≤1%)
money), mental status changes, neurological signs Genitourinary: Hematuria (9%)
and symptoms (hyperpyrexia and confusion [resem- Hepatic: Increased serum bilirubin (2% to 3%)
bling neuroleptic malignant syndrome]), orthostatic Renal: Increased serum creatinine (1% to 2%)
hypotension, pulmonary fibrosis, retroperitoneal fibro- <1%, postmarketing, and/or case reports: Alopecia,
sis, rhabdomyolysis, sudden onset of sleep anaphylactoid shock, dizziness, drowsiness, hepato-
Mechanism of Action Entacapone is a reversible and megaly, hepatomegaly with steatosis, hypoalbumine-
selective inhibitor of catechol-O-methyltransferase mia, increased serum transaminases, insomnia, lactic
(COMT). When entacapone is taken with levodopa, acidosis, macular edema (Muqit 2011), thrombocyto-
the pharmacokinetics are altered, resulting in more penia
sustained levodopa serum levels compared to levodopa Mechanism of Action Entecavir is intracellularly phos-
taken alone. The resulting levels of levodopa provide for phorylated to guanosine triphosphate which competes
increased concentrations available for absorption with natural substrates to effectively inhibit hepatitis B
across the blood-brain barrier, thereby providing for viral polymerase; enzyme inhibition blocks reverse tran-
increased CNS levels of dopamine, the active metabo- scriptase activity thereby reducing viral DNA synthesis.
lite of levodopa. Pharmacodynamics/Kinetics
Pharmacodynamics/Kinetics Half-life Elimination Terminal: ~5-6 days; accumu-
Onset of Action Rapid lation: ~24 hours
493
ENTECAVIR
Time to Peak 0.5-1.5 hours inhibits androgen receptor nuclear translocation, DNA
Pregnancy Considerations binding, and coactivator mobilization, leading to cellular
Teratogenic effects have been observed in animal apoptosis and decreased prostate tumor volume.
studies. Information related to use in pregnancy is Pharmacodynamics/Kinetics
limited. Other agents may be preferred for the treatment Half-life Elimination Parent drug: 5.8 days (range:
of chronic hepatitis B in pregnancy (AASLD [Terrault 2.8 to 10.2 days); N-desmethyl enzalutamide: 7.8 to
2016]). 8.6 days
Time to Peak 1 hour (range: 0.5 to 3 hours)
Pregnant women taking entecavir should enroll in the
pregnancy registry by calling 1-800-258-4263. Pregnancy Considerations Enzalutamide is not indi-
cated for use in females. Based on animal reproduction
studies and on the mechanism of action, fetal harm and
Enzalutamide (en za LOO ta mide) loss of pregnancy would be expected. Male patients
with female partners of reproductive potential should
Brand Names: US Xtandi use effective contraception during treatment and for 3
Brand Names: Canada Xtandi months after the last enzalutamide dose. Females who
Pharmacologic Category Antineoplastic Agent, Anti- are or may become pregnant should not handle enza-
androgen lutamide. May cause hypospermatogenesis; may impair
Use Prostate cancer: Treatment of castration-resistant male fertility.
prostate cancer
No information available to require special precautions EPHEDrine (Systemic) (e FED rin)
Brand Names: US Akovaz
Effects on Bleeding Although significant myelosup- Pharmacologic Category Alpha/Beta Agonist
pression with associated altered hemostasis has been Use Hypotension, anesthesia-induced: Treatment of
reported for many chemotherapeutic agents, myelosup- anesthesia-induced hypotension
pression is not common with enzalutamide and no Note: The use of ephedrine for the treatment of acute
specific precautions appear to necessary. bronchospasm, Stokes-Adams syndrome (ie, presyn-
Adverse Reactions cope/syncope) with complete heart block, narcolepsy,
>10%: depression, or myasthenia gravis has fallen out of
Cardiovascular: Peripheral edema (12% to 15%), favor given the availability of more effective agents
hypertension (6% to 14%) for these conditions.
Central nervous system: Fatigue (≤51%), falling (5% Local Anesthetic/Vasoconstrictor Precautions
to 13%), dizziness (10% to 12%), headache (9% Use vasoconstrictor with caution since ephedrine may
to 12%) enhance cardiostimulation and vasopressor effects of
Endocrine & metabolic: Hypoglycemia (78%), hypo- sympathomimetics such as epinephrine
magnesemia (26%), hot flash (13% to 20%), hypo- Effects on Dental Treatment Key adverse event(s)
natremia (16%), weight loss (6% to 12%) related to dental treatment: Xerostomia (normal salivary
Gastrointestinal: Constipation (9% to 23%), diarrhea flow resumes upon discontinuation)
(12% to 22%), decreased appetite (10% to 19%), Effects on Bleeding No information available to
nausea (11% to 14%) require special precautions
Hematologic & oncologic: Neutropenia (8% to 15%; Adverse Reactions Frequency not defined.
grades 3/4: 1%) Cardiovascular: Angina pectoris, bradycardia, cardiac
Neuromuscular & skeletal: Asthenia (≤51%), back arrhythmia, hypertension, palpitations, pulse irregular-
pain (19% to 29%), arthralgia (21%), musculoskele- ity, tachycardia, ventricular ectopy, visceral vasocon-
tal pain (15% to 16%) striction (renal)
Respiratory: Upper respiratory tract infection (11% to Central nervous system: Anxiety, confusion, delirium,
16%), dyspnea (11%) dizziness, hallucination, headache, insomnia, intracra-
1% to 10%: nial hemorrhage, nervousness, precordial pain, rest-
Cardiovascular: Ischemic heart disease (3%) lessness, tension, vertigo
Central nervous system: Myasthenia (10%), insomnia Dermatologic: Diaphoresis, pallor
(8% to 9%), paresthesia (7%), cauda equina syn-
Gastrointestinal: Anorexia, nausea, vomiting
drome (≤7%), spinal cord compression (≤7%), anxi-
Genitourinary: Dysuria, oliguria, urinary retention
ety (3% to 7%), altered mental status (4% to 6%),
(males with prostatism)
cognitive dysfunction (5%), hypoesthesia (4%), rest-
Neuromuscular & skeletal: Tremor, vesicle sphincter
less leg syndrome (2%)
spasm, weakness
Dermatologic: Pruritus (4%), xeroderma (4%)
Respiratory: Dyspnea
Endocrine & metabolic: Gynecomastia (3%)
Gastrointestinal: Dysgeusia (8%) Miscellaneous: Tachyphylaxis
Genitourinary: Hematuria (7% to 9%), pollakiuria (5%) Mechanism of Action Releases tissue stores of nor-
Neuromuscular & skeletal: Bone fracture (4% to 10%), epinephrine and thereby produces an alpha- and beta-
stiffness (3%) adrenergic stimulation; longer-acting and less potent
Respiratory: Lower respiratory tract infection (8% to than epinephrine
9%), epistaxis (3%) Pharmacodynamics/Kinetics
<1%, postmarketing, and/or case reports: Hypersensi- Onset of Action IM: Within 10 to 20 minutes.
tivity reaction, reversible posterior leukoencephalop- Duration of Action Pressor/cardiac effects: SubQ: 1
athy syndrome, seizure, skin rash, vomiting hour
Mechanism of Action Enzalutamide is a pure andro- Half-life Elimination Dependent upon urinary pH;
gen receptor signaling inhibitor; unlike other antiandro- Urine pH 5: ~3 hours; Urine pH 6.3: ~6 hours
gen therapies, it has no known agonistic properties. It Pregnancy Risk Factor C
494
EPINEPHRINE (SYSTEMIC)
Pregnancy Considerations Animal reproduction Guideline recommendations: Septic shock: The

studies have not been conducted. Ephedrine crosses Surviving Sepsis Campaign guidelines recommend
the placenta (Hughes, 1985). Ephedrine injection is epinephrine, if needed, be used in addition to nor-
used at delivery for the prevention and/or treatment of epinephrine (the preferred first-line single-agent vas-
maternal hypotension associated with spinal anesthesia opressor) for the intent of raising mean arterial
in women undergoing cesarean section (ASA, 2007). pressure (MAP) to target (Rhodes 2017).
Serious postpartum hypertension and possibly stroke Mydriasis during intraocular surgery (product spe-
may occur if administered with oxytocic medications. cific): Induction and maintenance of mydriasis during
Metabolic acidosis has been reported in neonates intraocular surgery. Note: Not all formulations of epi-
following maternal use of ephedrine; monitor. nephrine injection are suitable for intraocular use;
consult the prescribing information.
Epinastine (ep i NAS teen) Local Anesthetic/Vasoconstrictor Precautions
Brand Names: US Elestat Effects on Dental Treatment Key adverse event(s)
Pharmacologic Category Histamine H1 Antagonist; related to dental treatment: Xerostomia (normal salivary
Histamine H1 Antagonist, Second Generation flow resumes upon discontinuation) and dry throat.
Use Treatment of allergic conjunctivitis Effects on Bleeding No information available to
No information available to require special precautions Adverse Reactions Frequency not defined.
Effects on Dental Treatment No significant effects or Cardiovascular: Angina pectoris, cardiac arrhythmia,
complications reported cardiomyopathy (stress), cerebrovascular accident,
Effects on Bleeding No information available to chest pain, hypertension, ischemic heart disease, limb
require special precautions ischemia, localized blanching, myocardial infarction,
Adverse Reactions palpitations, supraventricular tachycardia, tachyar-
Frequency not always defined. rhythmia, tachycardia, vasoconstriction, ventricular
1% to 10%: arrhythmia, ventricular ectopy, ventricular fibrillation
Central nervous system: Headache (1% to 3%) Central nervous system: Anxiety, apprehension, disori-
Infection: Infection (10%; defined as cold symptoms entation, dizziness, drowsiness, exacerbation of Par-
and upper respiratory tract infection) kinson disease, excitability, headache, memory
Ophthalmic: Burning sensation of eyes, eye pruritus, impairment, nervousness, panic, paresthesia, psycho-
follicular conjunctivitis, ocular hyperemia motor agitation, restlessness, tingling sensation
Respiratory: Cough (1% to 3%), pharyngitis (1% to Dermatologic: Diaphoresis, gangrene of skin or other
3%), rhinitis (1% to 3%), sinusitis (1% to 3%) tissue (at injection site), pallor, piloerection, skin
<1%, postmarketing, and/or case reports: Increased necrosis (with extravasation)
lacrimation Endocrine & metabolic: Hyperglycemia, hypoglycemia,
Mechanism of Action Selective H1-receptor antago- hypokalemia, increased serum glucose (transient),
nist; inhibits release of histamine from the mast cell; insulin resistance, lactic acidosis
also has affinity for the H2, alpha1, alpha2, and the Gastrointestinal: Nausea, vomiting
5-HT2 receptors Hematologic & oncologic: Hemorrhage (CNS)
Pharmacodynamics/Kinetics Local: Injection site tissue necrosis (including necrotiz-
Onset of Action 3-5 minutes ing fasciitis and myonecrosis)
Duration of Action 8 hours Neuromuscular & skeletal: Tremor, weakness
Half-life Elimination 12 hours Renal: Renal insufficiency
Pregnancy Risk Factor C Respiratory: Dyspnea, pulmonary edema, rales
Pregnancy Considerations Teratogenic effects were Dental Usual Dosage Hypersensitivity reaction: Self-
not observed in animal studies. There are no adequate administration following severe allergic reactions (eg,
and well-controlled studies in pregnant women. insect stings, food): Note: World Health Organization
(WHO) and Anaphylaxis Canada recommend the avail-
EPINEPHrine (Systemic) (ep i NEF rin) ability of 1 dose for every 10 to 20 minutes of travel time
to a medical emergency facility. More than 2 sequential
Brand Names: US Adrenaclick [DSC]; Adrenalin; doses should only be administered under direct medical
Adyphren; Adyphren Amp; Adyphren Amp II; Adyphren supervision.
II; Auvi-Q; EpinephrineSnap-EMS; Epinephrinesnap-v; Children:
EpiPen 2-Pak; EpiPen Jr 2-Pak; EPIsnap; EPY II Adrenaclick: IM, SubQ:
[DSC]; EPY [DSC]; Symjepi Children 15 to 29 kg: 0.15 mg
Brand Names: Canada Adrenalin; Allerject; Anapen; Children ≥30 kg: 0.3 mg
Anapen Junior; EpiPen; EpiPen Jr; Twinject Auvi-Q: IM, SubQ:
Generic Availability (US) May be product dependent Children 15 to 29 kg: 0.15 mg; if anaphylactic symp-
Pharmacologic Category Alpha/Beta Agonist toms persist, dose may be repeated
Dental Use Emergency drug for treatment of anaphy- Children ≥30 kg: 0.3 mg; if anaphylactic symptoms
lactic reactions; used as vasoconstrictor to prolong local persist, dose may be repeated
anesthesia EpiPen Jr: IM, SubQ: Children 15 to 29 kg: 0.15 mg; if
Use anaphylactic symptoms persist, dose may be
Hypersensitivity: Treatment of type I allergic reac- repeated in 5 to 15 minutes using an additional
tions, including anaphylactic reactions. EpiPen Jr
Hypotension/shock: Treatment of hypotension asso- EpiPen: IM, SubQ: Children ≥30 kg: 0.3 mg; if ana-
ciated with septic shock in adults (increase mean phylactic symptoms persist, dose may be repeated in
arterial blood pressure). 5 to 15 minutes using an additional EpiPen
495
Twinject: IM SubQ: [Lieberman 2015]; AHA [Vanden Hoek 2010];

Children 15 to 29 kg: 0.15 mg; if anaphylactic symp- WAO [Kemp 2008]).
toms persist, dose may be repeated in 5 to 15 IV:
minutes using the same device after partial disas- Slow IV bolus: 0.1 mg using the 0.1 mg/mL solu-
sembly tion (further diluted in 10 mL of NS) administered
Children ≥30 kg: 0.3 mg; if anaphylactic symptoms over 5 to 10 minutes (Barach 1984)
persist, dose may be repeated in 5 to 15 minutes Continuous infusion: May initiate with an infusion at
using the same device after partial disassembly 2 to 15 mcg/minute (with crystalloid administra-
Adults: tion) (AAAAI [Lieberman 2015]; AHA [Vanden
Adrenaclick: IM, SubQ: 0.3 mg Hoek 2010]; Brown 2004).
Auvi-Q: IM, SubQ: 0.3 mg; if anaphylactic symptoms Note: In general, IV administration should only be
persist, dose may be repeated done in patients who are unresponsive or pro-
EpiPen: IM, SubQ: 0.3 mg; if anaphylactic symptoms foundly hypotensive who have failed to respond
persist, dose may be repeated in 5 to 15 minutes to IV fluid replacement and several epinephrine
using an additional EpiPen injections (WAO [Kemp 2008]). If the patient is in
Twinject: IM, SubQ: 0.3 mg; if anaphylactic symptoms cardiopulmonary arrest, use of higher IV/IO push
persist, dose may be repeated in 5 to 15 minutes doses (ie, 1 mg every 3 to 5 minutes) should be
using the same device after partial disassembly employed or appropriate endotracheal doses
Dosing administered if an advanced airway is in place
Adult & Geriatric Note: Adrenaclick has been dis- (AAAAI [Lieberman 2015]; AHA [Neumar 2010]).
continued in the US for more than 1 year. Self-administration following severe allergic reac-
Note: As of May 1, 2016, ratio expressions of tions (eg, insect stings, food): Note: The World
epinephrine concentrations are prohibited on Health Organization (WHO) and Anaphylaxis Can-
drug labels. Ampules, vials, and syringes of epi- ada recommend the availability of one dose for
nephrine with ratio expressions may, however, every 10 to 20 minutes of travel time to a medical
remain in inventory until replaced by products emergency facility. If anaphylactic symptoms per-
with revised labeling. Therefore, the ratio expres- sist after first dose, may repeat dose in 5 to 15
sion of 1:1,000 is equivalent to 1 mg/mL and minutes (AHA [Vanden Hoek 2010]); more than 2
1:10,000 is equivalent to 0.1 mg/mL (ISMP 2015). sequential doses should only be administered
Acute severe asthma unresponsive to inhaled under direct medical supervision.
beta-agonist (off-label use): IM, SubQ: 0.01 mg/kg Adrenaclick: IM, SubQ: 0.3 mg; if anaphylactic
divided into 3 doses of approximately 0.3 to 0.5 mg symptoms persist, dose may be repeated using
every 20 minutes; the 1 mg/mL concentration is an additional Adrenaclick injector
recommended (AHA [Vanden Hoek 2010]; Cydulka Allerject [Canadian product]: IM: 0.3 mg; if anaphy-
2016; Shah 2012). lactic symptoms persist, dose may be repeated
Asystole/pulseless arrest, pulseless VT/VF (ACLS using an additional Allerject injector
[Neumar 2010]): Auvi-Q: IM, SubQ: Weight ≥30 kg: 0.3 mg; if ana-
IV, Intraosseous: 1 mg every 3 to 5 minutes until phylactic symptoms persist, dose may be
return of spontaneous circulation; if this approach repeated
fails, higher doses of epinephrine (up to 0.2 mg/kg) EpiPen: IM, SubQ: 0.3 mg; if anaphylactic symp-
have been used for treatment of specific problems toms persist, dose may be repeated using an
(eg, beta-blocker or calcium channel blocker additional EpiPen
overdose) Symjepi: IM, SubQ: Weight ≥30 kg: 0.3 mg; if
Note: High IV dose epinephrine (ie, >1 mg per anaphylactic symptoms persist, dose may be
dose) has not been shown to improve survival or repeated
neurological outcomes as compared to standard Twinject [Canadian product]: IM, SubQ: 0.3 mg; if
dose epinephrine and is not recommended (ACLS anaphylactic symptoms persist, dose may be
[Neumar 2010]; ACLS [Neumar 2015]). repeated in 5 to 15 minutes using the same device
Endotracheal: 2 to 2.5 mg every 3 to 5 minutes until after partial disassembly
IV/intraosseous access established or return of Hypotension/shock:
spontaneous circulation; dilute in 5 to 10 mL NS American Heart Association recommendation:
or sterile water. Note: Absorption may be greater Severe and fluid resistant (off-label dosing): IV
with sterile water (Naganobu 2000). May cause infusion: Initial: 0.1 to 0.5 mcg/kg/minute (7 to 35
false-negative reading with exhaled CO2 detectors; mcg/minute in a 70 kg patient); titrate to desired
use second method to confirm tube placement if response (AHA [Peberdy 2010]).
CO2 is not detected (ACLS [Neumar 2010]). Manufacturer's labeling: Dosing in the prescribing
Bradycardia (symptomatic; unresponsive to atro- information may not reflect current clinical practice.
pine or pacing): IV infusion: 2 to 10 mcg/minute or Septic shock: IV infusion: Initial: 0.05 to 2 mcg/kg/
0.1 to 0.5 mcg/kg/minute (7 to 35 mcg/minute in a 70 minute (3.5 to 140 mcg/minute in a 70 kg patient);
kg patient); titrate to desired effect (ACLS [Neumar titrate to desired mean arterial pressure (MAP).
2010]; AHA [Peberdy 2010]). May adjust dose every 10 to 15 minutes by 0.05
Hypersensitivity reaction (eg, anaphylaxis): Note: to 0.2 mcg/kg/minute to achieve desired blood
SubQ administration results in slower absorption and pressure goal.
is less reliable. IM administration in the anterolateral Mydriasis during intraocular surgery, induction
aspect of the middle third of the thigh is preferred in and maintenance (product specific): Intraocular:
the setting of anaphylaxis (AHA [Vanden Hoek 2010]; Must dilute 1 mL of a 1 mg/mL single-use solution to
WAO [Kemp 2008]). a concentration of 1 to 10 mcg/mL prior to intraocular
IM (preferred), SubQ: 0.2 to 0.5 mg using the use: May use as an irrigation solution as needed
1 mg/mL solution every 5 to 15 minutes in the during the procedure or may administer intracamer-
absence of clinical improvement (AAAAI ally (ie, directly into the anterior chamber of the eye)
496
with a bolus dose of 0.1 mL of a 2.5 to 10 mcg/mL adolescent: 0.5 mg/dose; administered every 5 to
dilution. Note: Not all formulations of epinephrine 15 minutes (Hegenbarth 2008; AAP [Sicherer
injection are suitable for intraocular use; consult the 2017]; Simons 2011; Simons 2015)
prescribing information (ISMP 2017). Self/caregiver-administration following severe aller-
Renal Impairment: Adult There are no dosage gic reactions (eg, insect stings, food): Autoinjector
adjustments provided in the manufacturer's labeling. dose: Note: If anaphylactic symptoms persist after
Hepatic Impairment: Adult There are no dosage first dose, may repeat dose in 5 to 15 minutes
adjustments provided in the manufacturer's labeling. (Simons 2011)
Pediatric Note: As of May 1, 2016, ratio expres- Manufacturer's labeling (eg, Adrenaclick, Auvi-Q,
sions of epinephrine concentrations are prohib- EpiPen Jr, EpiPen): IM, SubQ:
ited on drug labels. Ampules, vials, and syringes 7.5 to <15 kg: 0.1 mg; if anaphylactic symptoms
of epinephrine with ratio expressions may, how- persist, dose may be repeated based on severity
ever, remain in inventory until replaced by prod- and response to initial dose; more than 2
ucts with revised labeling. Therefore, the ratio sequential doses should only be administered
expression of 1:1,000 is equivalent to 1 mg/mL under direct medical supervision
and 1:10,000 is equivalent to 0.1 mg/mL (ISMP 15 to <30 kg: 0.15 mg; if anaphylactic symptoms
2015). Adrenaclick has been discontinued in the US persist, dose may be repeated based on severity
for more than 1 year. and response to initial dose; more than 2
Asystole or pulseless arrest (PALS [Kleinman sequential doses should only be administered
2010]): Infants, Children, and Adolescents: under direct medical supervision
IV, Intraosseous: 0.01 mg/kg (0.1 mL/kg of ≥30 kg: 0.3 mg; if anaphylactic symptoms persist,
0.1 mg/mL solution) (maximum single dose: dose may be repeated based on severity and
1 mg); every 3 to 5 minutes until return of sponta- response to initial dose; more than 2 sequential
neous circulation doses should only be administered under direct
Endotracheal: 0.1 mg/kg (0.1 mL/kg of 1 mg/mL medical supervision
solution) (maximum single dose: 2.5 mg) every 3 Alternate dosing: AAP Recommendations (Sicherer
to 5 minutes until return of spontaneous circulation 2017): Limited data available:
or IV/intraosseous access established. Note: 7.5 to <25 kg: 0.15 mg
Recent clinical studies suggest that lower epinephr- ≥25 kg: 0.3 mg
ine concentrations delivered by endotracheal Refractory cases (unresponsive to IM doses): Con-
administration may produce transient beta 2-adre- tinuous IV infusion: Prepared 1 mcg/mL solution:
nergic effects which may be detrimental (eg, hypo- Initial: 0.1 mcg/kg/minute; titrate dose to response.
tension, lower coronary artery perfusion pressure). Usual range: 0.1 to 1 mcg/kg/minute; maximum
IV or intraosseous are the preferred methods of dose: 10 mcg/minute (Campbell 2014; Cheng
administration. 2011; AAAAI [Lieberman 2015]). Note: Suggested
Bradycardia (PALS [Kleinman 2010]): Infants, Chil- concentration of initial solution is more dilute than
dren, and Adolescents: those typically utilized in other clinical conditions;
IV, Intraosseous: 0.01 mg/kg (0.1 mL/kg of evaluate infusion concentration with continued ther-
0.1 mg/mL solution) (maximum dose: 1 mg or 10 apy and patient fluid status.
mL); may repeat every 3 to 5 minutes as needed Hypotension/shock, fluid-resistant: Infants, Chil-
Endotracheal: 0.1 mg/kg (0.1 mL/kg of 1 mg/mL dren, and Adolescents:
solution) (maximum single dose: 2.5 mg); doses Continuous IV infusion: 0.1 to 1 mcg/kg/minute;
as high as 0.2 mg/kg may be effective; may repeat rates >0.3 mcg/kg/minute associated with vaso-
every 3 to 5 minutes as needed until IV/intraoss- pressor activity; doses up to 5 mcg/kg/minute may
eous access established. Note: Recent clinical rarely be necessary; for fluid-resistant shock, may
studies suggest that lower epinephrine concentra- be combined with inotropic support (ACCM [Davis
tions delivered by endotracheal administration may 2017]; Hegenbarth 2008)
produce transient beta 2-adrenergic effects which SubQ: 0.01 mg/kg (0.01 mL/kg of 1 mg/mL solution)
may be detrimental (eg, hypotension, lower coro- (maximum single dose: 0.5 mg) every 20 minutes
nary artery perfusion pressure). IV or intraosseous for 3 doses (Hegenbarth 2008)
are the preferred methods of administration. Mydriasis during intraocular surgery, induction,
Cardiac output increase or maintenance/post- and maintenance (product specific): Note: Not
resuscitation stabilization: Infants, Children, and all formulations of epinephrine injection are suitable
Adolescents: Continuous IV or intraosseous infusion: for intraocular use; consult product labeling prior to
0.05 to 1 mcg/kg/minute; doses <0.3 mcg/kg/ use. Infants, Children, and Adolescents: Intraocular:
minute generally produce beta-adrenergic effects Must dilute 1 mL of a 1 mg/mL preservative-/sulfite-
and higher doses (>0.3 mcg/kg/minute) generally free, single-use solution to a concentration of 1 mcg/
produce alpha-adrenergic vasoconstriction; titrate mL to 10 mcg/mL prior to intraocular use: May use
dosage to desired effect (ACCM [Davis 2017]; PALS as an irrigation solution as needed during the proce-
[Kleinman 2010]) dure or may administer intracamerally (ie, directly
Hypersensitivity reaction/Anaphylaxis: Infants, into the anterior chamber of the eye) with a bolus
Children, and Adolescents: Note: The preferred dose of 0.1 mL of a 2.5 mcg/mL to 10 mcg/mL
route of administration is IM administration in the dilution.
anterolateral aspect of the middle third of the thigh; Renal Impairment: Pediatric There are no dosage
SubQ administration results in slower absorption and adjustments provided in the manufacturer's labeling.
is less reliable (Campbell 2014; AAAAI [Lieberman Hepatic Impairment: Pediatric There are no dos-
2015]; Simons 2011). age adjustments provided in the manufacturer's label-
General dosing or health care settings: IM, SubQ: ing.
0.01 mg/kg (0.01 mL/kg/dose of 1 mg/mL solution) Mechanism of Action Stimulates alpha-, beta1-, and
not to exceed: Prepubertal child: 0.3 mg/dose; beta2-adrenergic receptors resulting in relaxation of
497
smooth muscle of the bronchial tree, cardiac stimulation IV administration: Rapid IV administration may cause
(increasing myocardial oxygen consumption), and dila- death from cerebrovascular hemorrhage or cardiac
tion of skeletal muscle vasculature; small doses can arrhythmias. However, rapid IV administration during
cause vasodilation via beta2-vascular receptors; large pulseless arrest is necessary. Vesicant; ensure proper
doses may produce constriction of skeletal and vascu- needle or catheter placement prior to and during infu-
lar smooth muscle sion; avoid extravasation. Accidental injection into dig-
Contraindications its, hands, or feet may result in local reactions, including
There are no absolute contraindications to the use of injection-site pallor, coldness, and hypoesthesia or
injectable epinephrine (including Adrenaclick, Auvi-Q, injury, resulting in bruising, bleeding, discoloration,
EpiPen, EpiPen Jr, Symjepi, Allerject [Canadian prod- erythema, or skeletal injury; patient should seek imme-
uct], and Twinject [Canadian product]) in a life-threat- diate medical attention if this occurs.
ening situation. Some products include the following
contraindications: Hypersensitivity to sympathomi- Intraocular administration: Not all formulations of epi-
metic amines; general anesthesia with halogenated nephrine injection are suitable for intraocular use; con-
hydrocarbons (eg, halothane) or cyclopropane; narrow sult the prescribing information prior to selecting a
angle glaucoma; nonanaphylactic shock; in combina- product. Appropriate products should have an indica-
tion with local anesthesia of certain areas such as tion for induction and maintenance of mydriasis during
fingers, toes, and ears; use in situations where vaso- intraocular surgery, and should not contain any sulfites
pressors may be contraindicated (eg, thyrotoxicosis, or preservatives (ISMP 2017). Prior to intraocular use of
diabetes, in obstetrics when maternal blood pressure an appropriate product, must dilute single-use 1 mg/mL
is in excess of 130/80 mm Hg and in hypertension and (1 mL) solution to a concentration of 1 mcg/mL to 10
other cardiovascular disorders). mcg/mL. Corneal endothelial damage has occurred
Injectable solution (Adrenalin, Epinephrine injection, when products containing sodium bisulfite have been
USP): There are no contraindications listed in the used undiluted; therefore, dilution is advised prior to any
manufacturer's labeling. intraocular use. In addition, products containing chlor-
Warnings/Precautions Use with caution in elderly obutanol must also not be used intraocularly (may be
patients, patients with diabetes mellitus, cardiovascular harmful to corneal endothelium).
diseases (eg, coronary artery disease, arrhythmias, Drug Interactions
cerebrovascular disease, heart disease hypertension), Metabolism/Transport Effects Substrate of COMT
thyroid disease, pheochromocytoma, or Parkinson dis- Avoid Concomitant Use
ease. May precipitate or aggravate angina pectoris or Avoid concomitant use of EPINEPHrine (Systemic)
induce cardiac arrhythmias; use with caution especially with any of the following: Blonanserin; Bromperidol;
in patients with cardiac disease or those receiving drugs Ergot Derivatives; Lurasidone
that sensitize the myocardium. Due to peripheral con- Increased Effect/Toxicity
striction and cardiac stimulation, pulmonary edema may EPINEPHrine (Systemic) may increase the levels/
occur. Due to renal blood vessel constriction, effects of: Doxofylline; Lurasidone; Solriamfetol; Sym-
decreased urine output may occur. In hypovolemic pathomimetics
patients, correct blood volume depletion before admin-
The levels/effects of EPINEPHrine (Systemic) may be
istering any vasopressor. Some products contain sul-
increased by: AtoMOXetine; Beta-Blockers (Nonse-
fites as preservatives; the presence of sulfites in some
lective); Cannabinoid-Containing Products; Chloropro-
products should not deter administration during a seri-
caine; Cocaine (Topical); COMT Inhibitors; Ergot
ous allergic or other emergency situation even if the
Derivatives; Guanethidine; Hyaluronidase; Inhala-
patient is sulfite-sensitive. Potentially significant drug-
tional Anesthetics; Linezolid; Monoamine Oxidase
drug interactions may exist, requiring dose or frequency
Inhibitors; Serotonin/Norepinephrine Reuptake Inhib-
adjustment, additional monitoring, and/or selection of
itors; Tedizolid; Tricyclic Antidepressants
alternative therapy.
Decreased Effect
Hypersensitivity reactions: Do not inject into the but- EPINEPHrine (Systemic) may decrease the levels/
tock; may not effectively treat anaphylaxis and has effects of: Antidiabetic Agents; Benzylpenicilloyl Poly-
been associated with Clostridial infections (gas gan- lysine
grene). Serious skin and soft tissue infections, including
necrotizing fasciitis and myonecrosis caused by Clos- The levels/effects of EPINEPHrine (Systemic) may be
tridia (gas gangrene), have been reported rarely at the decreased by: Alpha1-Blockers; Benperidol; Beta-
injection site. Cleansing skin with alcohol may reduce Blockers (Beta1 Selective); Beta-Blockers (with
bacteria at the injection site, but alcohol cleansing does Alpha-Blocking Properties); Blonanserin; Bromperidol;
not kill Clostridium spores. Preferred injection site is CloZAPine; Promethazine; Spironolactone
anterolateral aspect of the thigh. Do not administer Pharmacodynamics/Kinetics
repeated injections at the same site (tissue necrosis Onset of Action Bronchodilation: SubQ: ~5 to 10
may occur). Monitor for signs/symptoms of injection-site minutes
infection. Lacerations, bent needles, and embedded Half-life Elimination IV: <5 minutes
needles have been reported in young children who Pregnancy Considerations
are uncooperative during injection for hypersensitivity Epinephrine crosses the placenta (Sandler 1964).
reaction. To minimize risk, hold the child's leg firmly in Epinephrine is recommended for the treatment of ana-
place and limit movement prior to and during injection. phylaxis in pregnant women. Specific dosing is not
Although the manufacturers of auto-injectors recom- available; use with caution and monitor hemodynamic
mend varying lengths of time for holding the device in response (Hepner 2013). Medications used for the
the thigh (range: 2 to 10 seconds), longer times have treatment of cardiac arrest in pregnancy are the same
occasionally resulted in injury. For all devices, the as in the non-pregnant woman. Doses and indications
needle should remain in the thigh for the least amount should follow current Advanced Cardiovascular Life
of time as possible (~3 seconds) (Brown 2016). Support guidelines. Appropriate medications should
498
EPINEPHRINE (ORAL INHALATION)
not be withheld due to concerns of fetal teratogenicity Dosing

(Jeejeebhoy [AHA] 2015). Adult & Geriatric
Breastfeeding Considerations Bronchospasm, relief of mild asthma symptoms:
It is not known if epinephrine is present in breast milk. Note: Not recommended for routine management
Epinephrine is generally considered compatible in and treatment of asthma (GINA 2018; NAEPP 2007).
breastfeeding and is recommended for the treatment Metered-dose inhaler: Oral inhalation: 1 inhalation
of anaphylaxis in breastfeeding women (WHO 2002). (0.125 mg) once; if symptoms not relieved after 1
Product Availability minute, may repeat; wait ≥ 4 hours between addi-
tional doses (maximum dose: 8 inhalations/24
Symjepi 0.15 mg prefilled syringe: FDA approved Sep-
hours).
tember 2018; anticipated availability is currently
Nebulization solution: Hand-bulb nebulizer: 1 to 3
unknown.
inhalations of 2.25% (1 vial); may repeat dose after
Adrenaclick: Adrenaclick has been discontinued in the
at least 3 hours as needed (maximum dose: 12
US for more than 1 year. inhalations/24 hours).
Dosage Forms: US Renal Impairment: Adult There are no dosage
Kit, Injection: adjustment provided in the manufacturer's labeling.
Adyphren: 1 mg/mL Hepatic Impairment: Adult There are no dosage
Adyphren Amp: 1 mg/mL adjustment provided in the manufacturer's labeling.
Adyphren Amp II: 1 mg/mL Pediatric
Adyphren II: 1 mg/mL Bronchospasm, relief of mild asthma symptoms:
EpinephrineSnap-EMS: 1 mg/mL Note: Not recommended for routine management
Epinephrinesnap-v: 1 mg/mL and treatment of asthma (GINA 2018; NAEPP 2007).
EPIsnap: 1 mg/mL Nebulization solution: Children ≥4 years and Adoles-
Kit, Injection [preservative free]: cents: Handheld bulb nebulizer: Add 0.5 mL (1 vial)
Epinephrinesnap-v: 1 mg/mL of 2.25% solution to nebulizer; 1 to 3 inhalations;
Solution, Injection: may repeat dose after at least 3 hours if needed.
Adrenalin: 30 mg/30 mL (30 mL) Maximum daily dose: 12 inhalations/24 hours.
Generic: 30 mg/30 mL (30 mL) Metered-dose inhaler: Children ≥12 years and Ado-
Solution, Injection [preservative free]: lescents: Oral inhalation: 1 inhalation once; if symp-
Adrenalin: 1 mg/mL (1 mL) toms not relieved after 1 minute, may repeat 1
Generic: 1 mg/mL (1 mL) inhalation; wait ≥4 hours between additional doses;
Solution Auto-injector, Injection: maximum daily dose: 8 inhalations/24 hours
Auvi-Q: 0.1 mg/0.1 mL (2 ea); 0.15 mg/0.15 mL (2 Croup (laryngotracheobronchitis), airway edema;
ea); 0.3 mg/0.3 mL (2 ea) moderate to severe: Limited data available: Infants,
EpiPen 2-Pak: 0.3 mg/0.3 mL (2 ea) Children, and Adolescents: Note: Typically relief of
EpiPen Jr 2-Pak: 0.15 mg/0.3 mL (2 ea) symptoms occurs within 10 to 30 minutes and lasts 2
Generic: 0.15 mg/0.3 mL (1 ea, 2 ea); 0.15 mg/0.15 to 3 hours; patients should be observed for rapid
mL (1 ea, 2 ea); 0.3 mg/0.3 mL (1 ea, 2 ea) symptom recurrence and possible repeat treatment.
Solution Prefilled Syringe, Injection [preservative Racemic epinephrine (2.25% solution): Nebulization:
0.05 to 0.1 mL/kg (maximum dose: 0.5 mL) diluted
free]:
in 2 to 3 mL NS, may repeat dose every 20 minutes;
Symjepi: 0.3 mg/0.3 mL (2 ea)
others have reported use of 0.5 mL as a fixed dose
for all patients; use lower end of dosing range for
younger infants (Hegenbarth 2008; Kliegman 2016;
EPINEPHrine (Oral Inhalation) (ep i NEF rin) Rosekrans 1998; Rotta 2003; Wright 2002)
L-epinephrine (using parenteral 1 mg/mL solution):
Brand Names: US Asthmanefrin Refill [OTC]; S2 Nebulization: 0.5 mL/kg of 1:1,000 solution (max-
(Racepinephrine) [OTC] imum dose: 5 mL) diluted in NS, may repeat dose
Brand Names: Canada S2 every 20 minutes; Note: Racemic epinephrine
Generic Availability (US) No 10 mg = 5 mg L-epinephrine (Hegenbarth 2008)
Pharmacologic Category Alpha/Beta Agonist Renal Impairment: Pediatric There are no dosage
Dental Use Emergency drug for treatment of anaphy- adjustments provided in the manufacturer's labeling.
lactic reactions; used as vasoconstrictor to prolong local Hepatic Impairment: Pediatric There are no dos-
anesthesia age adjustments provided in the manufacturer's label-
Use Bronchospasm, relief of mild asthma symp- ing.
toms: Temporary relief of mild symptoms of intermittent Mechanism of Action Stimulates alpha-, beta1-, and
asthma (ie, shortness of breath, tightness of chest, beta2-adrenergic receptors resulting in relaxation of
smooth muscle of the bronchial tree, cardiac stimulation
wheezing). Note: Not recommended for routine man-
(increasing myocardial oxygen consumption), and dila-
agement and treatment of asthma (GINA 2018; NAEPP
tion of skeletal muscle vasculature; small doses can
2007).
cause vasodilation via beta2-vascular receptors; large
Local Anesthetic/Vasoconstrictor Precautions doses may produce constriction of skeletal and vascu-
No information available to require special precautions lar smooth muscle
Effects on Dental Treatment Key adverse event(s) Contraindications
related to dental treatment: Xerostomia (normal salivary OTC labeling: When used for self-medication, do not
flow resumes upon discontinuation) and dry throat. use with or within 2 weeks of discontinuing an MAOI or
Effects on Bleeding No information available to in patients without a diagnosis of asthma.
require special precautions Documentation of allergenic cross-reactivity for sympa-
Adverse Reactions There are no adverse reactions thomimetics is limited. However, because of similar-
listed in the manufacturer's labeling. ities in chemical structure and/or pharmacologic
499
EPINEPHRINE (ORAL INHALATION)
actions, the possibility of cross-sensitivity cannot be Dosage Forms: US

ruled out with certainty. Nebulization Solution, Inhalation:
Warnings/Precautions Use with caution in patients Asthmanefrin Refill [OTC]: 2.25% (1 ea)
with diabetes mellitus, heart disease and/or hyperten- Nebulization Solution, Inhalation [preservative free]:
sion, increased intraocular pressure or glaucoma, thy- S2 (Racepinephrine) [OTC]: 2.25% (1 ea)
roid disease, cerebrovascular disease, prostatic
hyperplasia and/or urinary retention, psychiatric or emo-
tional conditions, or in patients with seizure disorders. Epinephrine (Racemic) and Aluminum
Do not use if product is brown in color or cloudy. Potassium Sulfate
(ep i NEF rin, ra SEE mik and a LOO mi num poe TASS ee um SUL
Self-medication (OTC use): When used for self-medi- fate)
cation (OTC), notify health care provider if symptoms
are not relieved in 20 minutes or become worse; if >8 Related Information
inhalations of Primatene Mist, >12 inhalations of Asth- EPINEPHrine (Systemic) on page 495
manefrin, S2 are needed in 24 hours; if >9 inhalations in Brand Names: US GingiBRAID +
24 hours for ≥3 days a week of Asthmanefrin, S2 are Generic Availability (US) No
needed, or if >2 asthma attacks have occurred within a Pharmacologic Category Adrenergic Agonist Agent;
week. Discontinue use and notify health care provider if Alpha/Beta Agonist; Astringent; Vasoconstrictor
your asthma is getting worse, or if difficulty sleeping, Dental Use Gingival retraction
rapid heartbeat, tremors, nervousness, or seizure Use Dental aid: Aids in temporary gingival retraction
occur. The product should not be used more frequently and hemostasis procedures
or at higher doses than recommended. Local Anesthetic/Vasoconstrictor Precautions
Drug Interactions No information available to require special precautions
Metabolism/Transport Effects Substrate of COMT
Avoid Concomitant Use related to dental treatment: Tissue retraction around
Avoid concomitant use of EPINEPHrine (Oral Inhala- base of the tooth (therapeutic effect).
tion) with any of the following: Ergot Derivatives;
Monoamine Oxidase Inhibitors
Adverse Reactions No data reported.
EPINEPHrine (Oral Inhalation) may increase the lev-
els/effects of: Doxofylline; Solriamfetol; Sympathomi- Dental Usual Dosage Gingival retraction: Adults: Pass
metics the impregnated cord around the neck of the tooth and
place into gingival sulcus; normal tissue moisture,
The levels/effects of EPINEPHrine (Oral Inhalation) water, or gingival retraction solutions activate impreg-
may be increased by: AtoMOXetine; Beta-Blockers nated cord. Limit use to one quadrant of the mouth at a
(Nonselective); Cannabinoid-Containing Products; time; recommended use is for 3-8 minutes in the mouth.
Chloroprocaine; Cocaine (Topical); COMT Inhibitors; Dosing
Ergot Derivatives; Guanethidine; Inhalational Anes- Adult & Geriatric Dental aid: Pass the impregnated
thetics; Monoamine Oxidase Inhibitors; Serotonin/Nor- cord around the neck of the tooth and place into
e p i n e p h r i n e R e u p t a k e I n h i b i t o r s ; Tr i c y c l i c gingival sulcus; leave cord in sulcus for up to 5
Antidepressants minutes; normal tissue moisture, water, or gingival
Decreased Effect retraction solutions activate impregnated cord. Limit
The levels/effects of EPINEPHrine (Oral Inhalation) use to one quadrant of the mouth at a time.
may be decreased by: Alpha1-Blockers; Beta-Block- Mechanism of Action Epinephrine stimulates alpha1
ers (Beta1 Selective); Beta-Blockers (with Alpha- adrenergic receptors to cause vasoconstriction in blood
Blocking Properties); Promethazine; Spironolactone vessels in gingiva; aluminum potassium sulfate, precip-
Food Interactions Avoid food or beverages that con- itates tissue and blood proteins
tain caffeine. Contraindications Hypersensitivity to epinephrine,
Dietary Considerations Avoid food or beverages that sulfites, aluminum-containing products, or any compo-
contain caffeine. nent of the formulation; cardiovascular disease, hyper-
Pharmacodynamics/Kinetics tension, hyperthyroidism, diabetes, or congestive
Onset of Action Bronchodilation: Inhalation: ~1 glaucoma; concurrent antidepressant use; do not apply
minute to areas of heavy or deep bleeding or overexposed
Pregnancy Considerations bone
Epinephrine crosses the placenta following injection Warnings/Precautions Caution should be exercised
(Sandler 1964). whenever using gingival retraction cords with epinephr-
Uncontrolled asthma is associated with adverse events ine since it delivers vasoconstrictor doses of racemic
on pregnancy (increased risk of perinatal mortality, epinephrine to patients; the general medical history
preeclampsia, preterm birth, low birth weight infants). should be thoroughly evaluated before using in any
Poorly controlled asthma or asthma exacerbations may patient
have a greater fetal/maternal risk than what is associ- Drug Interactions
ated with appropriately used asthma medications Metabolism/Transport Effects None known.
(ACOG 90 2008; GINA 2018; NAEPP 2007). Epinephr- Avoid Concomitant Use There are no known inter-
ine is not recommended for routine management and actions where it is recommended to avoid concomitant
treatment of asthma (GINA 2018; NAEPP 2007). use.
Breastfeeding Considerations Breastfeeding Increased Effect/Toxicity
females with asthma should be encouraged to breast- The levels/effects of Epinephrine (Racemic) and Alu-
feed (GINA 2018). Use of epinephrine is generally minum Potassium Sulfate may be increased by: Beta-
considered acceptable in breastfeeding females Blockers (Nonselective); Monoamine Oxidase Inhibi-
(WHO 2002). tors
500
EPLERENONE
Decreased Effect Hypersensitivity: Hypersensitivity reaction

The levels/effects of Epinephrine (Racemic) and Alu- Infection: Infection (15% to 22%; grades 3/4: ≤2%)
minum Potassium Sulfate may be decreased by: Beta- Local: Injection site reaction (3% to 20%; grades
Blockers (Beta1 Selective); Beta-Blockers (with Alpha- 3/4: <1%)
Blocking Properties); Promethazine Ophthalmic: Conjunctivitis (1% to 15%)
Dosage Forms: US Respiratory: Dyspnea, pulmonary edema
Retraction cord, for gingival sulcus placement: Miscellaneous: Fever (1% to 5%)
GingiBRAID +: <1%, postmarketing, case reports: Anaphylaxis, arterial
0e fine: Epinephrine 0.10 – 0.30 mg and aluminum embolism, burning sensation of gastrointestinal tract,
potassium sulfate 0.05 – 0.25 mg per inch chills, dehydration, erythema, flushing, gastrointestinal
1e small: Epinephrine 0.20 – 0.60 mg and aluminum erosion, gastrointestinal hemorrhage, gastrointestinal
potassium sulfate 0.15 – 0.35 mg per inch pain, gastrointestinal ulcer, hyperuricemia, nail hyper-
2e medium: Epinephrine 0.40 – 0.80 mg and alumi- pigmentation, oral mucosa hyperpigmentation, phlebi-
num potassium sulfate 0.20 – 0.50 mg per inch tis, pneumonia, pulmonary embolism, radiation recall
3e large: Epinephrine 0.60 – 1.20 mg and aluminum phenomenon, red urine discoloration, sepsis, shock,
potassium sulfate 0.30 – 0.80 mg per inch skin hyperpigmentation, skin photosensitivity, throm-
bophlebitis, urticaria
Mechanism of Action Epirubicin is an anthracycline
EpiRUBicin (ep i ROO bi sin)
antineoplastic agent; known to inhibit DNA and RNA
Brand Names: US Ellence synthesis by steric obstruction after intercalating
Brand Names: Canada Ellence; Epirubicin for Injec- between DNA base pairs; active throughout entire cell
tion; Epirubicin Hydrochloride Injection; Pharmorubicin cycle. Intercalation triggers DNA cleavage by topoiso-
Pharmacologic Category Antineoplastic Agent, merase II, resulting in cytocidal activity. Also inhibits
Anthracycline; Antineoplastic Agent, Topoisomerase II DNA helicase, and generates cytotoxic free radicals.
Inhibitor
Half-life Elimination Triphasic; Mean terminal: 33
Use Breast cancer, adjuvant treatment: Adjuvant ther-
hours
apy component for primary breast cancer in patients
with evidence of axillary node involvement following Pregnancy Risk Factor D
tumor resection Pregnancy Considerations
Local Anesthetic/Vasoconstrictor Precautions Adverse events were observed in animal reproduction
No information available to require special precautions studies. Women of reproductive potential should be
advised to use effective contraception and avoid
related to dental treatment: Mucositis becoming pregnant during treatment. Men undergoing
treatment should use effective contraception. Epirubicin
Effects on Bleeding Causes severe myelosuppres-
may cause irreversible amenorrhea in premenopausal
sion, including severe thrombocytopenia (grades 3/4:
women.
<5%) and anemia. In patients who are under active
treatment with this agent, medical consult is suggested. Limited information is available from a retrospective
Adverse Reactions Frequency not always defined. study of women who received epirubicin (in combina-
Percentages reported as part of combination chemo- tion with cyclophosphamide or weekly as a single-
therapy regimens. agent) during the second or third (prior to week 35)
Cardiovascular: Decreased left ventricular ejection frac- trimester for the treatment of pregnancy-associated
tion (asymptomatic; delayed: 1% to 2%), cardiac fail- breast cancer (Ring 2005) and from a study of women
ure (≤2%), atrioventricular block, bradycardia, bundle who received epirubicin (weekly as a single-agent) at
branch block, cardiac arrhythmia, cardiomyopathy, gestational weeks 16 through 30 for the treatment of
ECG abnormality, myocarditis, non-specific T wave pregnancy-associated breast cancer (Peccatori 2009).
on ECG, sinus tachycardia, ST segment changes on Some pharmacokinetic properties of epirubicin may be
ECG, tachyarrhythmia, thromboembolism, ventricular altered in pregnant women (van Hasselt 2014). The
premature contractions, ventricular tachycardia European Society for Medical Oncology (ESMO) has
Central nervous system: Lethargy (1% to 46%) published guidelines for diagnosis, treatment, and fol-
Dermatologic: Alopecia (70% to 96%), skin rash (1% to low-up of cancer during pregnancy (Peccatori 2013);
9%), skin changes (1% to 5%) the guidelines recommend referral to a facility with
Endocrine & metabolic: Amenorrhea (69% to 72%), hot expertise in cancer during pregnancy and encourage
flash (5% to 39%) a multidisciplinary team (obstetrician, neonatologist,
Gastrointestinal: Nausea and vomiting (83% to 92%; oncology team). If chemotherapy is indicated, it should
grades 3/4: 22% to 25%), mucositis (9% to 59%; not be administered in the first trimester, but may begin
grades 3/4: ≤9%), diarrhea (7% to 25%), anorexia in the second trimester. There should be a 3-week time
(2% to 3%), abdominal pain, esophagitis, neutropenic period between the last chemotherapy dose and antici-
enterocolitis, stomatitis, toxic megacolon pated delivery, and chemotherapy should not be admin-
Genitourinary: Menopause (premature or early) istered beyond week 33 of gestation.
Hematologic & oncologic: Neutropenia (54% to 80%;
grades 3/4: 11% to 67%; nadir: 10 to 14 days; recov- A pregnancy registry is available for all cancers diag-
ery: by day 21), leukopenia (50% to 80%; grades 3/4: nosed during pregnancy at Cooper Health
2% to 59%), anemia (13% to 72%; grades 3/4: ≤6%), (877-635-4499).
thrombocytopenia (5% to 49%; grades 3/4: ≤5%),
febrile neutropenia (grades 3/4: ≤6%), acute lympho- Eplerenone (e PLER en one)
cytic leukemia, acute myelocytic leukemia, myelodys-
plastic syndrome Related Information
Hepatic: Ascites, hepatomegaly, increased serum Cardiovascular Diseases on page 1442
transaminases Brand Names: US Inspra
501
EPLERENONE
Brand Names: Canada Inspra in pregnant women and should generally be avoided
Pharmacologic Category Antihypertensive; Diuretic, in women of reproductive potential (ACOG 2013).
Potassium-Sparing; Mineralocorticoid (Aldosterone)
Receptor Antagonists Epoetin Alfa (e POE e tin AL fa)
Use
Heart failure post-MI: To improve survival of stable Brand Names: US Epogen; Procrit; Retacrit
patients with symptomatic heart failure (HF) (LVEF Brand Names: Canada Eprex
≤40%) following acute MI. Pharmacologic Category Colony Stimulating Factor;
Guideline recommendations: The American College of Erythropoiesis-Stimulating Agent (ESA); Hematopoietic
Cardiology and the American Heart Association Agent
(ACCF/AHA) 2013 heart failure guidelines recom- Use
mend the use of aldosterone antagonists, along with Anemia due to chemotherapy in patients with can-
other guideline directed medical therapies, to reduce cer: Treatment of anemia in patients with nonmyeloid
morbidity and mortality in patients with an LVEF malignancies in which anemia is due to the effect of
≤40% following acute MI who develop symptoms of concomitant myelosuppressive chemotherapy, and
HF or have a history of diabetes mellitus (ACC/AHA upon initiation, there is a minimum of 2 additional
[Yancy 2013]). months of planned chemotherapy.
Hypertension: Management of hypertension. Note: Anemia due to chronic kidney disease: Treatment of
Not recommended for the initial treatment of hyper- anemia due to chronic kidney disease, including
tension (ACC/AHA [Whelton 2017]). patients on dialysis and not on dialysis, to decrease
Local Anesthetic/Vasoconstrictor Precautions the need for RBC transfusion.
No information available to require special precautions Anemia due to zidovudine in HIV-infected patients:
Effects on Dental Treatment No significant effects or Treatment of anemia due to zidovudine administered
complications reported at ≤4,200 mg/week in HIV-infected patients with
Effects on Bleeding No information available to endogenous serum erythropoietin levels of ≤500 milli-
require special precautions units/mL.
Adverse Reactions Reduction of allogeneic RBC transfusion in patients
>10%: Endocrine & metabolic: Hyperkalemia ([cardiac undergoing elective, noncardiac, nonvascular sur-
failure, post-myocardial infarction: >5.5 mEq/L: 16%; gery: To reduce the need for allogeneic RBC trans-
fusions among patients with perioperative hemoglobin
≥6 mEq/L: 6%], [hypertension, >5.5 mEq/L: at dose of
>10 to ≤13 g/dL who are at high risk of perioperative
400 mg: 9%; dose ≤200 mg: ≤1%]), hypertriglyceride-
blood loss from elective, noncardiac, nonvascular
mia (1% to 15%; dose-related)
surgery. Epoetin alfa is not indicated for patients who
1% to 10%:
are willing to donate autologous blood preoperatively.
Central nervous system: Dizziness (3%), fatigue (2%)
Endocrine & metabolic: Hyponatremia (2%; dose- Limitations of use: Epoetin alfa has not been shown to
related), albuminuria (1%), gynecomastia (≤1%), improve quality of life, fatigue, or patient well-being.
hypercholesterolemia (≤1%) Epoetin alfa is not indicated for use under the follow-
Gastrointestinal: Diarrhea (2%), abdominal pain (1%) ing conditions:
Genitourinary: Abnormal vaginal hemorrhage (≤2%), - Cancer patients receiving hormonal therapy, thera-
mastalgia (males: ≤1%) peutic biologic products, or radiation therapy unless
Renal: Increased serum creatinine (cardiac failure, also receiving concurrent myelosuppressive chemo-
post-myocardial infarction: 6%) therapy
Respiratory: Cough (2%), flu-like symptoms (2%) - Cancer patients receiving myelosuppressive chemo-
<1%, postmarketing, and/or case reports: Angioedema, therapy when the expected outcome is curative
increased blood urea nitrogen, increased liver - Cancer patients receiving myelosuppressive chemo-
enzymes, increased uric acid, skin rash therapy when anemia can be managed by trans-
Mechanism of Action Aldosterone, a mineralocorti- fusion
coid, increases blood pressure primarily by inducing - Surgery patients who are willing to donate autolo-
sodium and water retention. Overexpression of aldos- gous blood
terone is thought to contribute to myocardial fibrosis - Surgery patients undergoing cardiac or vascular
(especially following myocardial infarction) and vascular surgery
fibrosis. Mineralocorticoid receptors are located in the - As a substitute for RBC transfusion in patients
kidney, heart, blood vessels, and brain. Eplerenone requiring immediate correction of anemia
selectively blocks mineralocorticoid receptors reducing Local Anesthetic/Vasoconstrictor Precautions
blood pressure in a dose-dependent manner and No information available to require special precautions
appears to prevent myocardial and vascular fibrosis. Effects on Dental Treatment No significant effects or
Pharmacodynamics/Kinetics complications reported
Half-life Elimination ~3 to 6 hours Effects on Bleeding Although ESAs have been asso-
Time to Peak Plasma: ~1.5 to 2 hours; may take up to ciated with thromboembolic events, there is no informa-
4 weeks for full antihypertensive effect tion available to require special precautions for dental
Pregnancy Considerations procedures.
Information related to eplerenone use in pregnancy is Adverse Reactions
limited to case reports (Cabassi 2012; Gunganah 2015; >10%:
Hutter 2006; Morton 2011). Cardiovascular: Hypertension (6% to 28%)
Untreated hypertension and heart failure are both asso- Dermatologic: Pruritus (16% to 21%), skin rash (2%
ciated with adverse pregnancy outcomes. The use of to 19%)
mineralocorticoid receptor antagonists is not recom- Gastrointestinal: Nausea (35% to 56%), vomiting
mended to treat chronic uncomplicated hypertension (19% to 28%)
502
EPOPROSTENOL
Local: Injection site pain (9% to 13%) Recombinant erythropoietin alfa has been evaluated as
Neuromuscular & skeletal: Arthralgia (10% to 16%) adjunctive treatment for severe pregnancy associated
Respiratory: Cough (4% to 26%) iron deficiency anemia (Breymann 2001; Krafft 2009)
Miscellaneous: Fever (10% to 42%) and has been used in pregnant women with iron-
1% to 10%: deficiency anemia associated with chronic kidney dis-
Cardiovascular: Thrombosis of hemodialysis vascular ease (CKD) (Furaz-Czerpak 2012; Josephson 2007).
access (8%), thrombosis (≤6%), deep vein thrombo-
Amenorrheic premenopausal women should be cau-
sis (5% to 6%), edema (3%)
tioned that menstruation may resume following treat-
Central nervous system: Dizziness (10%), chills (4%
ment with recombinant erythropoietin (Furaz-Czerpak
to 7%), insomnia (6%), depression (5%)
2012). Multidose formulations containing benzyl alcohol
Dermatologic: Urticaria (3%)
are contraindicated for use in pregnant women; if treat-
Endocrine & metabolic: Weight loss (9%), hyperglyce-
ment during pregnancy is needed, single dose prepa-
mia (6%), hypokalemia (5%)
rations should be used.
Gastrointestinal: Stomatitis (10%), dysphagia (5%)
Hematologic & oncologic: Leukopenia (8%) Product Availability Retacrit (epoetin alfa-epbx): FDA
Local: Irritation at injection site (7%) approved May 2018; availability anticipated in the fourth
Neuromuscular & skeletal: Myalgia (10%), muscle quarter of 2018.
spasm (7%), ostealgia (7%)
Respiratory: Upper respiratory tract infection (7%) Epoprostenol (e poe PROST en ole)
<1%, postmarketing, and/or case reports: Antibody
development (neutralizing), cardiac failure, cerebro- Brand Names: US Flolan; Veletri
vascular accident, erythema, erythema multiforme, Brand Names: Canada Caripul; Flolan
exfoliation of skin, hypertensive encephalopathy, myo- Pharmacologic Category Prostacyclin; Prostaglan-
cardial infarction, porphyria, pure red cell aplasia, din; Vasodilator
seizure, severe anemia, skin blister, Stevens-Johnson Use Pulmonary arterial hypertension: Treatment of
syndrome, toxic epidermal necrolysis pulmonary arterial hypertension (PAH) (WHO Group I)
Mechanism of Action Epoetin alfa induces erythropoi- in patients with NYHA Class III or IV symptoms to
esis by stimulating the division and differentiation of improve exercise capacity. Note: According to treat-
committed erythroid progenitor cells; induces the ment guidelines from the Fifth World Symposium on
release of reticulocytes from the bone marrow into the Pulmonary Hypertension (WSPH) and the American
bloodstream, where they mature to erythrocytes. There College of Chest Physicians (ACCP), continuous IV
is a dose response relationship with this effect. This epoprostenol is recommended as first-line therapy in
results in an increase in reticulocyte counts followed by PAH patients with WHO-FC IV symptoms (ACCP
a rise in hematocrit and hemoglobin levels. [Taichman 2014]; WSPH [Gailè 2013]).
Pharmacodynamics/Kinetics Local Anesthetic/Vasoconstrictor Precautions
Onset of Action Reticulocyte count increase: Within No information available to require special precautions
10 days; Peak effect: Hemoglobin level: 2 to 6 weeks Effects on Dental Treatment No significant effects or
Half-life Elimination complications reported. Epoprostenol is an inhibitor of
Neonates: With high doses, nonlinear kinetics have platelet aggregation and may enhance the risk of bleed-
been observed (Wu 2012) ing with other antiplatelet agents (such as aspirin and/or
Anemia of prematurity: NSAIDs).
Post menstrual age (PMA) <32 week (weight: 800 ± Effects on Bleeding Epoprostenol is a potent inhibitor
206 grams): IV: 8.1 ± 2.7 hours; SubQ: 7.1 ± 4.1 of platelet aggregation and increases the risk of hem-
hours (Brown 1993) orrhagic complications. A medical consult is suggested.
PMA ≥32 weeks (weight range: 1,330 to 1,740 g): Adverse Reactions
SubQ: Median: 7.9 hours (range: 5.6 to 19.4 >10%:
hours) (Krishnan 1996) Cardiovascular: Flushing (23% to 58%), tachycardia
Neuroprotective/hypoxic ischemia encephalopathy (1% to 43%), hypotension (13% to 27%), chest
(HIE) (Wu 2012): ≥36 weeks GA; IV: pain (11%)
250 units/kg: 7.6 ± 6.9 hours Central nervous system: Headache (46% to 83%),
500 units/kg: 7.2 ± 1.9 hours dizziness (8% to 83%), chills (≤25%), anxiety
1,000 units/kg: 15 ± 4.5 hours (≤21%), nervousness (≤21%), hyperesthesia
2,500 units/kg: 18.7 ± 4.7 hours (≤12%), hypoesthesia (≤12%), paresthesia (≤12%),
Infants, Children, and Adolescents: Chronic kidney agitation (11%)
disease: IV: 4 to 13 hours Dermatologic: Dermal ulcer (39%), eczema (≤10% to
Adults: Cancer: SubQ: 16 to 67 hours; Chronic kidney ≤25%), skin rash (≤10% to ≤25%), urticaria (≤10%
disease: IV: 4 to 13 hours to ≤25%)
Time to Peak Serum: Pediatric patients >1 month and Gastrointestinal: Nausea and vomiting (32% to 67%),
Adults: Chronic kidney disease: SubQ: 5 to 24 hours anorexia (25% to 66%), diarrhea (37% to 50%)
Pregnancy Considerations Infection: Sepsis (≤25%)
Adverse events were observed in animal reproduction Neuromuscular & skeletal: Musculoskeletal pain (3%
studies. In vitro studies suggest that recombinant eryth- to 84%), arthralgia (≤84%), neck pain (≤84%), jaw
ropoietin does not cross the human placenta (Reisen- pain (54% to 75%), myalgia (44%), hyperkinesia
berger 1997). Polyhydramnios and intrauterine growth (≤21%), tremor (≤21%)
retardation have been reported with use in women with Respiratory: Flu-like symptoms (≤25%)
chronic kidney disease (adverse effects also associated Miscellaneous: Fever (≤25%)
with maternal disease). Hypospadias and pectus exca- 1% to 10%:
vatum have been reported with first trimester exposure Cardiovascular: Bradycardia (5%)
(case report). Dermatologic: Diaphoresis (1%)
503
EPOPROSTENOL
Gastrointestinal: Abdominal pain (5%), dyspep- Neuromuscular & skeletal: Arthralgia (2%), myal-
sia (1%) gia (≥1%)
Neuromuscular & skeletal: Back pain (2%) Renal: Increased blood urea nitrogen (1%)
Respiratory: Dyspnea (2%) Respiratory: Upper respiratory tract infection (8%),
<1%, postmarketing, and/or case reports: Anemia, car- pharyngitis (4%), rhinitis (4%), cough (ARBs: 3%;
diac failure, fatigue, hemorrhage, hepatic failure, Matchar 2008), bronchitis (≥1%), sinusitis (≥1%)
hypersplenism, hyperthyroidism, increased pulmonary Miscellaneous: Accidental injury (2%)
artery pressure, pallor, pancytopenia, pulmonary <1%, postmarketing, and/or case reports: Albuminuria,
edema, pulmonary embolism, splenomegaly, throm- alcohol intolerance, anemia, angina pectoris, ano-
bocytopenia rexia, anxiety, arthritis, asthenia, asthma, ataxia, atrial
Mechanism of Action Epoprostenol is also known as fibrillation, back pain, bradycardia, conjunctivitis, con-
prostacyclin and PGI2. It is a strong vasodilator of all stipation, cystitis, decreased hemoglobin (>20%
vascular beds. In addition, it is a potent endogenous decrease), diabetes mellitus, diaphoresis, drowsiness,
inhibitor of platelet aggregation. The reduction in plate- ECG abnormality, eczema, epistaxis, esophagitis,
let aggregation results from epoprostenol's activation of exacerbation of arthritis, extrasystoles, facial edema,
intracellular adenylate cyclase and the resultant fever, flatulence, flu-like symptoms, flushing sensa-
increase in cyclic adenosine monophosphate concen- tion, furunculosis, gastritis, gastroenteritis, gingivitis,
trations within the platelets. Additionally, it is capable of glycosuria, gout, hematuria, herpes simplex infection,
decreasing thrombogenesis and platelet clumping in hypercholesterolemia, hyperglycemia, hyperkalemia,
the lungs by inhibiting platelet aggregation. hypokalemia, hyponatremia, hypotension, increased
Pharmacodynamics/Kinetics creatine phosphokinase, increased serum alanine
Half-life Elimination ~6 minutes aminotransferase, increased serum aspartate amino-
Pregnancy Considerations transferase, insomnia, lower limb cramp, maculopap-
Information related to the use of epoprostenol in preg- ular rash, malaise, migraine, nausea, nephrolithiasis,
nancy is limited (Geohas 2003; Kawabe 2018; Martinez nervousness, neuritis, nonthrombocytopenic purpura,
2013; Smith 2012; Timofeev 2013); however, the man- orthostatic hypotension, osteoarthritis, otitis externa,
ufacturer notes adverse maternal or fetal outcomes otitis media, pain, palpitations, paresthesia, periodon-
have not been associated with its use based on the titis, peripheral edema, peripheral ischemia, polyuria,
available data. pruritus, rigors, skeletal pain, skin rash, substernal
pain, tachycardia, tendonitis, thrombocytopenia, tinni-
Pulmonary arterial hypertension (PAH) is associated
tus, toothache, tremor, urinary frequency, urinary
with adverse pregnancy outcomes. Women with PAH
incontinence, vertigo, visual disturbance, vomiting,
are encouraged to avoid pregnancy (McLaughlin 2009;
xerophthalmia, xerostomia
Taichman 2014).
Mechanism of Action Angiotensin II is formed from
Prescribing and Access Restrictions Orders for angiotensin I in a reaction catalyzed by angiotensin-
epoprostenol are distributed by two sources in the
converting enzyme (ACE, kininase II). Angiotensin II is
United States. Information on orders or reimbursement
the principal pressor agent of the renin-angiotensin
assistance may be obtained from either Accredo
system, with effects that include vasoconstriction, stim-
Health, Inc (1-866-344-4874) or CVS Caremark
ulation of synthesis and release of aldosterone, cardiac
(1-877-242-2738).
stimulation, and renal reabsorption of sodium. Eprosar-
tan blocks the vasoconstrictor and aldosterone-secret-
Eprosartan (ep roe SAR tan) ing effects of angiotensin II by selectively blocking the
binding of angiotensin II to the AT1 receptor in many
Related Information tissues, such as vascular smooth muscle and the
Cardiovascular Diseases on page 1442 adrenal gland. Its action is therefore independent of
Brand Names: Canada Teveten the pathways for angiotensin II synthesis. Blockade of
Pharmacologic Category Angiotensin II Receptor the renin-angiotensin system with ACE inhibitors, which
Blocker; Antihypertensive inhibit the biosynthesis of angiotensin II from angioten-
Use Hypertension: Management of hypertension sin I, is widely used in the treatment of hypertension.
Local Anesthetic/Vasoconstrictor Precautions ACE inhibitors also inhibit the degradation of bradyki-
No information available to require special precautions nin, a reaction also catalyzed by ACE. Because epro-
Effects on Dental Treatment Key adverse event(s) sartan does not inhibit ACE (kininase II), it does not
related to dental treatment: Patients may experience affect the response to bradykinin. Whether this differ-
orthostatic hypotension as they stand up after treat- ence has clinical relevance is not yet known. Eprosar-
ment; especially if lying in dental chair for extended tan does not bind to or block other hormone receptors
periods of time. Use caution with sudden changes in or ion channels known to be important in cardiovascular
position during and after dental treatment. regulation.
Effects on Bleeding No information available to Pharmacodynamics/Kinetics
require special precautions Half-life Elimination Terminal: 5 to 9 hours (Bottorff,
Adverse Reactions 1999)
1% to 10%: Time to Peak Serum: Fasting: 1 to 2 hours
Cardiovascular: Chest pain (≥1%) Pregnancy Risk Factor D
Central nervous system: Fatigue (2%), dizziness Pregnancy Considerations
(≥1%), headache (≥1%), depression (1%) [US Boxed Warning]: Drugs that act on the renin-
Endocrine & metabolic: Dependent edema (≥1%), angiotensin system can cause injury and death to
hypertriglyceridemia (1%) the developing fetus. Discontinue as soon as pos-
Gastrointestinal: Abdominal pain (2%), diarrhea sible once pregnancy is detected. The use of drugs
(≥1%), dyspepsia (≥1%) which act on the renin-angiotensin system are associ-
Genitourinary: Urinary tract infection (1%) ated with oligohydramnios. Oligohydramnios, due to
Infection: Viral infection (2%) decreased fetal renal function, may lead to fetal lung
504
ERAVACYCLINE
hypoplasia and skeletal malformations. Use is also receptor, the binding site for fibrinogen, von Willebrand
associated with anuria, hypotension, renal failure, skull factor, and other ligands. Inhibition of binding at this
hypoplasia, and death in the fetus/neonate. The final common receptor reversibly blocks platelet aggre-
exposed fetus should be monitored for fetal growth, gation and prevents thrombosis.
amniotic fluid volume, and organ formation. Infants Pharmacodynamics/Kinetics
exposed in utero should be monitored for hyperkalemia, Onset of Action Immediate after initial bolus (>80%
hypotension, and oliguria (exchange transfusions or inhibition of ADP-induced aggregation achieved 5
dialysis may be needed). These adverse events are minutes after bolus dose); maximal effect achieved
generally associated with maternal use in the second within 1 hour (Gilchrist, 2001; Tardiff, 2001)
and third trimesters. Duration of Action Platelet function restored ~4 to 8
Untreated chronic maternal hypertension is also asso- hours following discontinuation (Tardiff, 2001)
ciated with adverse events in the fetus, infant, and Half-life Elimination ~2.5 hours
mother. The use of angiotensin II receptor blockers is Pregnancy Risk Factor B
not recommended to treat chronic uncomplicated Pregnancy Considerations Adverse events have not
hypertension in pregnant women and should generally been observed in animal reproduction studies.
be avoided in women of reproductive potential
(ACOG 2013).
Eravacycline (ER a va SYE kleen)
Eptifibatide (ep TIF i ba tide) Brand Names: US Xerava

Pharmacologic Category Antibiotic, Tetracycline
Related Information Derivative
Cardiovascular Diseases on page 1442 Use
Brand Names: US Integrilin Intra-abdominal infections, complicated: Treatment
Brand Names: Canada Eptifibatide Injection; Integrilin of complicated intra-abdominal infections caused by
Pharmacologic Category Antiplatelet Agent, Glyco- susceptible microorganisms: Escherichia coli, Kleb-
protein IIb/IIIa Inhibitor siella pneumoniae, Citrobacter freundii, Enterobacter
Use cloacae, Klebsiella oxytoca, Enterococcus faecalis,
Acute coronary syndrome: Treatment of patients with Enterococcus faecium, Staphylococcus aureus, Strep-
acute coronary syndrome (unstable angina/non-ST- tococcus anginosus group, Clostridium perfringens,
segment elevation myocardial infarction [UA/ Bacteroides species, and Parabacteroides distasonis
NSTEMI]), including patients who are to be managed in patients ≥18 years.
medically and those undergoing percutaneous coro- Limitations of use: Not indicated for the treatment of
nary intervention (PCI) complicated urinary tract infections.
Percutaneous coronary intervention: Treatment of Local Anesthetic/Vasoconstrictor Precautions
patients undergoing PCI, including those undergoing No information available to require special precautions
intracoronary stenting. Effects on Dental Treatment Key adverse event(s)
Local Anesthetic/Vasoconstrictor Precautions related to dental treatment: Although ervacycline is a
No information available to require special precautions member of the tetracycline family, there is no dental
Effects on Dental Treatment Key adverse event(s) indication for its use. Therefore, the concerns of tetra-
related to dental treatment: Bleeding; patients weighing cyclines in dental patients relative to enamel incorpo-
<70 kg may have an increased risk of major bleeding. ration in pediatrics are not applicable for ervacycline.
See Effects on Bleeding. Use may result in fungal or bacterial superinfection.
Effects on Bleeding Bleeding is the most common Effects on Bleeding No information available to
complication. Eptifibatide inhibits platelet aggregation. require special precautions
Vascular and other trauma should be avoided. It is Adverse Reactions
unlikely that dental work would be performed in patients 1% to 10%:
undergoing treatment for acute coronary syndrome. Cardiovascular: Hypotension (1%)
Adverse Reactions Frequency not always defined. Gastrointestinal: Nausea (7%), vomiting (4%), diar-
Bleeding is the major drug-related adverse effect. rhea (2%)
Access site is often primary source of bleeding compli- Local: Infusion site reaction (8%)
cations. Incidence of bleeding is also related to heparin Miscellaneous: Wound dehiscence (1%)
intensity. Patients weighing <70 kg may have an <1%, postmarketing, and/or case reports: Acute pan-
increased risk of major bleeding. creatitis, anaphylaxis, anxiety, chest pain, decreased
>10%: Hematologic: & oncologic: Hemorrhage (major: creatinine clearance, decreased white blood cell
1% to 11%; minor: 3% to 14%; transfusion required: count, depression, dizziness, dysgeusia, dyspnea,
2% to 13%) hyperhidrosis, hypersensitivity reaction, hypocalce-
1% to 10%: mia, increased amylase, increased gamma-glutamyl
Cardiovascular: Hypotension (≤7%) transferase, increased serum alanine aminotransfer-
Hematologic & oncologic: Thrombocytopenia (1% to ase, increased serum lipase, insomnia, neutropenia,
3%; includes acute profound thrombocytopenia, palpitations, pancreatic necrosis, pleural effusion, pro-
immune-mediated thrombocytopenia) longed partial thromboplastin time, skin rash
Local: Injection site reaction Mechanism of Action Eravacycline is a fluorocycline
<1%, postmarketing and/or case reports: Anaphylaxis, antibiotic within the tetracycline class that binds to the
cerebrovascular accident, gastrointestinal hemor- 30S ribosomal subunit and prevents the incorporation
rhage, intracranial hemorrhage, pulmonary hemor- of amino acid residues into elongating peptide chains,
rhage thereby, inhibiting bacterial protein synthesis.
Mechanism of Action Eptifibatide is a cyclic hepta- Pharmacodynamics/Kinetics
peptide which blocks the platelet glycoprotein IIb/IIIa Half-life Elimination 20 hours
505
ERAVACYCLINE
Pregnancy Considerations Mechanism of Action Ergocalciferol (vitamin D2) is a

Tetracyclines cross the placenta. provitamin. The active metabolite, 1,25-dihydroxyvita-
min D (calcitriol), stimulates calcium and phosphate
As a class, tetracyclines accumulate in developing teeth
absorption from the small intestine, promotes secretion
and long tubular bones (Mylonas 2011). Exposure dur-
ing the second and third trimesters of pregnancy may of calcium from bone to blood; promotes renal tubule
cause reversible inhibition of bone growth. Permanent phosphate resorption.
discoloration of teeth (yellow, gray, brown) can occur
following in utero exposure and is more likely to occur Onset of Action 10 to 24 hours; Maximum effect: ~1
following long-term or repeated exposure. month following daily doses
Half-life Elimination Circulating: 25(OH)D: 2 to 3
weeks; 1,25-dihydroxyvitamin D ~4 hours
Erenumab-aooe (e REN ue mab aooe) Pregnancy Considerations Adverse events were
Brand Names: US Aimovig; Aimovig 140 Dose observed in some animal reproduction studies. The
ergocalciferol (vitamin D 2 ) metabolite, 25(OH)D,
Pharmacologic Category Calcitonin Gene-Related
Peptide (CGRP) Receptor Antagonist; Monoclonal Anti- crosses the placenta; maternal serum concentrations
body, CGRP Antagonist correlate with fetal concentrations at birth (Misra 2008;
Use Migraine prophylaxis: Preventive treatment of Wagner 2008).
migraine in adults Vitamin D deficiency in a pregnant woman may lead to
Local Anesthetic/Vasoconstrictor Precautions a vitamin D deficiency in the neonate (Misra 2008;
No information available to require special precautions Wagner 2008). Serum 25(OH)D concentrations should
Effects on Dental Treatment No significant effects or be measured in pregnant women considered to be at
complications reported increased risk of deficiency (ACOG 2011). The amount
Effects on Bleeding No information available to of vitamin D contained in prenatal vitamins may not be
require special precautions adequate to treat a deficiency during pregnancy;
Adverse Reactions although larger doses may be needed, current guide-
1% to 10%: lines recommend a total of 1000 to 2000 units/day until
Gastrointestinal: Constipation (3%) more safety data is available (ACOG 2011). In women
Immunologic: Antibody development (3% to 6%) not at risk for deficiency, doses larger than the RDA
Local: Injection site reaction (5% to 6%; including should be avoided during pregnancy (ACOG 2011).
injection site erythema, pain, and pruritus)
Neuromuscular & skeletal: Muscle cramps (≤2%), Maternal vitamin D requirements are the same for
muscle spasm (≤2%) breastfeeding and nonbreastfeeding females (IOM
Mechanism of Action Erenumab is a human mono- 2011). The maternal dose of vitamin D needed to
clonal antibody that antagonizes calcitonin gene-related provide the infant with an adequate amount of vitamin
peptide (CGRP) receptor function. D is still under study (Wagner 2008)
Half-life Elimination 28 days Ergoloid Mesylates (ER goe loid MES i lates)
Time to Peak ~6 days
Pregnancy Considerations Adverse events were not Brand Names: Canada Hydergine
observed in animal reproduction studies. Pharmacologic Category Ergot Derivative
Use
Ergocalciferol (er goe kal SIF e role) Mental capacity decline: Treatment of signs and
symptoms of an idiopathic decline in mental capacity.
Brand Names: US Calcidol [OTC]; Calciferol [OTC]; Note: Individuals who do respond come from groups of
Drisdol; Drisdol [OTC] [DSC] patients who would be considered clinically to suffer
Brand Names: Canada D-Forte; Erdol from some ill-defined process related to aging or to
Pharmacologic Category Vitamin D Analog have some underlying dementing condition (ie, pri-
Use mary progressive dementia, Alzheimer dementia,
Dietary supplement: For use as a vitamin D supple- senile onset, multi-infarct dementia).
ment. Local Anesthetic/Vasoconstrictor Precautions
Hypoparathyroidism: Treatment of hypoparathyroid- Although ergoloid mesylates are derivatives of the
ism. Note: Since parathyroid hormone (PTH) is natural ergot alkaloids, they lack any vasoconstricting
required for the conversion of vitamin D (ergocalciferol effects; there is no information available to require
or cholecalciferol) to the active metabolite of vitamin D special precautions with vasoconstrictor
(1,25-dihydroxyvitamin D), alternative vitamin D prep- Effects on Dental Treatment Key adverse event(s)
arations not dependent on this conversion (eg, alfa- related to dental treatment: Patients may experience
calcidol, calcitriol) are recommended for routine use orthostatic hypotension as they stand up after treat-
(Endocrine Society [Brandi 2016]). ment; especially if lying in dental chair for extended
Local Anesthetic/Vasoconstrictor Precautions periods of time. Use caution with sudden changes in
No information available to require special precautions position during and after dental treatment.
Effects on Dental Treatment Key adverse event(s) Effects on Bleeding No information available to
related to dental treatment: Metallic taste and xerosto- require special precautions
mia (normal salivary flow resumes upon discontinua-
Adverse Reactions Frequency not defined. Adverse
tion).
effects are minimal.
require special precautions Cardiovascular: Bradycardia, flushing, orthostatic hypo-
Adverse Reactions Frequency not defined: Endocrine tension
& metabolic: Hypervitaminosis D Dermatologic: Skin rash
506
ERGOTAMINE AND CAFFEINE
Gastrointestinal: Gastrointestinal distress (sublingual placenta should be delivered and the possibility of twin
administration), nausea (sublingual administration; pregnancy ruled out. Administration causes hyperstimu-
transient) lation of the uterus and may cause uterine tetany,
Local: Local irritation (sublingual administration) decreased uteroplacental blood flow, uterine rupture,
Ophthalmic: Blurred vision cervical and perineal lacerations, amniotic fluid embo-
Respiratory: Nasal congestion lism, and possible trauma to the infant.
Mechanism of Action Ergoloid mesylates do not have Product Availability Not available in the US
the vasoconstrictor effects of the natural ergot alkaloids;
exact mechanism in dementia is unknown; originally
classed as peripheral and cerebral vasodilator, now
Ergotamine (er GOT a meen)
considered a "metabolic enhancer"; there is no specific Related Information
evidence that clearly establishes the mechanism by Dentin Hypersensitivity, Acid Erosion, High Caries
which ergoloid mesylate preparations produce mental Index, Management of Alveolar Osteitis, and Xerosto-
effects, nor is there conclusive evidence that the drug mia on page 1548
particularly affects cerebral arteriosclerosis or cerebro-
Brand Names: US Ergomar
vascular insufficiency.
Pharmacodynamics/Kinetics Pharmacologic Category Antimigraine Agent; Ergot
Half-life Elimination Serum: ~2.6 to 5.1 hours Derivative
Time to Peak Serum: 1.5 to 3 hours Use Vascular headache: Abort or prevent vascular
headaches, such as migraine, migraine variants, or
so-called "histaminic cephalalgia"
Ergonovine (er goe NOE veen) Local Anesthetic/Vasoconstrictor Precautions
Use vasoconstrictor with caution in patients taking
Brand Names: Canada Ergonovine Maleate Injection ergotamine; this ergot alkaloid derivative causes con-
Pharmacologic Category Ergot Derivative; Oxytocic striction of peripheral blood vessels
Agent Effects on Dental Treatment No significant effects or
Use Note: Not approved in the US complications reported
Postpartum or postabortion hemorrhage: Preven- Effects on Bleeding No information available to
tion and treatment of postpartum and postabortion require special precautions
hemorrhage caused by uterine atony
Local Anesthetic/Vasoconstrictor Precautions Cardiovascular: Bradycardia, cold extremities, ECG
Use vasoconstrictor with caution in patients taking changes, edema, hypertension, ischemia, tachycar-
ergonovine; this ergot alkaloid derivative causes con- dia, valvular sclerosis, vasospasm
striction of peripheral blood vessels
Central nervous system: Numbness, paresthesia, pre-
Effects on Dental Treatment No significant effects or cordial pain, vertigo
complications reported Dermatologic: Gangrene of skin or other tissue, pruritus
Effects on Bleeding Rare but significant events Gastrointestinal: Nausea, vomiting
related to hemorrhage (cerebral hemorrhage, subar- Genitourinary: Retroperitoneal fibrosis
achnoid hemorrhage, and stroke) have occurred follow- Neuromuscular & skeletal: Myalgia, weakness
ing injection of some agents in this class. However, Respiratory: Cyanosis, pleuropulmonary fibrosis
there is no information related to special precautions
Mechanism of Action Has partial agonist and/or
associated with bleeding related to dental procedures.
antagonist activity against tryptaminergic, dopaminergic
Adverse Reactions Frequency not defined. and alpha-adrenergic receptors depending upon their
Cardiovascular: Angina pectoris (transient), bradycar- site; is a highly active uterine stimulant; it causes
dia, hypertension, myocardial infarction, palpitations, constriction of peripheral and cranial blood vessels
shock, thrombophlebitis and produces depression of central vasomotor centers
Central nervous system: Dizziness, hallucination, head- Pharmacodynamics/Kinetics
ache, vertigo Half-life Elimination 2-2.5 hours (Perrin 1985)
Dermatologic: Diaphoresis
Time to Peak Serum: Oral: 2 hours (Perrin 1985)
Endocrine & metabolic: Water intoxication
Gastrointestinal: Abdominal pain, diarrhea, nausea,
Pregnancy Risk Factor X
vomiting Pregnancy Considerations May cause prolonged
Genitourinary: Hematuria constriction of the uterine vessels and/or increased
Hypersensitivity: Hypersensitivity reaction myometrial tone leading to reduced placental blood
Respiratory: Dyspnea flow. This has contributed to fetal growth retardation in
Miscellaneous: Ergot alkaloids toxicity animals.
Mechanism of Action Similar smooth muscle actions
as seen with ergotamine; however, it affects primarily Ergotamine and Caffeine
uterine smooth muscles producing sustained contrac- (er GOT a meen & KAF een)
tions and thereby shortens the third stage of labor. Has
slight alpha-adrenergic blocking activity and produces Related Information
less vasoconstriction than ergotamine. Caffeine on page 245
Pharmacodynamics/Kinetics Ergotamine on page 507
Onset of Action IM: 2 to 5 minutes; IV: Immediate Brand Names: US Cafergot; Migergot
Duration of Action IM: Uterine effect: ≥3 hours; IV: Brand Names: Canada Cafergor
~45 minute Pharmacologic Category Antimigraine Agent; Cen-
Pregnancy Considerations Ergonovine is used in the tral Nervous System Stimulant; Ergot Derivative
third stage of labor for the prevention or treatment of Use Vascular headache: Prevention or treatment of
postpartum hemorrhage and should not be used prior to vascular headaches, such as migraine, migraine var-
delivery of the placenta. Prior to administration, the iants, or so-called "histaminic cephalalgia"
507
ERGOTAMINE AND CAFFEINE
Local Anesthetic/Vasoconstrictor Precautions Effects on Bleeding Anemia is a primary adverse

Use vasoconstrictor with caution in patients taking effect. A medical consult is suggested.
ergotamine; this ergot alkaloid derivative causes con- Adverse Reactions
striction of peripheral blood vessels >10%:
Effects on Dental Treatment Key adverse event(s) Cardiovascular: Peripheral edema (≥5% to 12%)
related to dental treatment: Ergotamine and caffeine Central nervous system: Fatigue (≤62%), peripheral
cause tachycardia, increases in blood pressure, and neuropathy (29% to 35%; grades 3/4: 3% to 8%),
palpitations. Consider monitoring blood pressure prior headache (18% to 19%)
to using local anesthetic with a vasoconstrictor. Symp- Dermatologic: Alopecia (35% to 45%)
toms associated with bruxism have been observed in Endocrine & metabolic: Hypokalemia (≥5% to 30%),
some patients. hypocalcemia (28%), weight loss (21%), hypophos-
Effects on Bleeding No information available to phatemia (20%)
require special precautions Gastrointestinal: Nausea (35% to 41%), constipation
Adverse Reactions Frequency not defined. (25% to 32%), abdominal pain (≥5% to 29%), ano-
Cardiovascular: Bradycardia, cold extremities, ECG rexia (20%), decreased appetite (19%), vomiting
changes, edema, hypertension, ischemia, tachycar- (18% to 19%), diarrhea (17% to 18%), stomatitis
dia, valvular sclerosis, vasospasm (≥5% to 14%)
Central nervous system: Numbness, paresthesia, pre- Genitourinary: Urinary tract infection (10% to 11%)
Hematologic & oncologic: Neutropenia (63% to 82%;
cordial pain, vertigo
grade 4: 29% grades 3/4: 12% to 57%; nadir: 13
Dermatologic: Gangrene of skin or other tissue, pruritus
days; recovery: 8 days), anemia (58% to 70%;
Gastrointestinal: Anal fissure (with overuse of supposi-
grades 3/4: 2% to 4%)
tory), nausea, rectal ulcer (with overuse of supposi-
Hepatic: Increased serum ALT (18% to 43%),
tory), vomiting
increased serum AST (36%)
Genitourinary: Retroperitoneal fibrosis
Neuromuscular & skeletal: Weakness (≤62%), arthral-
Neuromuscular & skeletal: Myalgia, weakness
gia (≤22%), myalgia (≤22%), back pain (16%),
Respiratory: Cyanosis, pleuropulmonary fibrosis ostealgia (12%), limb pain (11%)
Mechanism of Action Has partial agonist and/or Respiratory: Cough (14% to 18%), dyspnea (16%)
antagonist activity against tryptaminergic, dopaminergic Miscellaneous: Fever (21% to 28%)
and alpha-adrenergic receptors depending upon their 1% to 10%:
site; is a highly active uterine stimulant; it causes Cardiovascular: Hypotension (≥5% to <10%)
constriction of peripheral and cranial blood vessels Central nervous system: Anxiety (≥5% to <10%),
and produces depression of central vasomotor centers depression (≥5% to <10%), dizziness (≥5% to
Pharmacodynamics/Kinetics <10%), insomnia (≥5% to <10%), myasthenia (≥5%
Half-life Elimination 2 to 2.5 hours (Perrin, 1985) to <10%)
Time to Peak Serum: Ergotamine: 2 hours (Perrin, Dermatologic: Skin rash (≥5% to <10%)
1985) Endocrine & metabolic: Hyperglycemia (≥5% to <10%)
Pregnancy Risk Factor X Gastrointestinal: Dysgeusia (≥5% to <10%), dyspep-
Pregnancy Considerations Animal reproduction sia (≥5% to <10%), xerostomia (≥5% to <10%),
studies have not been conducted with this combination. mucosal inflammation (9%)
Ergotamine and caffeine both cross the placenta and Hematologic & oncologic: Thrombocytopenia (≥5% to
may cause prolonged constriction of the uterine vessels <10%; grades ≥3: 1%), febrile neutropenia (≤5%)
and/or increased myometrial tone leading to reduced Neuromuscular & skeletal: Muscle spasm (≥5% to
placental blood flow. Use is contraindicated in pregnant <10%), musculoskeletal pain (≥5% to <10%),
women. Ophthalmic: Increased lacrimation (≥5% to <10%)
Respiratory: Oropharyngeal pain (≥5% to <10%),
upper respiratory tract infection (≥5% to <10%)
EriBULin (er i BUE lin) <1%, postmarketing, and/or case reports: Dehydration,
Brand Names: US Halaven drug-induced hypersensitivity, hepatotoxicity, hypo-
magnesemia, interstitial pulmonary disease, lympho-
Brand Names: Canada Halaven
cytopenia, neutropenic sepsis, pancreatitis,
Pharmacologic Category Antineoplastic Agent, Anti- pneumonia, prolonged Q-T interval on ECG, pruritus,
microtubular sepsis, Stevens-Johnson syndrome, toxic epidermal
Use necrolysis
Breast cancer, metastatic: Treatment of metastatic Mechanism of Action Eribulin is a non-taxane micro-
breast cancer in patients who have received at least tubule inhibitor which is a halichondrin B analog. It
2 prior chemotherapy regimens for the treatment of inhibits the growth phase of the microtubule by inhibit-
metastatic disease (prior treatment should have ing formation of mitotic spindles causing mitotic block-
included an anthracycline and a taxane in either the age and arresting the cell cycle at the G2/M phase;
adjuvant or metastatic setting) suppresses microtubule polymerization yet does not
Liposarcoma, unresectable or metastatic: Treatment affect depolymerization.
of unresectable or metastatic liposarcoma in patients Pharmacodynamics/Kinetics
who have received a prior anthracycline-containing Half-life Elimination ~40 hours
regimen Pregnancy Considerations Adverse effects were
Local Anesthetic/Vasoconstrictor Precautions observed in animal reproduction studies. Based on its
No information available to require special precautions mechanism of action, eribulin would be expected to
Effects on Dental Treatment Key adverse event(s) cause fetal harm if administered during pregnancy.
related to dental treatment: Xerostomia (normal salivary Women of reproductive potential should use effective
flow resumes upon discontinuation), stomatitis, contraception to avoid pregnancy during eribulin treat-
mucosal inflammation, or taste alteration. ment and for at least 2 weeks following the last eribulin
508
ERLOTINIB
dose; males with female partners of reproductive poten- 1% to 10%:

tial should use effective contraception during eribulin Cardiovascular: Peripheral edema (≤5%)
treatment and for 3.5 months following the last dose. Central nervous system: Pain (≤9%), headache
The Canadian labeling recommends effective contra- (≤7%), anxiety (≤5%), dizziness (≤4%), insomnia
ception during and for at least 3 months after treatment (≤4%), neurotoxicity (≤4%), paresthesia (≤4%), voice
in women of reproductive potential. disorder (≤4%)
Dermatologic: Folliculitis (≤8%), nail disease (≤7%),
Erlotinib (er LOE tye nib) exfoliative dermatitis (5%), hypertrichosis (5%), skin
fissure (5%), acneiform eruption (4% to 5%), eryth-
Brand Names: US Tarceva ema (≤5%), dermatitis (4%), erythematous rash
Brand Names: Canada Tarceva; Teva-Erlotinib (≤4%), palmar-plantar erythrodysesthesia (≤4%),
Pharmacologic Category Antineoplastic Agent, Epi- bullous dermatitis
dermal Growth Factor Receptor (EGFR) Inhibitor; Anti- Endocrine & metabolic: Weight loss (4% to 5%)
neoplastic Agent, Tyrosine Kinase Inhibitor Gastrointestinal: Dyspepsia (≤5%), xerostomia (≤3%),
Use taste disorder (≤1%)
Non-small cell lung cancer, metastatic: Treatment of Hematologic & oncologic: Lymphocytopenia (≤4%;
metastatic non-small cell lung cancer (NSCLC) in grade 3: 1%), leukopenia (≤3%), thrombocytope-
tumors with epidermal growth factor receptor (EGFR) nia (≤1%)
exon 19 deletions or exon 21 (L858R) substitution Hepatic: Hyperbilirubinemia (7%; grade 3: ≤1%),
mutations as detected by an approved test either as increased serum ALT (grade 2: 2% to 4%; grade 3:
first-line, maintenance, or as second or greater line 1% to 3%), increased gamma-glutamyl transferase
treatment after progression following at least 1 prior (≤4%), hepatic failure (≤1%)
chemotherapy regimen. Neuromuscular & skeletal: Muscle spasm (≤4%), mus-
Limitations of use: Use in combination with platinum- culoskeletal chest pain (≤4%), ostealgia (≤4%)
based chemotherapy is not recommended. Safety Otic: Tinnitus (≤1%)
and efficacy of treatment for metastatic NSCLC with Renal: Increased serum creatinine (≤1%), renal fail-
EGFR mutations other than exon 19 deletion or exon ure (≤1%),
21 (L858R) substitution have not been established. Respiratory: Nasopharyngitis (≤7%), epistaxis (≤4%),
Pancreatic cancer: First-line treatment of locally pulmonary embolism (≤4%), respiratory tract infec-
advanced, unresectable, or metastatic pancreatic can- tion (≤4%), pneumonitis (3%), pulmonary fibro-
cer (in combination with gemcitabine) sis (3%)
Local Anesthetic/Vasoconstrictor Precautions <1%: Interstitial pulmonary disease
Adverse reactions reported with combination (erlo-
tinib plus gemcitabine) therapy:
>10%:
flow resumes upon discontinuation), mucositis, abnor-
Cardiovascular: Edema (37%), thrombosis (grades
mal taste, and stomatitis.
3/4: 11%)
Effects on Bleeding In treatment of pancreatic carci-
Central nervous system: Fatigue (73% to 79%),
noma, has been noted to cause microangiopathic
depression (19%), dizziness (15%), headache
hemolytic anemia with thrombocytopenia
(15%), anxiety (13%)
Adverse Reactions
Dermatologic: Skin rash (70%), alopecia (14%)
Adverse reactions reported with monotherapy:
Gastrointestinal: Nausea (60%), anorexia (52%), diar-
>10%:
rhea (48%), abdominal pain (46%), vomiting (42%),
Cardiovascular: Chest pain (≤18%)
Central nervous system: Fatigue (9% to 52%) weight loss (39%), stomatitis (22%), dyspepsia
Dermatologic: Skin rash (49% to 85%; grade 3: 5% to (17%), flatulence (13%)
13%; grade 4: <1%; median onset: 8 days), xero- Hepatic: Increased serum ALT (grade 2: 31%, grade
derma (4% to 21%), pruritus (7% to 16%), parony- 3: 13%, grade 4: <1%), increased serum AST (grade
chia (4% to 16%), alopecia (14% to 15%), acne 2: 24%, grade 3: 10%, grade 4 <1%), hyperbilirubi-
vulgaris (6% to 12%) nemia (grade 2: 17%, grade 3: 10%, grade 4: <1%)
Gastrointestinal: Diarrhea (20% to 62%; grade 3: 2% Infection: Increased susceptibility to infection (39%)
to 6%; grade 4: <1%; median onset: 12 days), Neuromuscular & skeletal: Ostealgia (25%), myalgia
anorexia (9% to 52%), nausea (23% to 33%), (21%), neuropathy (13%), rigors (12%)
decreased appetite (≤28%), vomiting (13% to 23%), Respiratory: Dyspnea (24%), cough (16%)
mucositis (≤18%), stomatitis (11% to 17%), abdomi- Miscellaneous: Fever (36%)
nal pain (3% to 11%), constipation (≤8%) 1% to 10%:
Genitourinary: Urinary tract infection (≤4%) Cardiovascular: Cardiac arrhythmia (<5%), syncope
Hematologic & oncologic: Anemia (≤11%; grade (<5%), deep vein thrombosis (4%), cerebrovascular
4: 1%) accident (3%; including cerebral hemorrhage), myo-
Infection: Increased susceptibility to infection (4% cardial infarction (2%)
to 24%) Gastrointestinal: Intestinal obstruction (<5%), pan-
Neuromuscular & skeletal: Weakness (≤53%), back creatitis (<5%)
pain (19%), arthralgia (≤13%), musculoskeletal Hematologic & oncologic: Hemolytic anemia (<5%),
pain (11%) microangiopathic hemolytic anemia with thrombocy-
Ophthalmic: Conjunctivitis (12% to 18%), keratocon- topenia (1%)
junctivitis sicca (12%) Renal: Renal insufficiency (<5%), renal failure (1%)
Respiratory: Cough (33% to 48%), dyspnea (41% to Respiratory: Interstitial pulmonary disease (<3%)
45%; grades 3/4: 8% to 28%) <1%: Bullous dermatitis, exfoliative dermatitis, hepatic
Miscellaneous: Fever (≤11%) failure
509
ERLOTINIB
Mono- or combination therapy: <1%, postmarketing, been studied in diabetic foot infections with concom-
and/or case reports: Acute peptic ulcer with hemor- itant osteomyelitis.
rhage, bronchiolitis, corneal perforation, corneal ulcer, Complicated urinary tract infections: For the treat-
decreased lacrimation, episcleritis, gastritis, gastro- ment of complicated urinary tract infections (UTIs),
intestinal hemorrhage, gastrointestinal perforation, including pyelonephritis caused by E. coli, including
hearing loss, hematemesis, hematochezia, hepatore- cases with concurrent bacteremia or K. pneumoniae.
nal syndrome, hepatotoxicity, hirsutism, hyperpigmen- Prophylaxis of surgical-site infection in colorectal
tation, hypokalemia, increased eyelash thickness, surgery: For the prophylaxis of surgical-site infection
increased growth in number of eyelashes, keratitis, in adults following elective colorectal surgery.
melena, misdirected growth of eyelashes, myopathy
(in combination with statin therapy), ocular inflamma- Note: Methicillin-resistant Staphylococcus aureus,
tion, peptic ulcer, rhabdomyolysis (in combination with Enterococcus spp, penicillin-resistant strains of Strep-
statin therapy), skin photosensitivity, skin rash (acnei- tococcus pneumoniae, Acinetobacter, and Pseudomo-
form; sparing prior radiation field), Stevens-Johnson nas aeruginosa are resistant to ertapenem while most
syndrome, toxic epidermal necrolysis, tympanic mem- extended-spectrum beta-lactamase (ESBL)-producing
brane perforation, uveitis bacteria remain sensitive to ertapenem.
Mechanism of Action Reversibly inhibits overall epi- Local Anesthetic/Vasoconstrictor Precautions
dermal growth factor receptor (HER1/EGFR) - tyrosine No information available to require special precautions
kinase activity. Intracellular phosphorylation is inhibited Effects on Dental Treatment Key adverse event(s)
which prevents further downstream signaling, resulting related to dental treatment: Oral candidiasis
in cell death. Erlotinib has higher binding affinity for Effects on Bleeding No information available to
EGFR exon 19 deletion or exon 21 L858R mutations require special precautions
than for the wild type receptor. Adverse Reactions
Pharmacodynamics/Kinetics >10%: Gastrointestinal: Diarrhea (6% to 12%)
Half-life Elimination 36.2 hours 1% to 10%:
Time to Peak Plasma: 4 hours Cardiovascular: Edema (3%), chest pain (<2%), phle-
Pregnancy Considerations Adverse events were bitis (<2%), thrombophlebitis (<2%), hypotension
observed in animal reproduction studies. Erlotinib (1% to 2%)
crosses the placenta (Ji 2015; Jovelet 2015). Informa- Central nervous system: Headache (2% to 7%),
tion related to the use of erlotinib in pregnancy is limited altered mental status (eg, agitation, confusion, dis-
(Ji 2015; Rivas 2012; Zambelli 2008). Based on the orientation, mental acuity decreased, somnolence,
mechanism of action, erlotinib may cause fetal harm if stupor) (3% to 5%), insomnia (3%), dizziness (2%),
administered in pregnancy. Advise females of reproduc- hypothermia (infants, children, and adoles-
tive potential to use effective contraception during treat- cents <2%)
ment and for at least 1 month after the last erlotinib Dermatologic: Diaper rash (infants and children 5%),
dose. skin rash (2% to 3%), pruritus (1% to 2%), genital
rash (infants, children, and adolescents <2%), skin
lesion (infants, children, and adolescents <2%)
Ertapenem (er ta PEN em)
Gastrointestinal: Vomiting (2% to 10%), nausea (6% to
Brand Names: US INVanz 9%), abdominal pain (4% to 5%), constipation (2% to
Brand Names: Canada Invanz 4%), decreased appetite (infants, children, and ado-
Pharmacologic Category Antibiotic, Carbapenem lescents <2%)
Use Moderate-to-severe infections: Genitourinary: Erythrocyturia (1% to 3%), vaginitis
Acute pelvic infections: For the treatment of acute (1% to 3%)
pelvic infections, including postpartum endomyometri- Hematologic & oncologic: Thrombocythemia (4% to
tis, septic abortion, and postsurgical gynecologic 7%), decreased neutrophils (3% to 6%), decreased
infections caused by Streptococcus agalactiae, hemoglobin (5%), decreased hematocrit (3%), leu-
Escherichia coli, Bacteroides fragilis, Porphyromonas kocyturia (2% to 3%), leukopenia (<2%), eosinophilia
asaccharolytica, Peptostreptococcus spp, or Prevo- (1% to 2%)
tella bivia. Hepatic: Increased serum ALT (8% to 9%), increased
Community-acquired pneumonia: For the treatment serum AST (7% to 8%), increased serum alkaline
of community-acquired pneumonia (CAP) caused by (4% to 7%)
Streptococcus pneumoniae (penicillin-susceptible iso- Infection: Herpes simplex infection (infants, children,
lates only), including cases with concurrent bactere- and adolescents <2%)
mia; Haemophilus influenzae (beta-lactamase- Local: Infused vein complication (4% to 7%)
negative isolates only); or Moraxella catarrhalis. Neuromuscular & skeletal: Arthralgia (infants, chil-
Complicated intra-abdominal infections: For the dren, and adolescents <2%)
treatment of complicated intra-abdominal infections Otic: Otic infection (infants, children, and adoles-
caused by E. coli, Clostridium clostridioforme, Eubac- cents <2%)
terium lentum, Peptostreptococcus spp, B. fragilis, Respiratory: Cough (≤4%), dyspnea (1% to 3%),
Bacteroides distasonis, Bacteroides ovatus, Bacter- nasopharyngitis (infants, children, and adolescents
oides thetaiotaomicron, or Bacteroides uniformis. <2%), rhinitis (infants, children, and adolescents
Complicated skin and skin structure infections: For <2%), rhinorrhea (infants, children, and adolescents
the treatment of complicated skin and skin structure <2%), upper respiratory tract infection (infants, chil-
infections, including diabetic foot infections without dren, and adolescents 2%), wheezing (infants, chil-
osteomyelitis caused by Staphylococcus aureus dren, and adolescents <2%)
(methicillin-susceptible isolates only), S. agalactiae, Miscellaneous: Fever (2% to 5%)
Streptococcus pyogenes, E. coli, Klebsiella pneumo- <1%, postmarketing, and/or case reports: Abdominal
niae, Proteus mirabilis, B. fragilis, Peptostreptococcus distention, acid regurgitation, aggressive behavior,
spp, P. asaccharolytica, or P. bivia. Ertapenem has not anaphylactoid reaction, anaphylaxis, anorexia, anuria,
510
ERTUGLIFLOZIN AND METFORMIN
anxiety, asthma, asystole, ataxia, atrial fibrillation, Adverse Reactions Incidences may include ertugliflo-
bladder dysfunction, bradycardia, bronchoconstriction, zin used as add on therapy.
cardiac arrest, cardiac arrhythmia, cardiac failure, >10%: Genitourinary: Genitourinary fungal infection
chills, cholelithiasis, Clostridioides (formerly Clostri- (females: 9% to 12%; males: 4%)
dium) difficile-associated diarrhea, decreased serum 1% to 10%:
albumin, dehydration, delirium, dental discoloration, Central nervous system: Headache (3% to 4%)
depression, dermatitis, desquamation, diaphoresis, Endocrine & metabolic: Hypovolemia (2% to 4%),
DRESS syndrome, duodenitis, dysgeusia, dyskinesia, hypoglycemia (3%), increased thirst (1% to 3%),
dyspepsia, dysphagia, epistaxis, erythema, esophagi- weight loss (2%), severe hypoglycemia (1%)
tis, extravasation, facial edema, fatigue, flank pain, Genitourinary: Increased urine output (2% to 3%),
flatulence, flushing, gastritis, gastrointestinal hemor- vulvovaginal pruritus (2% to 3%)
rhage, gout, hallucination, heart murmur, hematoma, Neuromuscular & skeletal: Back pain (3%)
hemoptysis, hemorrhoids, hiccups, hyperglycemia, Renal: Renal insufficiency (1% to 3%)
hyperkalemia, hypertension, hypoesthesia, hypokale- Respiratory: Nasopharyngitis (3%)
mia, hypoxemia, impaired consciousness, increased Frequency not defined:
blood urea nitrogen, increased serum bilirubin (total), Endocrine & metabolic: Increased LDL cholesterol,
increased serum creatinine, increased serum sodium, increased serum phosphate
induration at injection site, intestinal obstruction, jaun- Genitourinary: Decreased estimated GFR (eGFR)
dice, leg pain, malaise, muscle spasm, myoclonus, Renal: Increased serum creatinine
nervousness, oliguria, oral candidiasis, oral mucosa <1%, postmarketing, and/or case reports: Acute renal
ulcer, pain, pain at injection site, pancreatitis, pares- failure, increased hemoglobin, ketoacidosis, pyelo-
thesia, pharyngitis, pleural effusion, pleuritic chest nephritis, urinary tract infection, urinary tract infection
pain, prolonged prothrombin time, pyloric stenosis, with sepsis
rales, renal insufficiency, respiratory distress, rhonchi, Mechanism of Action By inhibiting sodium-glucose
seizure, septicemia, septic shock, sore throat, stoma- cotransporter 2 (SGLT2) in the proximal renal tubules,
titis, subdural hematoma, syncope, tachycardia,
ertugliflozin reduces reabsorption of filtered glucose
thrombocytopenia, tissue necrosis, tremor, unsteady
from the tubular lumen and lowers the renal threshold
gait, urinary retention, urticaria, ventricular tachycar-
for glucose (RTG). SGLT2 is the main site of filtered
dia, vertigo, voice disorder, vulvovaginal candidiasis,
glucose reabsorption; reduction of filtered glucose reab-
vulvovaginal pruritus, vulvovaginitis, weakness,
sorption and lowering of RTG result in increased urinary
weight loss
excretion of glucose, thereby reducing plasma glucose
concentrations.
Mechanism of Action Inhibits bacterial cell wall syn- Pharmacodynamics/Kinetics
thesis by binding to one or more of the penicillin-binding
Half-life Elimination 16.6 hours
proteins; which in turn inhibits the final transpeptidation
step of peptidoglycan synthesis in bacterial cell walls,
Time to Peak Plasma: 1 hour (fasting); 2 hours
(administered with high-fat, high-calorie meal)
thus inhibiting cell wall biosynthesis. Bacteria eventually
lyse due to ongoing activity of cell wall autolytic Pregnancy Considerations
enzymes (autolysins and murein hydrolases) while cell Based on animal data, adverse fetal effects on renal
wall assembly is arrested. development may occur in humans following in utero
Pharmacodynamics/Kinetics exposure during the second and third trimesters.
Half-life Elimination In women with diabetes, maternal hyperglycemia can
Infants ≥3 months and Children: ~2.5 hours be associated with congenital malformations as well as
Adolescents and Adults: ~4 hours adverse effects in the fetus, neonate, and the mother
Time to Peak IM: ~2.3 hours (ACOG 2005; ADA 2018c; Metzger 2007). To prevent
Pregnancy Considerations Ertapenem is approved adverse outcomes, prior to conception and throughout
for the treatment of postpartum endomyometritis, septic pregnancy, maternal blood glucose and HbA1c should
abortion, and postsurgical infections. Ertapenem may be kept as close to target goals as possible but without
be considered for use as an alternative antibiotic in the causing significant hypoglycemia (ADA 2018c; Blumer
treatment of intraamniotic infection (ACOG 712 2017). 2013). Agents other than ertugliflozin are currently
recommended to treat diabetes in pregnant women
Ertugliflozin (er too gli FLOE zin) (ADA 2018c).
Brand Names: US Steglatro Ertugliflozin and Metformin

Pharmacologic Category Antidiabetic Agent, (er too gli FLOE zin & met FOR min)
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor;
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Brand Names: US Segluromet
Use Diabetes mellitus, type 2: As an adjunct to diet Pharmacologic Category Antidiabetic Agent, Bigua-
and exercise to improve glycemic control in adults with nide; Antidiabetic Agent, Sodium-Glucose Cotrans-
type 2 diabetes mellitus p o r t e r 2 ( S G LT 2 ) I n h i b i t o r ; S o d i u m - G l u c o s e
Local Anesthetic/Vasoconstrictor Precautions Cotransporter 2 (SGLT2) Inhibitor
No information available to require special precautions Use Diabetes mellitus, type 2: As an adjunct to diet
Effects on Dental Treatment Key adverse event(s) and exercise to improve glycemic control in adults with
related to dental treatment: Schedule type 1 and type 2 type 2 diabetes mellitus who are not adequately con-
diabetic patients for dental treatment in the morning in trolled on a regimen containing ertugliflozin or metfor-
order to minimize chance of stress-induced hypoglyce- min or who are already treated with both ertugliflozin
mia. and metformin
require special precautions No information available to require special precautions
511
ERTUGLIFLOZIN AND METFORMIN
Effects on Dental Treatment Key adverse event(s) hormones are rapidly inactivated by the DPP-4
related to dental treatment: Schedule type 1 and type 2 enzyme.
diabetic patients for dental treatment in the morning in Pregnancy Considerations
order to minimize chance of stress-induced hypoglyce- Animal reproduction studies have not been conducted
mia. with this combination. Refer to individual agents.
Health care providers are encouraged to report any
prenatal exposure to sitagliptin to the pregnancy regis-
Adverse Reactions See individual agents. try (1-800-986-8999).
Mechanism of Action
Ertugliflozin: By inhibiting sodium-glucose cotransporter
2 (SGLT2) in the proximal renal tubules, ertugliflozin Erythromycin (Systemic) (er ith roe MYE sin)
reduces reabsorption of filtered glucose from the
tubular lumen and lowers the renal threshold for Related Information
glucose (RTG). SGLT2 is the main site of filtered Bacterial Infections on page 1525
glucose reabsorption; reduction of filtered glucose Clinical Risk Related to Drugs Prolonging QT Interval
reabsorption and lowering of RTG result in increased on page 1462
urinary excretion of glucose, thereby reducing plasma Related Sample Prescriptions
glucose concentrations. Bacterial Infections and Periodontal Diseases - Sample
Metformin: Decreases hepatic glucose production, Prescriptions on page 36
decreasing intestinal absorption of glucose and Brand Names: US E.E.S. 400; E.E.S. Granules; Ery-
improves insulin sensitivity (increases peripheral glu- Tab; EryPed 200; EryPed 400; Erythrocin Lactobionate;
cose uptake and utilization). Erythrocin Stearate; PCE [DSC]
Pregnancy Considerations Metformin crosses the Brand Names: Canada EES; Erybid; Eryc; Erythrocin;
placenta (ADA 2019). Refer to individual agents. PCE
Generic Availability (US) May be product dependent
Ertugliflozin and Sitagliptin Pharmacologic Category Antibiotic, Macrolide
(er too gli FLOE zin & sit a GLIP tin) Dental Use Alternative to penicillin VK for treatment of
orofacial infections
Brand Names: US Steglujan Use
Pharmacologic Category Antidiabetic Agent, Dipep- Bacterial infections: Treatment of susceptible bacte-
tidyl Peptidase 4 (DPP-4) Inhibitor; Antidiabetic Agent, rial infections, including S. pyogenes, some S. pneu-
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor; moniae, some S. aureus, M. pneumoniae, Legionella
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor pneumophila, diphtheria, pertussis, Chlamydia, eryth-
Use Diabetes mellitus, type 2: As an adjunct to diet rasma, N. gonorrhoeae, E. histolytica, syphilis and
and exercise to improve glycemic control in adults with nongonococcal urethritis, and Campylobacter gastro-
type 2 diabetes mellitus when treatment with both enteritis; used in conjunction with neomycin for decon-
ertugliflozin and sitagliptin is appropriate taminating the bowel
Local Anesthetic/Vasoconstrictor Precautions Surgical (preoperative) prophylaxis (colorectal):
No information available to require special precautions Colorectal decontamination, in conjunction with other
Effects on Dental Treatment Key adverse event(s) agents, prior to surgical intervention
related to dental treatment: Schedule type 1 and type 2 Local Anesthetic/Vasoconstrictor Precautions
diabetic patients for dental treatment in the morning in Erythromycin is one of the drugs confirmed to prolong
order to minimize chance of stress-induced hypoglyce- the QT interval and is accepted as having a risk of
mia. causing torsade de pointes. In terms of epinephrine, it
Effects on Bleeding No information available to is not known what effect vasoconstrictors in the local
require special precautions anesthetic regimen will have in patients with a known
Adverse Reactions See individual agents. history of congenital prolonged QT interval or in patients
Mechanism of Action taking any medication that prolongs the QT interval.
Ertugliflozin: By inhibiting sodium-glucose cotransporter Until more information is obtained, it is suggested that
2 (SGLT2) in the proximal renal tubules, ertugliflozin the clinician consult with the physician prior to the use of
reduces reabsorption of filtered glucose from the a vasoconstrictor in suspected patients, and that the
tubular lumen and lowers the renal threshold for vasoconstrictor (epinephrine, mepivacaine and levonor-
glucose (RTG). SGLT2 is the main site of filtered defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used
glucose reabsorption; reduction of filtered glucose with caution. See Dental Health Professional Consid-
reabsorption and lowering of RTG result in increased erations.
urinary excretion of glucose, thereby reducing plasma Effects on Dental Treatment Key adverse event(s)
glucose concentrations. related to dental treatment: Oral candidiasis.
Sitagliptin: Inhibits dipeptidyl peptidase 4 (DPP-4) Effects on Bleeding No information available to
enzyme resulting in prolonged active incretin levels. require special precautions
Incretin hormones (eg, glucagon-like peptide-1 [GLP- Adverse Reactions Frequency not defined. Incidence
1] and glucose-dependent insulinotropic polypeptide may vary with formulation.
[GIP]) regulate glucose homeostasis by increasing Cardiovascular: QTc prolongation, torsade de pointes,
insulin synthesis and release from pancreatic beta ventricular arrhythmia, ventricular tachycardia
cells and decreasing glucagon secretion from pancre- Central nervous system: Seizure
atic alpha cells. Decreased glucagon secretion results Dermatologic: Erythema multiforme, pruritus, skin rash,
in decreased hepatic glucose production. Under nor- Stevens-Johnson syndrome, toxic epidermal necroly-
mal physiologic circumstances, incretin hormones are sis, urticaria
released by the intestine throughout the day and Gastrointestinal: Abdominal pain, anorexia, diarrhea,
levels are increased in response to a meal; incretin nausea, oral candidiasis, pancreatitis,
512
ERYTHROMYCIN (SYSTEMIC)
pseudomembranous colitis, pyloric stenosis (infantile Chronic obstructive pulmonary disease (COPD),
hypertrophic), vomiting prevention of exacerbations (off-label use):
Hepatic: Abnormal hepatic function tests, cholestatic Oral: 200 to 400 mg/day (formulation not specified)
jaundice (most common with estolate), hepatitis (Suzuki 2001) or 250 mg (stearate) twice daily
Hypersensitivity: Anaphylaxis, hypersensitivity reaction (Seemungal 2008).
Local: Injection site phlebitis Endoscopy/esophagogastroduodenoscopy,
Neuromuscular & skeletal: Weakness adjunctive prokinetic agent (off-label use): IV:
Otic: Hearing loss 3 mg/kg as a single dose over 30 minutes admin-
Renal: Interstitial nephritis istered 30 to 90 minutes prior to endoscopy (Coffin
Postmarketing and/or case reports: Hepatotoxicity (idi- 2002; Saltzman 2019) or 250 mg as a single dose
osyncratic) (Chalasani 2014) over 5 to 30 minutes administered 20 to 30 minutes
Dental Usual Dosage Treatment of orofacial infec- prior to endoscopy (Carbonell 2006; Fros-
tions: Adults: Oral: sard 2002)
Base: 250 to 500 mg every 6 to 12 hours Gastroparesis (off-label use):
Ethylsuccinate: 400 to 800 mg every 6 to 12 hours
IV: 3 mg/kg administered over 45 minutes every 8
Dosing
hours (Camilleri 2013)
Adult & Geriatric Note: Due to differences in absorp-
Oral: Patients refractory/intolerant to other proki-
tion, 400 mg erythromycin ethylsuccinate produces
the same serum levels as 250 mg erythromycin base netic agents (eg, metoclopramide, domperidone):
or stearate. 250 to 500 mg (base) 3 times daily before meals.
Usual dosage range: Limit duration of therapy, tachyphylaxis may occur
Oral: after 4 weeks (Camilleri 2013).
Base: 250 to 500 mg every 6 to 12 hours; max- Granuloma inguinale (donovanosis) (off-label
imum: 4 g daily use): Oral: 500 mg (base) 4 times daily for at least
Ethylsuccinate: 400 to 800 mg every 6 to 12 hours; 21 days and resolution of lesions (CDC [Workowski
maximum: 4 g daily 2015]). Note: If symptoms do not improve within
IV: Lactobionate: 15 to 20 mg/kg/day divided every 6 the first few days of therapy, the addition of genta-
hours or 500 mg to 1 g every 6 hours; maximum: micin may be considered (CDC [Workowski 2015]).
4 g daily Impetigo (IDSA [Stevens 2014]): Oral:
Base: 250 mg 4 times daily for 7 days, depending
Indication-specific dosing:
on response
Acne vulgaris (alternative therapy) (off-label
Ethylsuccinate: 400 mg 4 times daily for 7 days,
use): Oral: Initial: 250 to 500 mg (base) twice daily,
followed by 250 to 500 mg (base) once daily (Tan depending on response
2003; Tan 2005). The shortest possible duration Legionnaire disease: Oral: 1.6 to 4 g (ethylsucci-
should be used to minimize development of bacte- nate) daily or 1 to 4 g (base) daily in divided doses
rial resistance; re-evaluate at 3 to 4 months (AAD for 21 days. Note: No longer preferred therapy and
[Zaenglein 2016]) only used in nonhospitalized patients.
Bartonella spp infections (bacillary angiomatosis Nongonococcal urethritis: Oral:
[BA], peliosis hepatis [PH]) (off-label use): Oral: 500 mg (base) 4 times daily or 800 mg (ethylsucci-
500 mg (base) 4 times daily for 3 months (BA) or 4 nate) 4 times daily for 7 days (CDC [Workow-
months (PH) (Koehler 1992; Rolain 2004; Stevens ski 2015]).
2014; Tappero 1993). Note: IDSA skin and soft Manufacturer's labeling: Dosing in the prescribing
tissue infection guidelines recommend a duration information may not reflect current clinical
of initial therapy of 2 weeks to 2 months for cuta- practice.
neous BA, although treatment durations are not Base: 500 mg (base) 4 times daily or two 333 mg
standardized (IDSA [Stevens 2014]) (base) tablets every 8 hours
Bartonella spp infections in HIV-infected patients Ethylsuccinate: 800 mg (ethylsuccinate) 3 times
(off-label use; HHS [OI adult 2015]): Note: Dura- daily. Note: May use 250 mg (base) or 400 mg
tion of therapy is at least 3 months; continuation of (ethylsuccinate) 4 times daily
therapy depends on relapse occurrence and clinical Pertussis: Oral: 500 mg (base) every 6 hours for
condition 14 days
Bacillary angiomatosis, peliosis hepatis, bactere- Surgical (preoperative) prophylaxis (colorectal)
mia, and osteomyelitis: Oral, IV: 500 mg every 6 (off-label dose): Oral: 1 g erythromycin base per
hours dose at 1 PM, 2 PM, and 11 PM on the day before 8
Other severe infections (excluding CNS infections AM surgery combined with mechanical cleansing of
or endocarditis): Oral, IV: 500 mg every 6 hours the large intestine, oral neomycin. Perioperative IV
with rifampin
antibiotics are also given on the day of surgery
Chancroid (off-label use): Oral: 500 mg (base) 3
(Bratzler 2013).
times daily for 7 days; Note: Isolates with inter-
mediate resistance have been documented (CDC Renal Impairment: Adult
[Workowski 2015]) There are no dosage adjustments provided in the
Chlamydia trachomatis infection, uncompli- manufacturer's labeling.
cated: Oral: Dialysis: Slightly dialyzable (5% to 20%). Supplemen-
Urogenital infections (off-label): 500 mg (base) four tal dose is not necessary in hemo- or peritoneal
times daily or 800 mg (ethylsuccinate) four times dialysis or in continuous arteriovenous or venove-
daily for 7 days (CDC [Workowski 2015]) nous hemofiltration (Aronoff 2007).
Lymphogranuloma venereum (off-label; alternative Hepatic Impairment: Adult There are no dosage
therapy to doxycycline): Oral: 500 mg (base) 4 adjustments provided in the manufacturer's labeling;
times daily for 21 days (CDC [Workowski 2015]) use with caution.
513
Pediatric Anogenital tract infection:

General dosing, susceptible infection: Infants, Children and Adolescents <45 kg: Oral (base or
Children, and Adolescents: ethylsuccinate): 50 mg/kg/day divided every 6
Manufacturer's labeling: hours for 14 days; maximum daily dose:
Oral: Base, ethylsuccinate, stearate: 30 to 2,000 mg/day
50 mg/kg/day divided every 6 to 8 hours usually; Adolescents ≥45 kg: Oral:
for severe infection may double dose; maximum Base: 500 mg 4 times daily for 7 days
daily dose: Mild to moderate infection: 2,000 mg/ Ethylsuccinate: 800 mg 4 times daily for 7 days
day; severe infection: 4,000 mg/day Lymphogranuloma venereum (LGV): Adolescents
IV: Lactobionate: 15 to 20 mg/kg/day divided ≥45 kg: Oral (base): 500 mg 4 times daily for
every 6 hours; maximum daily dose: 21 days
4,000 mg/day Impetigo: Infants, Children, and Adolescents: Oral:
Alternate dosing (Red Book 2012): 10 mg/kg/dose 4 times daily (Stevens 2005)
Mild to moderate infection: Oral: 50 mg/kg/day Lyme Disease: Infants, Children, and Adolescents:
divided every 6 to 8 hours; maximum daily dose: Oral: 50 mg/kg/day divided every 6 hours for 14 to
2,000 mg/day 21 days; maximum dose: 500 mg (Wormser 2006)
Severe infection: IV: Lactobionate: 5 mg/kg/dose Pertussis (CDC 2005; Red Book 2012):
every 6 hours, maximum daily dose: Infants 1 to 5 months: Oral: 10 mg/kg/dose 4 times
4,000 mg/day daily for 14 days
Acne, moderate to severe; treatment: Children Infants ≥6 months and Children: Oral: 10 mg/kg/
and Adolescents: Oral: 250 to 500 mg 1 to 2 times dose 4 times daily for 7 to 14 days; maximum daily
daily in conjunction with topical therapy (eg, ben- dose: 2,000 mg/day
zoyl peroxide); maximum daily dose: 50 mg/kg/ Adolescents: Oral: 500 mg 4 times daily for 7 to
day; duration of 4 to 8 weeks of therapy usually 14 days
necessary to evaluate initial clinical response with a Pneumonia, community-acquired (CAP) (Bradley
longer duration for a maximum effect (3 to 6 2011): Infants >3 months, Children, and Adoles-
months); resistance problematic with therapy, use cents: Note: A beta-lactam antibiotic should be
typically reserved for patients <8 years who cannot added if typical bacterial pneumonia cannot be
receive tetracycline derivatives (Eichenfield 2013) ruled out.
Anthrax, cutaneous, community-acquired (Ste- Presumed atypical (M. pneumoniae, C. pneumo-
vens 2005): Infants, Children, and Adolescents: niae, C. trachomatis); mild infection or step-down
Oral: 10 mg/kg/dose every 6 hours; treatment dura- therapy: Oral: 10 mg/kg/dose every 6 hours; max-
tion of 5 to 9 days usually adequate in most cases imum daily dose: 2,000 mg/day
IV: 20 to 40 mg/kg/day divided every 6 hours; Moderate to severe atypical infection: IV: Lactobio-
maximum daily dose: 4,000 mg; treatment dura- nate: 5 mg/kg/dose every 6 hours; maximum daily
tion of 5 to 9 days usually adequate in most cases dose: 4,000 mg/day
Bartonella sp infections [bacillary angiomatosis
Preoperative bowel preparation: Children and
(BA), peliosis hepatis (PH)]:
Adolescents: Oral: Base: 20 mg/kg; maximum
Non-HIV-exposed/-positive; treatment: Infants,
dose: 1,000 mg administered at 1, 2, and 11 PM
Children, and Adolescents: Oral: Ethylsuccinate:
on the day before surgery combined with mechan-
10 mg/kg/ dose 4 times daily; maximum daily
ical cleansing of the large intestine and oral neo-
dose: 2,000 mg/day; treatment duration: BA: 3
mycin (Bratzler 2013)
months; PH: 4 months (Rolain 2004)
Prokinetic (GI motility) agent: Limited data avail-
HIV-exposed/-positive:
able: Infants, Children, and Adolescents:
Prophylaxis: Infants and Children (CDC 2009):
Oral: 30 to 50 mg/kg/day divided into 2 to 4 Diagnosis; gastric emptying study (provocative test-
doses daily; maximum daily dose: 2,000 mg/day ing): IV: 2.8 mg/kg infused over 20 minutes was
Treatment: Duration of therapy: ≥3 months (of reported from one center's experience; maximum
sufficient duration to prevent relapse) dose: 250 mg (Waseem 2012)
Infants and Children (CDC 2009): Treatment: Oral: 3 mg/kg/dose 4 times daily; may
Oral: 30 to 50 mg/kg/day divided into 2 to 4 increase as needed to effect; maximum dose:
doses daily; maximum daily dose: 10 mg/kg or 250 mg (Rodriguez 2012)
2,000 mg/day Pneumococcal, prophylaxis in penicillin-allergic
IV: 15 to 50 mg/kg/day divided into 4 doses patients with sickle cell disease (SCD) and func-
daily; maximum daily dose: 2,000 mg/day tional or anatomic asplenia (Knight-Madden
Adolescents: IV, Oral: 500 mg every 6 hours with 2001): Oral:
or without rifampin (DHHS [adult] 2013) Infants and Children: 4 months to <3 years: 125 mg
Catheter (peritoneal dialysis); exit-site or tunnel twice daily; salt not specified
infection: Infants, Children, and Adolescents: Oral Children 3 to 4 years: 250 mg twice daily; salt not
(base): 30 to 50 mg/kg/day divided 3 to 4 times specified
daily; maximum dose: 500 mg/dose (Warady Renal Impairment: Pediatric
[ISPD 2012]) Infants, Children, and Adolescents: The following
Chlamydia trachomatis infection (CDC 2010; Red adjustments have been recommended (Aronoff
Book 2012): 2007). Note: Renally adjusted dose recommenda-
Conjunctivitis or pneumonia: Infants, Children, and tions are based on oral doses of 30 to 50 mg/kg/day
Adolescents: Oral (base or ethylsuccinate): divided every 6 to 8 hours.
50 mg/kg/day divided every 6 hours for 14 days; GFR ≥10 mL/minute/1.73 m 2 : No adjustment
maximum daily dose: 2,000 mg/day; a repeat required
course may be necessary; for severe trachoma, GFR <10 mL/minute/1.73 m2: Intermittent hemodial-
longer durations may be necessary (40 days) ysis, peritoneal dialysis: Not removed by peritoneal
514
dialysis or hemodialysis: 10 to 17 mg/kg/dose every Drug Interactions

8 hours Metabolism/Transport Effects Substrate of
Hepatic Impairment: Pediatric There are no dos- CYP2B6 (minor), CYP3A4 (major), P-glycoprotein/
age adjustments provided in the manufacturer's label- ABCB1; Note: Assignment of Major/Minor substrate
ing. status based on clinically relevant drug interaction
Mechanism of Action Inhibits RNA-dependent protein potential; Inhibits CYP3A4 (moderate), P-glycopro-
synthesis at the chain elongation step; binds to the 50S tein/ABCB1
ribosomal subunit resulting in blockage of transpeptida- Avoid Concomitant Use
tion Avoid concomitant use of Erythromycin (Systemic)
Contraindications Hypersensitivity to erythromycin, with any of the following: Amiodarone; Aprepitant;
Asunaprevir; Barnidipine; BCG (Intravesical); Bosuti-
any macrolide antibiotics, or any component of the
nib; Budesonide (Systemic); Cholera Vaccine; Clinda-
formulation
mycin (Topical); Cobimetinib; Domperidone;
Concomitant use with pimozide, cisapride, ergotamine
Dronedarone; Flibanserin; Fluconazole; Fosaprepi-
or dihydroergotamine, terfenadine, astemizole, lova-
tant; Ivabradine; Lincomycin; Lomitapide; Lovastatin;
statin, or simvastatin Mequitazine; Mizolastine; Naloxegol; Neratinib;
Warnings/Precautions Use caution in patients with PAZOPanib; Pimozide; QT-prolonging Class III Anti-
preexisting liver disease; hepatic impairment with or arrhythmics (Highest Risk); QuiNIDine; Saquinavir;
without jaundice has occurred, it may be accompanied Simeprevir; Simvastatin; Topotecan; Ulipristal; Vin-
by malaise, nausea, vomiting, abdominal colic, and CRIStine (Liposomal)
fever; discontinue use if these occur. Potentially signifi- Increased Effect/Toxicity
cant drug-drug interactions may exist, requiring dose or Erythromycin (Systemic) may increase the levels/
frequency adjustment, additional monitoring, and/or effects of: Abemaciclib; Acalabrutinib; Afatinib; Alfen-
selection of alternative therapy. Prolonged use may tanil; ALPRAZolam; Amiodarone; Antineoplastic
result in fungal or bacterial superinfection, including C. Agents (Vinca Alkaloids); Apixaban; Aprepitant; ARI-
difficile-associated diarrhea (CDAD) and pseudomem- Piprazole; Asunaprevir; AtorvaSTATin; Avanafil; Bar-
branous colitis; CDAD has been observed >2 months nidipine; Benzhydrocodone; Betrixaban; Bilastine;
postantibiotic treatment. Use in infants has been asso- Blonanserin; Bosentan; Bosutinib; Brentuximab Vedo-
ciated with infantile hypertrophic pyloric stenosis tin; Brexpiprazole; Brigatinib; Bromocriptine; Budeso-
(IHPS); observe for nonbilious vomiting or irritability nide (Systemic); Budesonide (Topical); BusPIRone;
with feeding. Macrolides have been associated with Calcium Channel Blockers; Cannabidiol; Cannabis;
rare QTc prolongation and ventricular arrhythmias, CarBAMazepine; Cardiac Glycosides; Celiprolol; Cer-
including torsade de pointes; avoid use in patients with itinib; Cilostazol; Citalopram; Cobimetinib; Colchicine;
prolonged QT interval, uncorrected hypokalemia or Crizotinib; CycloSPORINE (Systemic); CYP3A4 Sub-
hypomagnesemia, clinically significant bradycardia, or strates (High risk with Inhibitors); Dabigatran Etexilate;
concurrent use of Class IA (eg, quinidine, procaina- Dapoxetine; Deflazacort; Domperidone; Doxofylline;
mide) or Class III (eg, amiodarone, dofetilide, sotalol) DOXOrubicin (Conventional); Dronabinol; Dronedar-
antiarrhythmic agents. Avoid concurrent use with strong one; Edoxaban; Eletriptan; Eliglustat; Encorafenib;
CYP3A inhibitors; may increase the risk of sudden Eplerenone; Ergot Derivatives; Estazolam; Estrogen
cardiac death (Ray 2004). Use caution in elderly Derivatives; Everolimus; FentaNYL; Fexofenadine;
Flibanserin; Fosaprepitant; GuanFACINE; Haloperi-
patients; risk of adverse events, including hearing loss
dol; HYDROcodone; Ibrutinib; Imatinib; Ivabradine;
and/or torsades de pointes, may be increased, partic-
Ivacaftor; Ivosidenib; Larotrectinib; Lomitapide; Lova-
ularly if concurrent renal/hepatic impairment. Exacerba-
statin; Lurasidone; Mequitazine; Methadone; Midazo-
tion of and new onset of myasthenia gravis symptoms lam; Mirodenafil; Mizolastine; Naldemedine;
have been reported. Nalfurafine; Naloxegol; Neratinib; Nintedanib; Ola-
Benzyl alcohol and derivatives: Some dosage forms parib; Oxybutynin; OxyCODONE; PAZOPanib; P-gly-
may contain benzyl alcohol; large amounts of benzyl co protein/ABCB1 Substrate s; Pimec ro limus ;
alcohol (≥99 mg/kg/day) have been associated with a Pimozide; Pitavastatin; Pravastatin; QT-prolonging
potentially fatal toxicity ("gasping syndrome") in neo- Antipsychotics (Moderate Risk); QT-prolonging Class
nates; the "gasping syndrome" consists of metabolic IA Antiarrhythmics (Highest Risk); QT-prolonging
acidosis, respiratory distress, gasping respirations, Class III Antiarrhythmics (Highest Risk); QT-prolong-
CNS dysfunction (including convulsions, intracranial ing Kinase Inhibitors (Highest Risk); QT-prolonging
hemorrhage), hypotension and cardiovascular collapse Kinase Inhibitors (Moderate Risk); QT-prolonging Mis-
cellaneous Agents (Highest Risk); QT-prolonging Mis-
(AAP ["Inactive" 1997]; CDC 1982); some data sug-
cellaneous Agents (Moderate Risk); QT-prolonging
gests that benzoate displaces bilirubin from protein
Moderate CYP3A4 Inhibitors (Moderate Risk); QT-
binding sites (Ahlfors 2001); avoid or use dosage forms
prolonging Strong CYP3A4 Inhibitors (Moderate Risk);
containing benzyl alcohol with caution in neonates. See
QuiNIDine; Ranolazine; Repaglinide; Rifamycin Deriv-
manufacturer's labeling. atives; RifAXIMin; Rilpivirine; Rivaroxaban; Rupata-
Warnings: Additional Pediatric Considerations dine; Ruxolitinib; Salmeterol; Saquinavir;
Hepatic impairment with or without jaundice has SAXagliptin; Sertraline; Sildenafil; Silodosin; Simepre-
occurred primarily in older children and adults; reported vir; Simvastatin; Sirolimus; Sonidegib; Suvorexant;
incidence in children is ~0.1% and in adults is 0.25%; it Tacrolimus (Systemic); Tacrolimus (Topical); Talazo-
may be accompanied by malaise, nausea, vomiting, parib; Tamsulosin; Telithromycin; Tetrahydrocannabi-
abdominal colic, and fever; discontinue use if these nol; Tezacaftor; Theophylline Derivatives; Ticagrelor;
occur. Infantile hypertrophic pyloric stenosis with symp- Tolvaptan; Topotecan; Trabectedin; Triazolam; Udena-
toms of nonbilious vomiting or irritability with feeding fil; Ulipristal; Vardenafil; Venetoclax; Vilazodone; Vin-
has been reported in 5% of infants who received CRIStine (Liposomal); Vitamin K Antagonists;
erythromycin for pertussis prophylaxis. Zopiclone; Zuclopenthixol
515
The levels/effects of Erythromycin (Systemic) may be Breastfeeding Considerations

increased by: Amiodarone; Ceritinib; Citalopram; Erythromycin is present in breast milk.
Domperidone; Dronedarone; Encorafenib; Flucona- Loss of appetite, diarrhea, rash, and somnolence have
zole; Ivosidenib; Methadone; Ondansetron; Pentam- been reported in breastfeeding infants exposed to
idine (Systemic); P-glycoprotein/ABCB1 Inhibitors; macrolide antibiotics (Goldstein 2009). Irritability and
Pimozide; QT-prolonging Antidepressants (Moderate orange-red stool discoloration have also been
Risk); QT-prolonging Class IA Antiarrhythmics (High- reported following erythromycin exposure (Ito 1993;
est Risk); QT-prolonging Class IC Antiarrhythmics Stang 1986). In general, antibiotics that are present in
(Moderate Risk); QT-prolonging Class III Antiarrhyth- breast milk may cause non-dose-related modification
mics (Highest Risk); QT-prolonging Kinase Inhibitors of bowel flora. Monitor infants for GI disturbances,
(Highest Risk); QT-prolonging Quinolone Antibiotics such as thrush, dehydration, or diarrhea (Butler
(Moderate Risk); Simeprevir; Sirolimus
2014; WHO 2002).
Decreased Effect One case report and a cohort study raise the possibility
Erythromycin (Systemic) may decrease the levels/
for a connection with pyloric stenosis in neonates
effects of: BCG (Intravesical); BCG Vaccine (Immuni-
exposed to erythromycin via breast milk; an alternative
zation); Cholera Vaccine; Clindamycin (Topical); Clo-
antibiotic may be preferred for breastfeeding mothers
pidogrel; Codeine; Ifosfamide; Lactobacillus and
of infants in this age group (Sørensen 2003;
Estriol; Lincomycin; Pivmecillinam; Sincalide; Sodium
Picosulfate; Typhoid Vaccine; Zafirlukast Stang 1986).
Although the manufacturer recommends caution be
The levels/effects of Erythromycin (Systemic) may be used if administered to a breastfeeding female, eryth-
decreased by: Bosentan; CYP3A4 Inducers (Moder- romycin is considered compatible when used in usual
ate); CYP3A4 Inducers (Strong); Dabrafenib; Defera- recommended doses (WHO 2002). Erythromycin is a
sirox; Enzalutamide; Lorlatinib; Mitotane; Pitolisant; preferred agent for the treatment of granuloma ingui-
Sarilumab; Siltuximab; St John's Wort; Tocilizumab nale and lymphogranuloma venereum in breastfeed-
Food Interactions ing females (CDC [Workowski 2015]). If systemic
Ethanol: Ethanol may decrease absorption of erythro- erythromycin is needed for the treatment of dermato-
mycin or enhance effects of ethanol. Management: logic conditions, only short-term use is recommended
Avoid ethanol. if breastfeeding (Butler 2014).
Food: Erythromycin serum levels may be altered if Dosage Forms: US
taken with food (formulation-dependent). GI upset,
Capsule Delayed Release Particles, Oral:
including diarrhea, is common. Management: May be
Generic: 250 mg
taken with food to decrease GI upset, otherwise take
Solution Reconstituted, Intravenous:
around-the-clock with a full glass of water. Do not give
Erythrocin Lactobionate: 500 mg (1 ea)
with milk or acidic beverages (eg, soda, juice).
Dietary Considerations Some products may contain
E.E.S. Granules: 200 mg/5 mL (100 mL, 200 mL)
sodium.
Base, PCE or stearate dosage forms should be taken EryPed 200: 200 mg/5 mL (100 mL)
on an empty stomach (2 hours before or after a meal). EryPed 400: 400 mg/5 mL (100 mL)
Ethylsuccinate (EES) or delayed-release (ERY-TAB) Generic: 200 mg/5 mL (100 mL, 200 mL); 400 mg/5
dosage forms may be administered without regards mL (100 mL)
to meals. Tablet, Oral:
May consider administering after food to decrease GI E.E.S. 400: 400 mg
discomfort. Erythrocin Stearate: 250 mg
Pharmacodynamics/Kinetics Generic: 250 mg, 400 mg, 500 mg
Half-life Elimination Neonates (≤15 days of age): 2.1 Tablet Delayed Release, Oral:
hours; Adults: Peak: 1.5-2 hours; End-stage renal Ery-Tab: 250 mg, 333 mg, 500 mg
disease: 5-6 hours Dental Health Professional Considerations Many
Time to Peak Serum: Base: 4 hours; Ethylsuccinate: patients cannot tolerate erythromycin because of
0.5 to 2.5 hours; Stearate: 3 hours (Steigbigel 2000); abdominal pain and nausea; the mechanism of this
delayed with food due to differences in absorption adverse effect appears to be the motilin agonistic prop-
Pregnancy Risk Factor B erties of erythromycin in the GI tract. For these patients,
Pregnancy Considerations clindamycin is indicated as the alternative antibiotic for
Erythromycin crosses the placenta. Cardiovascular treatment of orofacial infections.
anomalies following exposure in early pregnancy have
HMG-CoA reductase inhibitors, also known as the
been reported in some observational studies. Serum
concentrations of erythromycin may be variable in statins, effectively decrease the hepatic cholesterol
pregnant women (Kiefer 1955; Philipson 1976). biosynthesis resulting in the reduction of blood LDL-
cholesterol concentrations. The AUC of atorvastatin
Erythromycin is the antibiotic of choice for preterm (Lipitor®) was increased 33% by erythromycin admin-
prelabor rupture of membranes <34 0/7 weeks' gesta- istration. Combination of erythromycin and lovastatin
tion) (ACOG 188 2018), the treatment of lymphogranu- (Mevacor®) has been associated with rhabdomyolysis
loma venereum in pregnancy, and the treatment of or (Ayanian, et al). The mechanism of erythromycin is
long-term suppression of Bartonella infection in HIV- inhibiting the CYP3A4 metabolism of atorvastatin, lov-
infected pregnant patients. Erythromycin is one of the astatin, and cerivastatin. Simvastatin (Zocor®) would
antibiotics that may be used for the treatment of chan- likely be affected in a similar manner by the coadminis-
croid or granuloma inguinale during pregnancy, and tration of erythromycin. Clarithromycin (Biaxin®) may
may be appropriate as an alternative agent for the exert a similar effect as erythromycin on atorvastatin,
treatment of chlamydial infections in pregnant women
lovastatin, cerivastatin, and simvastatin.
(consult current guidelines) (CDC [Workowski 2015];
HHS [opportunistic; adult] 2015). Also see Local Anesthetic/Vasoconstrictor Precautions
516
ESCITALOPRAM
appetite (3%), vomiting (3%), abdominal pain (2%),

Escitalopram (es sye TAL oh pram) flatulence (2%), toothache (2%)
Genitourinary: Impotence (2% to 3%), urinary tract
Related Information infection (children ≥2%)
Citalopram on page 313 Neuromuscular & skeletal: Neck pain (≤3%), shoulder
Clinical Risk Related to Drugs Prolonging QT Interval pain (≤3%), back pain (children ≥2%)
on page 1462 Respiratory: Flu-like symptoms (5%), rhinitis (5%),
Vasoconstrictor Interactions With Antidepressants on sinusitis (3%), nasal congestion (children ≥2%)
page 1606 <1%, postmarketing, and/or case reports: Abdominal
Brand Names: US Lexapro cramps, abnormal gait, acute renal failure, aggressive
Brand Names: Canada Cipralex behavior, agitated depression, agitation, agranulocy-
Pharmacologic Category Antidepressant, Selective tosis, akathisia, alopecia, amnesia, anaphylaxis, ane-
Serotonin Reuptake Inhibitor mia, angioedema, angle-closure glaucoma, anxiety,
Use apathy, aplastic anemia, arthralgia, ataxia, atrial fibril-
Major depressive disorder (unipolar): Acute and lation, blurred vision, bradycardia, bronchitis, cardiac
maintenance treatment of unipolar major depressive failure, cerebrovascular accident, chest pain, choreoa-
disorder (MDD) thetosis, cough, deep vein thrombosis, delirium, delu-
Generalized anxiety disorder: Acute treatment of sions, depersonalization, dermatitis, diabetes mellitus,
generalized anxiety disorder (GAD) diplopia, dyskinesia, dysmenorrhea, dysphagia, dysp-
Local Anesthetic/Vasoconstrictor Precautions nea, dystonia, dysuria, ecchymoses, edema, epis-
Although caution should be used in patients taking taxis, erythema multiforme, extrapyramidal reaction,
tricyclic antidepressants, no interactions have been fever, flushing, gastroenteritis, gastroesophageal
reported with vasoconstrictors and escitalopram, a non- reflux disease, gastrointestinal hemorrhage, hallucina-
tricyclic antidepressant which acts to increase seroto- tion, heartburn, hemolytic anemia, hepatic failure,
nin; no precautions appear to be needed hepatic necrosis, hepatitis, hot flash, hypercholester-
Escitalopram is one of the drugs confirmed to prolong olemia, hyperglycemia, hypermenorrhea, hyperprolac-
the QT interval and is accepted as having a risk of tinemia, hypersensitivity reaction, hypertension,
causing torsade de pointes. The risk of drug-induced hypertensive crisis, hypoesthesia, hypoglycemia,
torsade de pointes is extremely low when a single QT hypokalemia, hyponatremia, hypoprothrombinemia,
interval prolonging drug is prescribed. In terms of epi- hypotension, immune thrombocytopenia, increased
nephrine, it is not known what effect vasoconstrictors in appetite, increased INR, increased liver enzymes,
the local anesthetic regimen will have in patients with a increased serum bilirubin, irritability, jaw tightness,
known history of congenital prolonged QT interval or in lack of concentration, leukopenia, limb pain, migraine,
patients taking any medication that prolongs the QT myalgia, myasthenia, mydriasis, myocardial infarction,
interval. Until more information is obtained, it is sug- myoclonus, neuroleptic malignant syndrome (Stevens
gested that the clinician consult with the physician prior 2008), nightmares, nystagmus, orthostatic hypoten-
to the use of a vasoconstrictor in suspected patients, sion, palpitations, pancreatitis, panic, paranoia, Par-
and that the vasoconstrictor (epinephrine, mepivacaine, kinsonian-like syndrome, phlebitis, priapism,
and levonordefrin [Carbocaine® 2% with Neo-Cobe- prolonged Q-T interval on ECG, psychosis, pulmonary
frin®]) be used with caution. embolism, rectal hemorrhage, restless leg syndrome,
Effects on Dental Treatment Key adverse event(s) rhabdomyolysis, seizure, serotonin syndrome, SIADH,
related to dental treatment: Xerostomia (normal salivary sinus congestion, sinus headache, skin photosensitiv-
flow resumes upon discontinuation) and toothache (see ity, skin rash, spontaneous abortion, Stevens-Johnson
Effects on Bleeding and Dental Health Professional syndrome, suicidal ideation, suicidal tendencies, syn-
Considerations) cope, tachycardia, tardive dyskinesia, thrombocytope-
Effects on Bleeding Selective serotonin reuptake nia, thrombosis, tinnitus, torsades de pointes, toxic
inhibitors such as escitalopram may impair platelet epidermal necrolysis, tremor, urinary frequency, uri-
aggregation due to platelet serotonin depletion, possi- nary retention, urticaria, ventricular arrhythmia, ven-
bly increasing the risk of a bleeding complication. The tricular tachycardia, vertigo, visual disturbance, weight
risk of a bleeding complication can be increased by
gain, withdrawal syndrome
coadministration of other antiplatelet agents such as
Mechanism of Action Escitalopram is the S-enan-
NSAIDs and aspirin.
tiomer of the racemic derivative citalopram, which
Adverse Reactions
selectively inhibits the reuptake of serotonin with little
>10%:
to no effect on norepinephrine or dopamine reuptake. It
Central nervous system: Headache (24%), insomnia
has no or very low affinity for 5-HT1-7, alpha- and beta-
(7% to 14%), drowsiness (4% to 13%)
Gastrointestinal: Nausea (15% to 18%), diarrhea (6% adrenergic, D1-5, H1-3, M1-5, and benzodiazepine recep-
to 14%) tors. Escitalopram does not bind to or has low affinity for
Genitourinary: Ejaculatory disorder (9% to 14%) Na+, K+, Cl-, and Ca++ ion channels.
1% to 10%: Pharmacodynamics/Kinetics
Central nervous system: Fatigue (2% to 8%), dizzi- Onset of Action Depression: The onset of action is
ness (4% to 7%), anorgasmia (2% to 6%), abnormal within a week; however, individual response varies
dreams (3%), lethargy (3%), paresthesia (2%), greatly and full response may not be seen until 8 to
yawning (2%) 12 weeks after initiation of treatment.
Dermatologic: Diaphoresis (3% to 8%) Half-life Elimination Mean: Adolescents: 19 hours;
Endocrine & metabolic: Decreased libido (3% to 7%), Adults: ~27 to 32 hours (increased ~50% in the elderly
menstrual disease (2%) and doubled in patients with hepatic impairment)
Gastrointestinal: Xerostomia (4% to 9%), constipation Time to Peak Escitalopram: Adolescents: 2.9 hours;
(3% to 6%), dyspepsia (2% to 6%), decreased Adults: ~5 hours
517
ESCITALOPRAM
Pregnancy Considerations Effects on Bleeding No information available to

Adverse events have been observed in animal repro- require special precautions
duction studies. Escitalopram crosses the placenta and Adverse Reactions
is distributed into the amniotic fluid. An increased risk of >10%:
teratogenic effects, including cardiovascular defects, Central nervous system: Dizziness (20% to 28%),
may be associated with maternal use of escitalopram drowsiness (11% to 28%), headache (13% to 15%)
or other SSRIs; however, available information is con- Gastrointestinal: Nausea (10% to 16%)
flicting. Nonteratogenic effects in the newborn following Ophthalmic: Diplopia (9% to 11%)
SSRI/SNRI exposure late in the third trimester include 1% to 10%:
respiratory distress, cyanosis, apnea, seizures, temper- Cardiovascular: Hypertension (2%), peripheral
ature instability, feeding difficulty, vomiting, hypoglyce- edema (2%)
mia, hypo- or hypertonia, hyper-reflexia, jitteriness, Central nervous system: Fatigue (7%), cognitive dys-
irritability, constant crying, and tremor. Symptoms may function (4% to 7%), ataxia (4% to 6%), vertigo (2%
be due to the toxicity of the SSRIs/SNRIs or a discontin- to 6%), depression (3%), equilibrium disturbance
uation syndrome and may be consistent with serotonin (3%), falling (3%), abnormal gait (2%), insomnia
syndrome associated with SSRI treatment. Persistent (2%), dysarthria (1% to 2%), memory impairment
pulmonary hypertension of the newborn (PPHN) has (1% to 2%)
also been reported with SSRI exposure. The long-term Dermatologic: Skin rash (3%)
effects of in utero SSRI exposure on infant development Endocrine & metabolic: Hyponatremia (serum sodium
and behavior are not known. Escitalopram is the S- <125 mEq/L: 1% to 2%)
enantiomer of the racemic derivative citalopram; also Gastrointestinal: Vomiting (6% to 10%), diarrhea (4%),
refer to the Citalopram monograph. abdominal pain (2%), constipation (2%), gastri-
tis (2%)
pharmacokinetic parameters of escitalopram may be
Neuromuscular & skeletal: Tremor (2% to 4%), weak-
altered. The ACOG recommends that therapy with
ness (3%)
SSRIs or SNRIs during pregnancy be individualized;
Ophthalmic: Blurred vision (5% to 6%), decreased
treatment of depression during pregnancy should incor-
visual acuity (2%), nystagmus (1% to 2%)
porate the clinical expertise of the mental health clini-
Respiratory: Cough (2%)
cian, obstetrician, primary health care provider, and
pediatrician. According to the American Psychiatric
Endocrine & metabolic: Hypercholesterolemia, hypo-
Association (APA), the risks of medication treatment
chloremia (concurrent with hyponatremia), increased
should be weighed against other treatment options
LDL cholesterol, increased serum triglycerides
and untreated depression. For women who discontinue
Hematologic & oncologic: Decreased hematocrit,
antidepressant medications during pregnancy and who
decreased hemoglobin
may be at high risk for postpartum depression, the
medications can be restarted following delivery. Treat-
phokinase
ment algorithms have been developed by the ACOG
<1%, postmarketing, and/or case reports: Agranulocy-
and the APA for the management of depression in
tosis, anaphylaxis, angioedema, decreased T3 level,
women prior to conception and during pregnancy.
decreased T4 (free and total), DRESS syndrome,
Pregnant women exposed to antidepressants during increased serum bilirubin (>2 x ULN), increased
pregnancy are encouraged to enroll in the National serum transaminases (>3 x ULN), leukopenia, mega-
Pregnancy Registry for Antidepressants (NPRAD). loblastic anemia, pancytopenia, prolongation P-R
Women 18 to 45 years of age or their health care interval on ECG (mild [Vas-Da-Silva 2012]), severe
providers may contact the registry by calling dermatological reaction, SIADH, Stevens-Johnson
844-405-6185. Enrollment should be done as early in syndrome, thrombocytopenia, toxic epidermal nec-
pregnancy as possible. rolysis
Dental Health Professional Considerations Prob- Mechanism of Action Eslicarbazepine acetate is
lems with SSRI-induced bruxism have been reported extensively converted to eslicarbazepine, which is con-
and may preclude their use; clinicians attempting to sidered responsible for therapeutic effects. A precise
evaluate any patient with bruxism or involuntary muscle mechanism has not been defined, but is thought to
movement, who is simultaneously being treated with an involve inhibition of voltage-gated sodium channels.
SSRI drug, should be aware of the potential association Pharmacodynamics/Kinetics
(see Local Anesthetic/Vasoconstrictor Precautions) Half-life Elimination Pediatric patients 4 to 17 years:
10 to 16 hours; Adults: 13 to 20 hours
Time to Peak Eslicarbazepine: Pediatric patients 4 to
Eslicarbazepine (es li kar BAZ e peen)
17 years: 1 to 3 hours; Adults: 1 to 4 hours
Brand Names: US Aptiom Pregnancy Considerations
Brand Names: Canada Aptiom Adverse events have been observed in animal repro-
Pharmacologic Category Anticonvulsant, Miscella- duction studies. Eslicarbazepine may decrease plasma
neous concentrations of hormonal contraceptives; additional
Use Partial-onset seizures (epilepsy): Monotherapy or or alternative nonhormonal contraceptives are recom-
adjunctive therapy in the treatment of partial-onset mended in women of reproductive potential.
seizures in adults and pediatric patients ≥4 years of age Patients exposed to eslicarbazepine during pregnancy
Local Anesthetic/Vasoconstrictor Precautions are encouraged to enroll themselves into the AED
No information available to require special precautions Pregnancy Registry by calling 1-888-233-2334. Addi-
Effects on Dental Treatment No significant effects or tional information is available at http://www.-
complications reported aedpregnancyregistry.org.
518
ESOMEPRAZOLE
Esmolol (ES moe lol) Children ≥18 months and Adolescents ≤16 years:
Variable; mean range: 2.7 to 4.8 minutes (reported
Brand Names: US Brevibloc; Brevibloc in NaCl; Brevi- full range: 0.2 to 9.9 minutes) (Cuneo 1994; Tabbutt
bloc Premixed; Brevibloc Premixed DS 2008; Wiest 1991; Wiest 1998)
Brand Names: Canada Brevibloc; Brevibloc Premixed Adults: Esmolol: 9 minutes; Acid metabolite: 3.7
Pharmacologic Category Antiarrhythmic Agent, hours; elimination of metabolite decreases with
Class II; Antihypertensive; Beta-Blocker, Beta-1 Selec- end-stage renal disease
tive Pregnancy Considerations Adverse events were
Use observed in some animal reproduction studies. Esmolol
Intraoperative and postoperative tachycardia and/ has been shown to cause fetal bradycardia. Adverse
or hypertension: Treatment of intraoperative and fetal/neonatal events have also been observed with the
postoperative tachycardia and/or hypertension chronic use of beta-blockers during pregnancy; how-
Sinus tachycardia: Treatment of noncompensatory ever, esmolol is a short-acting beta-blocker and not
sinus tachycardia indicated for chronic use. Esmolol is approved for the
Supraventricular tachycardia and atrial fibrillation/ treatment of supraventricular tachycardia (SVT); how-
flutter: Control of ventricular rate in patients with ever, other agents are preferred in pregnant women
supraventricular tachycardia or atrial fibrillation/flutter (ACC/AHA/HRS [Page 2015]).
No information available to require special precautions Esomeprazole (es oh ME pray zol)
Effects on Dental Treatment Esmolol is a cardiose-
lective beta-blocker. Local anesthetic with vasoconstric- Related Information
tor can be safely used in patients medicated with Gastrointestinal Disorders on page 1465
esmolol. Nonselective beta-blockers (ie, propranolol, Omeprazole on page 999
nadolol) enhance the pressor response to epinephrine, Brand Names: US Esomep-EZS; GoodSense Esome-
resulting in hypertension and bradycardia; this has not prazole [OTC]; NexIUM; NexIUM 24HR Clear Minis
been reported for esmolol. Many nonsteroidal anti- [OTC]; NexIUM 24HR [OTC]; NexIUM I.V.
inflammatory drugs, such as ibuprofen and indometha- Brand Names: Canada Nexium
cin, can reduce the hypotensive effect of beta-blockers Pharmacologic Category Proton Pump Inhibitor;
after 3 or more weeks of therapy with the NSAID. Short- Substituted Benzimidazole
term NSAID use (ie, 3 days) requires no special pre- Use
cautions in patients taking beta-blockers. Oral:
Effects on Bleeding No information available to Esomeprazole magnesium and esomeprazole stron-
require special precautions tium:
Adverse Reactions Gastroesophageal reflux disease (Rx only):
>10%: Cardiovascular: Asymptomatic hypotension Healing of erosive esophagitis: Short-term (4 to 8
(25%), symptomatic hypotension (12%) weeks) treatment of erosive esophagitis
1% to 10%: Maintenance of healing of erosive esophagitis:
Cardiovascular: Peripheral ischemia (1%) Maintaining symptom resolution and healing of
Central nervous system: Dizziness (≤3%), drowsiness erosive esophagitis
(3%), headache (2%), agitation (≤2%), confu- Symptomatic gastroesophageal reflux disease:
sion (≤2%) Short-term (4 to 8 weeks) treatment of symptomatic
Gastrointestinal: Nausea (7%), vomiting (1%) gastroesophageal reflux disease (GERD)
Local: Infusion site reaction (8%; including inflamma- Helicobacter pylori eradication (Rx only): As part of
tion and induration) a multidrug regimen for Helicobacter pylori eradica-
<1%, postmarketing, and/or case reports: Abdominal tion in patients with duodenal ulcer disease (active or
distress, abnormality in thinking, angioedema, anxiety, history of within the past 5 years)
bradycardia, constipation, coronary artery vasospasm, Risk reduction of nonsteroidal anti-inflammatory
depression, dyspepsia, flushing, heart block, hyper- drug-associated gastric ulcer (Rx only): Preven-
kalemia, increased heart rate (moderate increase tion of gastric ulcers associated with continuous
above pretreatment levels 30 minutes after discontin- NSAID therapy in patients at risk (age ≥60 years
uation), infusion site irritation, local thrombophlebitis and/or history of gastric ulcer)
(at infusion site), local tissue necrosis (at infusion site), Pathological hypersecretory conditions, including
pallor, paresthesia, psoriasis, renal tubular acidosis Zollinger-Ellison syndrome (Rx only): Treatment
(hyperkalemic), seizure, severe bradycardia, sinus (long-term) of pathological hypersecretory conditions
pause, skin blister (at infusion site), syncope, urinary including Zollinger-Ellison syndrome
retention, urticaria, voice disorder, xerostomia Esomeprazole magnesium:
Mechanism of Action Class II antiarrhythmic: Com- Heartburn (OTC labeling): Treatment of frequent
petitively blocks response to beta1-adrenergic stimula- heartburn (≥2 days per week).
tion with little or no effect of beta2-receptors except at IV: Esomeprazole sodium:
high doses, no intrinsic sympathomimetic activity, no Gastroesophageal reflux disease (Rx only): Short-
membrane stabilizing activity term (≤10 days) treatment of gastroesophageal
Pharmacodynamics/Kinetics reflux disease (GERD) with erosive esophagitis in
Onset of Action Beta-blockade: IV: 2-10 minutes pediatric patients 1 month to 17 years of age and
(quickest when loading doses are administered) adults when oral therapy is not possible or appro-
Duration of Action Hemodynamic effects: 10-30 priate
minutes; prolonged following higher cumulative doses, Risk reduction of ulcer rebleeding postprocedure
extended duration of use (Rx only): Decrease the risk of rebleeding
519
ESOMEPRAZOLE
postendoscopy for acute bleeding gastric or duode- flu-like symptoms, flushing, frequent bowel move-
nal ulcers in adults ments, fungal infection, gastroenteritis, gastrointesti-
Local Anesthetic/Vasoconstrictor Precautions nal candidiasis, gastrointestinal dysplasia,
No information available to require special precautions gastrointestinal hemorrhage, genital candidiasis, gly-
Effects on Dental Treatment Key adverse event(s) cosuria, goiter, gynecomastia, hallucination, hematu-
ria, hepatic encephalopathy, hepatic failure, hepatitis,
Effects on Bleeding No information available to hepatotoxicity (idiosyncratic) (Chalasani 2014), hernia
require special precautions of abdominal cavity, hiccups, hot flash, hyperbilirubi-
Adverse Reactions Unless otherwise specified, per- nemia, hyperhidrosis, hypersensitivity reaction, hyper-
centages represent adverse reactions identified in clin- tension, hypertonia, hyperuricemia, hypochromic
ical trials evaluating the oral formulation. anemia, hypoesthesia, hypomagnesemia (with or
>10%: Central nervous system: Headache (2% to 11%) without hypocalcemia and/or hypokalemia), hypona-
1% to 10%: tremia, impotence, increased appetite, increased
Central nervous system: Irritability (infants: ≥5%), diz- thirst, insomnia, interstitial nephritis, jaundice, laryng-
ziness (intravenous: ≤3%; oral: <1%), vertigo (intra-
eal edema, leukocytosis, leukopenia, maculopapular
venous: ≤3%), drowsiness (children: 2%;
adults: <1%) rash, malaise, melena, menstrual disease, migraine,
Dermatologic: Pruritus (intravenous: 1%; oral: <1%) mouth disease, muscle cramps, myalgia, myasthenia,
Endocrine & metabolic: Altered thyroid hormone levels nervousness, otalgia, otitis media, pain, pancreatitis,
(increased thyroxine: ≤1%), decreased serum potas- pancytopenia, paresthesia, pathological fracture due
sium (≤1%), decreased serum sodium (≤1%), to osteoporosis, peripheral edema, pharyngeal dis-
decreased thyroid hormones (thyroxine: ≤1%), ease, pharyngitis, polymyalgia rheumatica, polyp (fun-
increased gastrin (≤1%), increased serum potassium dic gland), polyuria, pruritus ani, rectal disease, renal
(≤1%), increased serum sodium (≤1%), increased
disease (chronic; [Lazarus 2016]), rhinitis, rigors,
thyroid stimulating hormone level (≤1%), increased
uric acid (≤1%) sinusitis, skin photosensitivity, skin rash, sleep disor-
Gastrointestinal: Flatulence (intravenous: 10%; oral: der, Stevens-Johnson syndrome, stomatitis, systemic
≥1%), diarrhea (2% to 4%), abdominal pain (1% to lupus erythematosus (including exacerbations), tachy-
6%), nausea (intravenous: 6%; oral: ≥1% to 2%), cardia, thrombocytopenia, tinnitus, tongue disease,
vomiting (infants: 1% to ≥5%; adults: <1%), xerosto- tongue edema, toxic epidermal necrolysis, tremor,
mia (intravenous: 4%; oral: ≥1%), constipation (intra- urinary frequency, urine abnormality, urticaria, vagini-
venous: 3%; oral: ≥1%) tis, vertigo, visual disturbance, visual field defect,
Hematologic & oncologic: Quantitative disorders of
weight gain, weight loss
platelets (≤1%)
Hepatic: Increased serum alkaline phosphatase Mechanism of Action Proton pump inhibitor sup-
(≤1%), increased serum alanine aminotransferase presses gastric acid secretion by inhibition of the H+/
(≤1%), increased serum aspartate aminotransferase K+-ATPase in the gastric parietal cell. Esomeprazole is
(≤1%) the S-isomer of omeprazole.
Local: Injection site reaction (intravenous: 2% to 4%) Pharmacodynamics/Kinetics
Renal: Increased serum creatinine (≤1%) Half-life Elimination
Respiratory: Cough (intravenous: 1%; oral: <1%), Infants: 0.93 hours
tachypnea (infants, oral: 1%)
Children 1 to 5 years: 0.42 to 0.74 hours (Zhao 2006)
Miscellaneous: Fever (intravenous: 4%; oral: <1%)
Frequency not defined: Children 6 to 11 years: 0.73 to 0.88 hours (Zhao 2006)
Cardiovascular: Esophageal varices Children ≥12 years and Adolescents ≤17 years: 0.82
Gastrointestinal: Barrett esophagus, duodenitis, to 1.22 hours (Li 2006)
esophageal stenosis, esophageal ulcer, esophagitis, Adults: ~1 to 1.5 hours
gastritis, mucosal discoloration Time to Peak Oral:
Hematologic & oncologic: Benign polyp Infants: Median: 3 hours
Miscellaneous: Benign nodule Children 1 to 5 years: 1.33 to 1.44 hours (Zhao 2006)
<1%, postmarketing, and/or case reports: Acne vulga-
Children 6 to 11 years: 1.75 to 1.79 hours (Zhao 2006)
ris, acute interstitial nephritis, aggressive behavior,
ageusia, agitation, agranulocytosis, albuminuria, alo- Children ≥12 years and Adolescents ≤17 years: 1.96
pecia, altered sense of smell, anaphylactic shock, to 2.04 hours (Li 2006)
anaphylaxis, anemia, angioedema, anorexia, apathy, Adults: 1.5 to 2 hours
aphthous stomatitis, arthralgia, arthropathy, asthenia, Pregnancy Considerations
back pain, blurred vision, bone fracture, broncho- Recommendations for the treatment of GERD in preg-
spasm, candidiasis (urogenital), cervical lymphaden- nancy are available. As in nonpregnant patients, life-
opathy, change in bowel habits, chest pain,
style modifications followed by other medications are
Clostridioides (formerly Clostridium) difficile-associ-
ated diarrhea, colitis (microscopic), confusion, con- the initial treatments (Body 2016; Huerta-Iga 2016; Katz
junctivitis, cutaneous lupus erythematosus (including 2013; van der Woude 2014). Based on available data,
exacerbations), cyanocobalamin deficiency, cystitis, PPIs may be used when clinically indicated (use of an
depression, dermatitis, diaphoresis, dysgeusia, dys- agent with more data in pregnancy may be preferred)
menorrhea, dyspepsia, dysphagia, dyspnea, dysuria, (Body 2016; Matok 2012; Pasternak 2010; van der
edema, enlargement of abdomen, epigastric pain, Woude 2014).
epistaxis, eructation, erythema multiforme, erythema-
tous rash, exacerbation of arthritis, exacerbation of Esomeprazole is the s-isomer of omeprazole; refer to
asthma, facial edema, fatigue, fibromyalgia syndrome, the omeprazole monograph for additional information.
520
ESTRADIOL (SYSTEMIC)
Pregnancy Considerations Although information

Estazolam (es TA zoe lam) specific to estazolam has not been located, all benzo-
diazepines are assumed to cross the placenta. Terato-
Related Information genic effects have been observed with some
Dentin Hypersensitivity, Acid Erosion, High Caries benzodiazepines; however, additional studies are
Index, Management of Alveolar Osteitis, and Xerosto- needed. The incidence of premature birth and low birth
mia on page 1548 weights may be increased following maternal use of
Pharmacologic Category Benzodiazepine benzodiazepines; hypoglycemia and respiratory prob-
Use Insomnia: Short-term management of insomnia lems in the neonate may occur following exposure late
characterized by difficulty in falling asleep, frequent in pregnancy. Neonatal withdrawal symptoms may
nocturnal awakenings, and/or early morning awaken- occur within days to weeks after birth and "floppy infant
ings. syndrome" (which also includes withdrawal symptoms)
Local Anesthetic/Vasoconstrictor Precautions has been reported with some benzodiazepines (Berg-
No information available to require special precautions man 1992; Iqbal 2002; Wikner 2007). The use of
Effects on Dental Treatment Key adverse event(s) estazolam is contraindicated in pregnant women.
related to dental treatment: Significant xerostomia (nor- Controlled Substance C-IV
mal salivary flow resumes upon discontinuation)
require special precautions Estradiol (Systemic) (es tra DYE ole)
Adverse Reactions Related Information
>10%: Central nervous system: Drowsiness (42%) Endocrine Disorders and Pregnancy on page 1471
1% to 10%:
Central nervous system: Dizziness (7%), ataxia (4%),
on page 1484
hangover effect (3%), abnormality in thinking (2%),
confusion (2%), anxiety (≥1%) Brand Names: US Alora; Climara; Delestrogen; Depo-
Dermatologic: Pruritus (1%) Estradiol; Divigel; Elestrin; Estrace; Estrogel; Evamist;
Gastrointestinal: Constipation (≥1%), xerosto- Femring; Menostar; Minivelle; Vivelle-Dot
mia (≥1%) Brand Names: Canada Climara; Depo-Estradiol; Div-
Neuromuscular & skeletal: Hypokinesia (8%), leg pain igel; Estrace; Estradot; EstroGel; Menostar; Oesclim
(3%), stiffness (1%) Pharmacologic Category Estrogen Derivative
<1%, postmarketing, and/or case reports: Acne vulga- Use
ris, adenopathy, agitation, agranulocytosis, amnesia, Breast cancer, metastatic: Treatment of metastatic
apathy, arm pain, arthralgia, arthritis, asthma, auditory breast cancer (palliation) in appropriately selected
impairment, breast swelling, cardiac arrhythmia, chills, men and postmenopausal women.
cough, decreased appetite, decreased libido, diapho- Hypoestrogenism (female): Treatment of hypoestro-
resis, diplopia, dysgeusia, dyspnea, edema, emotional genism due to hypogonadism, castration, or primary
lability, enterocolitis, epistaxis, euphoria, eye irritation, ovarian failure
eye pain, fever, flatulence, flushing, gastritis, genital Osteoporosis prevention (female): Prevention of
discharge, hallucination, hematuria, hostility, hyper- postmenopausal osteoporosis
sensitivity reaction, hyperventilation, hyporeflexia, Limitations of use: For use only in women at significant
increased appetite, increased serum AST, increased risk of postmenopausal osteoporosis; consider use
thirst, jaw pain, laryngitis, leukopenia, melena, muscle of nonestrogen medications.
spasm, myalgia, neck pain, neuritis, nocturia, nystag- Prostate cancer, advanced: Treatment of androgen
mus, oliguria, oral mucosa ulcer, oral paresthesia, dependent advanced prostatic cancer (palliation)
otalgia, palpitations, paresthesia, pelvic cramps (men- Vasomotor symptoms associated with menopause:
strual cramps), photophobia, polyuria, purpura, rhini- Treatment of moderate to severe vasomotor symp-
tis, scotoma, seizure, sinusitis, skin photosensitivity, toms associated with menopause.
skin rash, sleep disorder, Stevens-Johnson syndrome, Vulvar and vaginal atrophy associated with meno-
stupor, swelling of eye, syncope, thyroid nodule, tinni- pause: Treatment of moderate to severe vulvar and
tus, tremor, twitching, urinary hesitancy, urinary incon- vaginal atrophy associated with menopause.
tinence, urinary urgency, urticaria, visual disturbance, Limitations of use: When used solely for the treatment
vomiting, vulvovaginal pruritus, weight gain, weight of vulvar and vaginal atrophy, topical vaginal prod-
loss, xeroderma ucts should be considered.
Mechanism of Action Binds to stereospecific benzo- Note: The International Society for the Study of Wom-
diazepine receptors on the postsynaptic GABA neuron en’s Sexual Health and The North American Meno-
at several sites within the central nervous system, pause Society have endorsed the term genitourinary
including the limbic system, reticular formation. syndrome of menopause (GSM) as new terminology
Enhancement of the inhibitory effect of GABA on neuro- for vulvovaginal atrophy. The term GSM encom-
nal excitability results by increased neuronal membrane passes all genital and urinary signs and symptoms
permeability to chloride ions. This shift in chloride ions associated with a loss of estrogen due to menopause
results in hyperpolarization (a less excitable state) and Portman 2014.
stabilization. Benzodiazepine receptors and effects Local Anesthetic/Vasoconstrictor Precautions
appear to be linked to the GABA-A receptors. Benzo- No information available to require special precautions
diazepines do not bind to GABA-B receptors (Vinkers Effects on Dental Treatment No significant effects or
2012). complications reported
Pharmacodynamics/Kinetics Effects on Bleeding No information available to
Duration of Action Variable require special precautions
Half-life Elimination 10 to 24 hours Adverse Reactions Frequency not always defined.
Time to Peak Serum: ~2 hours (range: 0.5 to 6 hours) Some adverse reactions observed with estrogen
Pregnancy Risk Factor X and/or progestin combination therapy.
521
ESTRADIOL (SYSTEMIC)
Cardiovascular: Edema (10% to 13%), hypertension cholecystitis, cholelithiasis, cognitive dysfunction,

(3% to 7%), cerebrovascular accident, deep vein dyspnea, emotional lability, fatigue, genitourinary com-
thrombosis, local thrombophlebitis, myocardial infarc- plaint (inadvertent ring insertion into the bladder
tion, pulmonary thromboembolism, retinal thrombosis, should be considered with unexplained urinary com-
thrombophlebitis, venous thromboembolism plaints), hemorrhage, hepatitis, hyperhidrosis, hyper-
Central nervous system: Headache (9% to 50%), pain menorrhea, ischemic heart disease, lip swelling, local
(6% to 13%), depression (1% to 11%), anxiety (4% to irritation (transdermal patch), localized erythema
10%), dizziness (≤8%), migraine (7%), nipple pain (1% (transdermal patch), malaise, mechanical complica-
to 7%), hypoesthesia (3%), chorea, dementia, exac- tion of genitourinary device (ring adherence to vaginal
erbation of epilepsy, irritability, mood disorder, nerv- or bladder wall), meningioma, muscle spasm, myoclo-
ousness nus, night sweats, oral paresthesia, ovarian cyst,
Dermatologic: Skin rash (7% to 9%), pruritus (4% to palpitations, paresthesia, peripheral edema, pharyng-
7%), chloasma, erythema multiforme, erythema nodo- eal edema, phlebitis, portal vein thrombosis, purpura,
sum, localized erythema (transdermal patch), loss of retinal vein occlusion, soft tissue sarcoma (malignant
scalp hair, skin discoloration (melasma), urticaria mesenchymoma), swollen tongue, tachyphylaxis,
Endocrine & metabolic: Weight gain (4% to 9%), hot toxic shock syndrome (vaginal ring), transient ische-
flash (6%), hirsutism (≤5%), change in libido, change mic attacks, unstable angina pectoris, uterine enlarge-
in menstrual flow (alterations in frequency and flow of ment, uterine neoplasm, vaginal discharge
bleeding patterns), exacerbation of diabetes mellitus, Mechanism of Action Estrogens are responsible for
exacerbation of porphyria, fibrocystic breast changes, the development and maintenance of the female repro-
fluid retention, galactorrhea, hypocalcemia, increased ductive system and secondary sexual characteristics.
serum triglycerides, weight loss Estradiol is the principle intracellular human estrogen
Gastrointestinal: Abdominal pain (6% to 16%), dyspep- and is more potent than estrone and estriol at the
sia (3% to 9%), constipation (4% to 7%), flatulence receptor level; it is the primary estrogen secreted prior
(3% to 7%), nausea (3% to 7%), gastroenteritis (3% to to menopause. Following menopause, estrone and
4%), diarrhea (3%), abdominal cramps, bloating, car- estrone sulfate are more highly produced. Estrogens
bohydrate intolerance, gallbladder disease, pancreati- modulate the pituitary secretion of gonadotropins, lutei-
tis, vomiting nizing hormone, and follicle-stimulating hormone
Genitourinary: Mastalgia (5% to 35%), vaginal hemor- through a negative feedback system; estrogen replace-
rhage (33%), breast tenderness (3% to 17%), endo- ment reduces elevated levels of these hormones in
metrium disease (15%), breakthrough bleeding (6% to postmenopausal women.
11%), leukorrhea (2% to 11%), abnormal uterine Pregnancy Considerations
bleeding (4% to 10%), breast hypertrophy (7%), dys-
Products approved for use only in postmenopausal
menorrhea (7%), cervical polyp (6%), vulvovaginal
women are not appropriate for use in pregnancy; use
candidiasis (6%), urinary tract infection (4% to 6%),
of some products is specifically contraindicated in the
change in cervical ectropion, change in cervical secre-
manufacturer's labeling.
tions, endometrial hyperplasia, nipple discharge, spot-
ting, uterine fibroids (size increased), uterine pain, In general, the use of estrogen and progestin as in
vaginal discomfort (vaginal ring; burning, irritation, combination hormonal contraceptives has not been
itching), vaginitis associated with teratogenic effects when inadvertently
Hematologic & oncologic: Hemorrhagic eruption, hyper- taken early in pregnancy.
coagulability state, malignant neoplasm of breast,
ovarian cancer
Hepatic: Cholestatic jaundice, exacerbation of hepatic
Estradiol and Dienogest
(es tra DYE ole & dye EN oh jest)
hemangioma
Hypersensitivity: Hypersensitivity reaction (4% to 5%), Related Information
anaphylactoid reaction, anaphylaxis, angioedema Dienogest on page 431
Infection: Infection (3% to 12%), fungal infection (3% Endocrine Disorders and Pregnancy on page 1471
to 10%) Estradiol (Systemic) on page 521
Local: Application site reaction (gel, spray, transdermal Brand Names: US Natazia
patch ≤1%)
Pharmacologic Category Contraceptive; Estrogen
Neuromuscular & skeletal: Arthralgia (4% to 12%), back
and Progestin Combination
pain (3% to 11%), weakness (8%), limb pain (7% to
8%), myalgia (5% to 6%), neck pain (3% to 6%), Use
arthropathy (4% to 5%), exacerbation of systemic Contraception: Prevention of pregnancy.
lupus erythematosus, leg cramps Limitations of use: Efficacy has not been evaluated in
Ophthalmic: Conjunctivitis (3%), change in corneal women with a BMI >30 kg/m2.
curvature (steepening), contact lens intolerance Heavy menstrual bleeding: Treatment of heavy men-
Otic: Otitis media (3%) strual bleeding in women without organic pathology
Respiratory: Nasopharyngitis (4% to 20%), upper res- who choose to use an oral contraceptive as their
piratory tract infection (6% to 17%), flu-like symptoms method for contraception.
(8% to 13%), sinusitis (4% to 13%), sinus headache Local Anesthetic/Vasoconstrictor Precautions
(9% to 11%), bronchitis (6% to 8%), sinus congestion No information available to require special precautions
(7%), pharyngitis (2% to 7%), rhinitis (2% to 6%), Effects on Dental Treatment No significant effects or
cough (3% to 4%), asthma (3%), exacerbation of complications reported
asthma Effects on Bleeding No information available to
Miscellaneous: Accidental injury (7% to 14%), cyst (7%) require special precautions
Postmarketing and/or case reports: Abnormal gait, Adverse Reactions
abnormal hepatic function tests, aphasia, blindness, >10%: Central nervous system: Headache (13%,
bowel obstruction (vaginal ring), chest pain, including migraine)
522
ESTRADIOL AND NORETHINDRONE

Central nervous system: Mood changes (3%, includ- No information available to require special precautions
ing depression) Effects on Dental Treatment No significant effects or
Dermatologic: Acne vulgaris (4%) complications reported
Endocrine & metabolic: Menstrual disease (≤7% to Effects on Bleeding No information available to
8%), breast changes (discomfort: ≤7%), weight require special precautions related to hemostasis in
gain (3%) dental procedures.
Gastrointestinal: Nausea (≤7%), vomiting (≤7%) Adverse Reactions Percentages reported as greater
Genitourinary: Uterine hemorrhage (≤7% to 8%), in ClimaraPro when compared to estradiol alone.
breast tenderness (≤7%), mastalgia (≤7%)
>10%:
Mechanism of Action Combination hormonal contra- Central nervous system: Depression (12%)
ceptives inhibit ovulation and may also cause changes Genitourinary: Vaginal hemorrhage (78%), mastal-
in the cervical mucus, rendering it unfavorable for gia (40%)
sperm penetration even if ovulation occurs. The four- Local: Application site reaction (86%)
phasic formulation provides the estrogen in decreasing Neuromuscular & skeletal: Back pain (13%)
concentrations and the progestin in increasing concen- Respiratory: Upper respiratory tract infection (28%)
trations over the 28-day cycle. 1% to 10%: Cardiovascular: Edema (8%)
Pharmacodynamics/Kinetics Mechanism of Action Estrogens are responsible for
Half-life Elimination Estradiol: ~14 hours; Dieno- the development and maintenance of the female repro-
gest: ~11 hours ductive system and secondary sexual characteristics.
Time to Peak Estradiol: ~6 hours; Dienogest: ~1 hour Estradiol is the principle intracellular human estrogen
Pregnancy Considerations and is more potent than estrone and estriol at the
Use is contraindicated in pregnant women. Combina- receptor level; it is the primary estrogen secreted prior
tion hormonal contraceptives are used to prevent preg- to menopause. Following menopause, estrone and
nancy; treatment should be discontinued if pregnancy estrone sulfate are more highly produced. Estrogens
occurs. In general, the use of combination hormonal modulate the pituitary secretion of gonadotropins, lutei-
contraceptives when inadvertently taken early in preg- nizing hormone, and follicle-stimulating hormone
nancy has not been associated with adverse fetal or through a negative feedback system; estrogen replace-
maternal effects (Curtis 2016b). ment reduces elevated levels of these hormones in
postmenopausal women.
The manufacturer does not recommend use until ≥4
weeks after delivery in women who choose not to Levonorgestrel inhibits gonadotropin production; when
breastfeed or ≥4 weeks after a second trimester used in this combination, it counteracts the proliferative
abortion. effects of estradiol on the endometrium.
Due to the increased risk of venous thromboembolism Half-life Elimination Estradiol: 3 ± 0.67 hours; Lev-
(VTE) postpartum, combination hormonal contracep- onorgestrel: 28 ± 6.4 hours
tives should not be started in any woman <21 days Time to Peak Serum: Topical: Estradiol (mean): 2-2.5
following delivery. The risk decreases to baseline by days; Levonorgestrel: 2.5 days
postpartum day 42. Use of combination hormonal con- Pregnancy Considerations
traceptives in women between 21 and 42 days after Use during pregnancy is contraindicated.
delivery should take into consideration the individual
woman’s risk factors for VTE (eg, age ≥35 years, Refer to individual monographs.
previous VTE, thrombophilia, immobility, preeclampsia,
transfusion at delivery, cesarean delivery, peripartum Estradiol and Norethindrone
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- (es tra DYE ole & nor eth IN drone)
rhage, smoking) (Curtis 2016b).
Related Information
Estradiol and Levonorgestrel Estradiol (Systemic) on page 521
(es tra DYE ole & LEE voe nor jes trel) Norethindrone on page 981
Related Information Brand Names: US Activella; Amabelz; CombiPatch;
Endocrine Disorders and Pregnancy on page 1471 Lopreeza; Mimvey; Mimvey Lo
Estradiol (Systemic) on page 521 Brand Names: Canada Activelle; Activelle LD; Estalis
Brand Names: US ClimaraPro Pharmacologic Category Estrogen and Progestin
Combination
Brand Names: Canada Climara Pro
Use
Pharmacologic Category Estrogen and Progestin Hypoestrogenism (female) (patch): Treatment of
Combination hypoestrogenism due to hypogonadism, castration,
Use or primary ovarian failure
Moderate to severe vasomotor symptoms: Treat- Osteoporosis prevention (females): (tablet): Preven-
ment of moderate to severe vasomotor symptoms tion of postmenopausal osteoporosis
associated with menopause in women with an intact Limitations of use: For use only in women at significant
uterus risk of postmenopausal osteoporosis; consider use
Osteoporosis prevention: Prevention of postmeno- of nonestrogen medications.
pausal osteoporosis in women with an intact uterus Vasomotor symptoms associated with menopause
Limitations of use: Osteoporosis: For use only in (patch, tablet): Treatment of moderate to severe vaso-
women at significant risk of osteoporosis and for motor symptoms associated with menopause
whom other nonestrogen medications are not con- Vulvar and vaginal atrophy associated with meno-
sidered appropriate pause (patch, tablet): Treatment of moderate to
523
ESTRADIOL AND NORETHINDRONE
severe vulvar and vaginal atrophy associated with syndrome, dementia, edema, endometrial carcinoma,
menopause erythema multiforme, erythema nodosum, exacerba-
Limitations of use: When used solely for the treatment tion of asthma, exacerbation of endometriosis, exac-
of vulvar and vaginal atrophy, topical vaginal prod- erbation of porphyria, fallopian tube disease (cyst),
ucts should be considered. fatigue, fibrocystic breast changes, galactorrhea, gall-
Note: The International Society for the Study of Wom- bladder disease, hemorrhagic eruption, hirsutism,
en’s Sexual Health and The North American Meno- hypersensitivity, hypertension, increased serum trans-
pause Society have endorsed the term genitourinary aminases, increased serum triglycerides, irregular
syndrome of menopause (GSM) as new terminology menses, irritability, leg cramps, loss of scalp hair,
for vulvovaginal atrophy. The term GSM encom- malignant neoplasm of breast, migraine, mood
passes all genital and urinary signs and symptoms changes, myalgia, myocardial infarction, nipple dis-
associated with a loss of estrogen due to menopause charge, ovarian carcinoma, pancreatitis, paresthesia,
Portman 2014. premenstrual-like syndrome, pruritus, pulmonary
Local Anesthetic/Vasoconstrictor Precautions thromboembolism, retinal thrombosis, seborrhea, sig-
No information available to require special precautions nificant cardiovascular event, skin discoloration, stom-
Effects on Dental Treatment No significant effects or ach cramps, thrombophlebitis, uterine fibroids (size
complications reported increased), uterine spasm, varicose veins, venous
Effects on Bleeding No information available to thromboembolism, vertigo, vomiting, weight loss
require special precautions related to hemostasis in Pharmacodynamics/Kinetics
dental procedures. Half-life Elimination Oral tablet: Estradiol: 12 to 14
Adverse Reactions Frequency not always defined. hours; Norethindrone: 8 to 11 hours
Cardiovascular: Peripheral edema (transdermal: 6%) Time to Peak Oral tablet: Estradiol: 5 to 8 hours;
Central nervous system: Headache (11% to 25%), pain Norethindrone: 0.5 to 1.5 hours
(transdermal: 15% to 19%), depression (transdermal: Pregnancy Considerations
8% to 9%), insomnia (6% to 8%), dizziness (trans- Use during pregnancy is contraindicated.
dermal: 6% to 7%), nervousness (transdermal: 3% to
6%), emotional lability (oral: 1% to 6%) Not for use prior to menopause. Refer to individual
Dermatologic: Skin rash (transdermal: 5% to 6%), acne monographs.
vulgaris (transdermal: 4% to 5%)
Endocrine & metabolic: Menstrual disease (transder- Estradiol and Norgestimate
mal: 6% to 19%), weight gain (oral: ≤9%), ovarian cyst (es tra DYE ole & nor JES ti mate)
(oral: 3% to 7%), breast hypertrophy (transdermal: 2%
to 7%), hypermenorrhea (transdermal: 2% to 5%) Related Information
Gastrointestinal: Diarrhea (transdermal: 9% to 14%), Endocrine Disorders and Pregnancy on page 1471
abdominal pain (transdermal: 6% to 14%), nausea Estradiol (Systemic) on page 521
(3% to 12%), dyspepsia (transdermal: 6% to 8%), Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
flatulence (transdermal: 5% to 7%), gastroenteritis on page 1484
(oral: 2% to 6%), constipation (transdermal: 2% to 5%) Brand Names: US Prefest
Genitourinary: Mastalgia (transdermal: 25% to 48%; Pharmacologic Category Estrogen and Progestin
oral: 17% to 24%), dysmenorrhea (transdermal: 20% Combination
to 31%), vaginal hemorrhage (oral: 26%; transdermal: Use
3% to 6%), vaginitis (transdermal: 6% to 13%), post- Osteoporosis prevention: Prevention of osteoporosis
menopausal bleeding (oral: 5% to 11%), leukorrhea Limitations of use: For use only in women at significant
(transdermal: 5% to 10%), endometrial hyperplasia
risk of postmenopausal osteoporosis; consider use
(oral: ≤1% to 10%), abnormal pap smear (transdermal:
of nonestrogen medications.
8%), vulvovaginal candidiasis (oral: 4% to 6%)
Vasomotor symptoms associated with menopause:
Hematologic & oncologic: Uterine fibroids (oral: 5%)
Treatment of moderate to severe vasomotor
Infection: Infection (transdermal: 3% to 5%), viral infec-
symptoms
tion (oral: 4%)
Vulvar and vaginal atrophy associated with meno-
Local: Application site reaction (transdermal: 6%
pause: Treatment of moderate to severe symptoms of
to 23%)
vulvar and vaginal atrophy
Neuromuscular & skeletal: Back pain (6% to 15%),
weakness (transdermal: 8% to 13%), arthralgia (trans- Limitations of use: When used solely for the treatment
dermal: 6%), limb pain (oral: 5%) of vulvar and vaginal atrophy, topical vaginal prod-
Respiratory: Rhinitis (transdermal: 13% to 22%), naso- ucts should be considered.
pharyngitis (oral: 21%), upper respiratory tract infec- Note: The International Society for the Study of Wom-
tion (oral: 10% to 18%), sinusitis (7% to 15%), flu-like en’s Sexual Health and The North American Meno-
symptoms (transdermal: 9% to 14%), respiratory tract pause Society have endorsed the term genitourinary
disease (transdermal: 9% to 13%), pharyngitis (trans- syndrome of menopause (GSM) as new terminology
dermal: 4% to 10%), bronchitis (transdermal: 3% for vulvovaginal atrophy. The term GSM encom-
to 5%) passes all genital and urinary signs and symptoms
Miscellaneous: Accidental injury (3% to 17%) associated with a loss of estrogen due to menopause
<1%, postmarketing, and/or case reports: Alopecia, Portman 2014.
altered blood pressure, anaphylactoid reaction, ana- Local Anesthetic/Vasoconstrictor Precautions
phylaxis, angioedema, bloating, breast tenderness, No information available to require special precautions
carbohydrate intolerance, cerebrovascular accident, Effects on Dental Treatment No significant effects or
cervical polyp, change in appetite, change in cervical complications reported
secretions, change in corneal curvature, change in Effects on Bleeding No information available to
libido, chloasma, cholelithiasis, cholestatic jaundice, require special precautions related to hemostasis in
chorea, contact lens intolerance, cystitis-like dental procedures.
524
ESTROGENS (CONJUGATED B/SYNTHETIC)
Adverse Reactions >10%:

>10%: Cardiovascular: Edema (20%)
Central nervous system: Headache (23%) Endocrine & metabolic: Gynecomastia (75%),
Gastrointestinal: Abdominal pain (12%) increased lactate dehydrogenase (2% to 33%),
Genitourinary: Mastalgia (16%) decreased libido
Neuromuscular & skeletal: Back pain (12%) Gastrointestinal: Nausea (16%), diarrhea (13%), gas-
Respiratory: Upper respiratory tract infection (21%), trointestinal irritation (12%)
flu-like symptoms (11%) Genitourinary: Breast tenderness (71%)
1% to 10%: Hepatic: Increased serum AST (2% to 33%)
Central nervous system: Fatigue (6%), pain (6%), Respiratory: Dyspnea (12%)
depression (5%), dizziness (5%) 1% to 10%:
Gastrointestinal: Nausea (6%), flatulence (5%) Cardiovascular: Cardiac failure (3%), local thrombo-
Genitourinary: Vaginal hemorrhage (9%), dysmenor- phlebitis (3%), myocardial infarction (3%), cerebro-
rhea (8%), vaginitis (7%) vascular accident (2%), pulmonary embolism (2%),
Infection: Viral infection (6%) chest pain (1%), flushing (1%)
Neuromuscular & skeletal: Arthralgia (9%), myal- Central nervous system: Lethargy (4%), insomnia
gia (5%) (3%), emotional lability (2%), anxiety (1%), headache
Respiratory: Sinusitis (8%), pharyngitis (7%), (1%)
cough (5%) Dermatologic: Pruritus (2%), xeroderma (2%), exfolia-
Mechanism of Action Estrogens are responsible for tion of skin (1%), skin rash (1%), thinning hair (1%)
the development and maintenance of the female repro- Endocrine & metabolic: Increased thirst (1%)
ductive system and secondary sexual characteristics. Gastrointestinal: Anorexia (4%), flatulence (2%), gas-
Estradiol is the principle intracellular human estrogen trointestinal hemorrhage (1%), sore throat (1%),
and is more potent than estrone and estriol at the vomiting (1%)
receptor level; it is the primary estrogen secreted prior Hematologic & oncologic: Leukopenia (4%), bruise
to menopause. Following menopause, estrone and (3%), thrombocytopenia (1%)
estrone sulfate are more highly produced. Estrogens Hepatic: Increased serum bilirubin (1% to 2%)
modulate the pituitary secretion of gonadotropins, lutei- Neuromuscular & skeletal: Leg cramps (9%)
nizing hormone, and follicle-stimulating hormone Ophthalmic: Lacrimation (1%)
through a negative feedback system; estrogen replace- Respiratory: Hoarseness (1%), rhinorrhea (1%)
ment reduces elevated levels of these hormones in <1%, postmarketing, and/or case reports: Anemia,
postmenopausal women. angina pectoris, angioedema, cerebral ischemia, con-
Progestins inhibit gonadotropin production which then fusion, depression, decreased glucose tolerance,
prevents follicular maturation and ovulation. In women hypercalcemia, hypocalcemia, hypersensitivity reac-
with adequate estrogen, progestins transform a prolif- tion, hypertension, impotence, ischemic heart disease,
erative endometrium into a secretory endometrium; myasthenia, venous thrombosis
when administered with estradiol, reduces the inci- Mechanism of Action Estramustine is an estradiol
dence of endometrial hyperplasia and risk of adenocar- and nornitrogen mustard carbamate-linked combination
cinoma. which has antiandrogen effects (due to estradiol) and
Pharmacodynamics/Kinetics antimicrotubule effects (due to nornitrogen mustard); it
Half-life Elimination Norgestimate: 17-deacetylnor- causes a marked decrease in plasma testosterone and
gestimate: 37 hours an increase in estrogen levels.
Time to Peak Norgestimate: ~2 hours Pharmacodynamics/Kinetics
Pregnancy Considerations Half-life Elimination Estromustine: 13.6 hours
Use is contraindicated in pregnant women. (range: 9 to 23 hours); Estrone: 16.5 hours (Bergen-
heim 1998)
In general, the use of estrogen and progestin as in Time to Peak 2 to 3 hours (Bergenheim 1998)
combination hormonal contraceptives has not been Pregnancy Considerations Estramustine is not indi-
associated with teratogenic effects when inadvertently cated for use in women. Some men who were impotent
taken early in pregnancy. on estrogen therapy have regained potency while tak-
ing estramustine; effective contraception should be
Estramustine (es tra MUS teen) used for male patients with partners of childbearing
potential.
Brand Names: US Emcyt
Brand Names: Canada Emcyt Estrogens (Conjugated B/Synthetic)
Pharmacologic Category Antineoplastic Agent, Alky- (ES troe jenz, KON joo gate ed, bee, sin THET ik)
lating Agent; Antineoplastic Agent, Antimicrotubular;
Antineoplastic Agent, Hormone (Estrogen/Nitrogen Related Information
Mustard) Endocrine Disorders and Pregnancy on page 1471
Use Brand Names: US Enjuvia [DSC]
See Use: Unsupported. Pharmacologic Category Estrogen Derivative
Local Anesthetic/Vasoconstrictor Precautions Use
No information available to require special precautions Vasomotor symptoms associated with menopause:
Effects on Dental Treatment No significant effects or Treatment of moderate to severe vasomotor symp-
complications reported toms associated with menopause
Effects on Bleeding Thrombocytopenia has been Vulvar and vaginal atrophy associated with meno-
reported in a small number of patients pause: Treatment of moderate to severe vaginal dry-
Adverse Reactions ness and pain with intercourse, symptoms of vulvar
Frequency not always defined. and vaginal atrophy, associated with menopause
525
ESTROGENS (CONJUGATED B/SYNTHETIC)
Limitations of use: When used solely for the treatment Pharmacodynamics/Kinetics

of vulvar and vaginal atrophy, topical vaginal prod- Half-life Elimination Conjugated estrone: 8-20
ucts should be considered. hours; conjugated equilin: 5-17 hours
Note: The International Society for the Study of Wom- Pregnancy Considerations
en’s Sexual Health and The North American Meno- Use is contraindicated in pregnant women.
pause Society have endorsed the term genitourinary
In general, the use of estrogen and progestin as in
syndrome of menopause (GSM) as new terminology
combination hormonal contraceptives have not been
for vulvovaginal atrophy. The term GSM encom-
associated with teratogenic effects when inadvertently
passes all genital and urinary signs and symptoms taken early in pregnancy.
associated with a loss of estrogen due to menopause
Product Availability Enjuvia has been discontinued in
(Portman 2014). the US for more than 1 year.
Effects on Dental Treatment No significant effects or Estrogens (Conjugated/Equine,
complications reported Systemic) (ES troe jenz KON joo gate ed, EE kwine)
require special precautions related to hemostasis in Related Information
dental procedures. Endocrine Disorders and Pregnancy on page 1471
Adverse Reactions Brand Names: US Premarin
>10%: Brand Names: Canada C.E.S.; Congest; PMS-Con-
Central nervous system: Headache (25%), pain (10% jugated Estrogens C.S.D.; Premarin
to 19%) Pharmacologic Category Estrogen Derivative
Gastrointestinal: Abdominal pain (4% to 15%), nausea Use
(10% to 12%) Abnormal uterine bleeding (injection only): Treat-
Genitourinary: Mastalgia (13% to 15%) ment of abnormal uterine bleeding due to hormonal
1% to 10%: imbalance in the absence of organic pathology.
Cardiovascular: Peripheral edema (4%), chest pain Limitations of use: For short term use only to provide a
(3% to 4%) rapid and temporary increase in estrogen levels.
Central nervous system: Dizziness (7%), paresthesia Breast cancer, metastatic: Treatment of breast cancer
(1% to 6%), chills (4%), depression (3% to 4%), (palliation) in appropriately selected men and postme-
emotional lability (3% to 4%) nopausal women.
Dermatologic: Pruritus (6%), fungal dermatitis (2% to Hypoestrogenism (female): Treatment of hypoestro-
4%), acne vulgaris (1% to 4%) genism due to hypogonadism, castration, or primary
Gastrointestinal: Flatulence (4% to 7%), constipa- ovarian failure.
tion (4%) Osteoporosis prevention (female): Prevention of
postmenopausal osteoporosis.
Genitourinary: Dysmenorrhea (8%), vaginitis (7%),
Limitations of use: For use only in women at significant
breast tenderness (4%)
risk of osteoporosis; consider use of nonestrogen
Neuromuscular & skeletal: Back pain (4%), weakness
medications.
(3% to 4%)
Prostate cancer, advanced: Treatment of androgen-
Respiratory: Bronchitis (7%), rhinitis (7%), flu-like
dependent prostatic cancer (palliation).
symptoms (6% to 7%), sinusitis (4% to 7%),
Vasomotor symptoms associated with menopause:
increased cough (4%), upper respiratory tract infec- Treatment of moderate to severe vasomotor symp-
tion (4%), pharyngitis (3% to 4%) toms associated with menopause.
Miscellaneous: Accidental injury (9%) Vulvar and vaginal atrophy associated with meno-
<1%, postmarketing, and/or case reports: Abdominal pause: Treatment of moderate to severe vulvar and
distention, abdominal distress, alopecia, anaphylaxis, vaginal atrophy due to menopause.
deep vein thrombosis, dementia, exacerbation of Limitations of use: When used solely for the treatment
endometriosis (including malignant transformation), of vulvar and vaginal atrophy, topical vaginal prod-
gallbladder disease, hypercalcemia, hypersensitivity ucts should be considered.
reaction, insomnia, muscle spasm, retinal thrombosis, Note: The International Society for the Study of Wom-
skin rash, thrombosis, urticaria en’s Sexual Health and The North American Meno-
Mechanism of Action Conjugated B/synthetic estro- pause Society have endorsed the term genitourinary
gens contain a mixture of 10 synthetic estrogen sub- syndrome of menopause (GSM) as new terminology
stances, including sodium estrone sulfate, sodium for vulvovaginal atrophy. The term GSM encom-
equilin sulfate, sodium 17-alpha-dihydroequilin, sodium passes all genital and urinary signs and symptoms
17-alpha-estradiol, and sodium 17-beta-dihydroequilin. associated with a loss of estrogen due to menopause
Estrogens are responsible for the development and (Portman 2014).
maintenance of the female reproductive system and Local Anesthetic/Vasoconstrictor Precautions
secondary sexual characteristics. Estradiol is the prin- No information available to require special precautions
ciple intracellular human estrogen and is more potent Effects on Dental Treatment No significant effects or
than estrone and estriol at the receptor level; it is the complications reported
primary estrogen secreted prior to menopause. Follow- Effects on Bleeding No information available to
ing menopause, estrone and estrone sulfate are more require special precautions
highly produced. Estrogens modulate the pituitary Adverse Reactions Percentages reported in postme-
secretion of gonadotropins, luteinizing hormone, and nopausal women following oral use.
follicle-stimulating hormone through a negative feed- >10%:
back system; estrogen replacement reduces elevated Central nervous system: Headache (26% to 32%),
levels of these hormones in postmenopausal women. pain (17% to 20%)
526
ESTROGENS (CONJUGATED/EQUINE, TOPICAL)
Gastrointestinal: Abdominal pain (15% to 17%)

Genitourinary: Vaginal hemorrhage (2% to 14%), mas- Estrogens (Conjugated/Equine,
talgia (7% to 12%) Topical) (ES troe jenz KON joo gate ed, EE kwine)
Neuromuscular & skeletal: Back pain (13% to 14%),
arthralgia (7% to 14%) Brand Names: US Premarin
Respiratory: Pharyngitis (10% to 12%), sinusitis (6% Brand Names: Canada Premarin®
to 11%) Pharmacologic Category Estrogen Derivative
1% to 10%: Use
Central nervous system: Depression (5% to 8%), Vulvar and vaginal atrophy associated with meno-
dizziness (4% to 6%), nervousness (2% to 5%) pause: Treatment of atrophic vaginitis and kraurosis
Dermatologic: Pruritus (4% to 5%) vulvae and moderate-to-severe dyspareunia (pain
Gastrointestinal: Diarrhea (6% to 7%), flatulence (6% during intercourse) due to vaginal/vulvar atrophy of
to 7%) menopause
Genitourinary: Vaginitis (5% to 7%), leukorrhea (4% to Note: The International Society for the Study of Wom-
7%), vulvovaginal candidiasis (5% to 6%) en’s Sexual Health and The North American Meno-
Neuromuscular & skeletal: Weakness (7% to 8%), leg pause Society have endorsed the term genitourinary
cramps (3% to 7%) syndrome of menopause (GSM) as new terminology
Respiratory: Increased cough (4% to 7%) for vulvovaginal atrophy. The term GSM encom-
Frequency not defined (injection): Local: Injection site passes all genital and urinary signs and symptoms
phlebitis, pain at injection site, swelling at injection site associated with a loss of estrogen due to menopause
<1%, postmarketing, and/or case reports: Abnormal (Portman 2014).
uterine bleeding, alopecia, anaphylaxis, angioedema, Local Anesthetic/Vasoconstrictor Precautions
bloating, breast hypertrophy, breast tenderness, cere- No information available to require special precautions
brovascular accident, change in cervical secretions, Effects on Dental Treatment No significant effects or
change in libido, chloasma, cholestatic jaundice, con- complications reported
tact lens intolerance, decreased glucose tolerance, Effects on Bleeding No information available to
deep vein thrombosis, dementia, dysmenorrhea, require special precautions
edema, endometrial carcinoma, endometrial hyper- Adverse Reactions Due to systemic absorption, other
plasia, erythema multiforme, erythema nodosum, adverse effects associated with systemic therapy may
exacerbation of asthma, exacerbation of epilepsy, also occur. Frequency of adverse events reported with
exacerbation of hepatic hemangioma, exacerbation daily use.
of porphyria, fibrocystic breast changes, galactorrhea, 1% to 10%:
gallbladder disease, growth potentiation of benign Cardiovascular: Vasodilatation (4%)
meningioma, gynecomastia, hirsutism, hypersensitiv- Central nervous system: Pain (7%)
ity reaction, hypertension, increased serum triglycer- Gastrointestinal: Abdominal pain (8%)
ides, irritability, ischemic colitis, malignant neoplasm of Genitourinary: Mastalgia (6%), vaginitis (6%)
Neuromuscular & skeletal: Weakness (6%), back
breast, migraine, mood changes, myocardial infarc-
pain (5%)
tion, nausea, nipple discharge, ovarian carcinoma,
pancreatitis, pelvic pain, pulmonary embolism, retinal
cramps, abnormal uterine bleeding, acne vulgaris,
thrombosis, skin rash, superficial venous thrombosis,
alopecia, anaphylaxis, application site reaction (appli-
thrombophlebitis, urticaria, uterine fibroids (increased cation site burning, application site irritation, genital
size), vomiting, vulvovaginal candidiasis, weight pruritus), arthralgia, bloating, breast hypertrophy,
changes breast tenderness, cerebrovascular accident, change
Mechanism of Action Conjugated estrogens contain a in cervical secretions, change in libido, chloasma,
mixture of estrone sulfate, equilin sulfate, 17 alpha- contact lens intolerance, cystitis-like syndrome,
dihydroequilin, 17 alpha-estradiol and 17 beta-dihy- decreased glucose tolerance, deep vein thrombosis,
droequilin. Estrogens are responsible for the develop- dementia, depression, dizziness, dysmenorrhea,
ment and maintenance of the female reproductive dysuria, edema, endometrial carcinoma, endometrial
system and secondary sexual characteristics. Estradiol hyperplasia, exacerbation of asthma, fibrocystic
is the principle intracellular human estrogen and is more breast changes, gallbladder disease, gynecomastia,
potent than estrone and estriol at the receptor level; it is headache, hirsutism, hypersensitivity reaction, hyper-
the primary estrogen secreted prior to menopause. tension, increased serum triglycerides, irritability, leg
Following menopause, estrone and estrone sulfate are cramps, leukorrhea, malignant neoplasm of breast,
more highly produced. Estrogens modulate the pituitary migraine, mood disorder, muscle cramps, myocardial
secretion of gonadotropins, luteinizing hormone, and infarction, nausea, nervousness, nipple discharge,
follicle-stimulating hormone through a negative feed- pelvic pain, polyuria, precocious puberty, pulmonary
back system; estrogen replacement reduces elevated embolism, retinal thrombosis, skin rash, spotting, uri-
levels of these hormones in postmenopausal women. nary tract infection, urinary urgency, urticaria, uterine
Pharmacodynamics/Kinetics fibroids (increase in size), vomiting, vulvovaginal dis-
Half-life Elimination Total estrone: 27 hours ease, weight changes
Time to Peak Total estrone: 7 hours Mechanism of Action Conjugated estrogens contain a
Pregnancy Considerations mixture of estrone sulfate, equilin sulfate, 17 alpha-
Use is contraindicated during pregnancy. dihydroequilin, 17 alpha-estradiol and 17 beta-dihy-
droequilin. Estrogens are responsible for the develop-
Estrogens are not indicated for use during pregnancy or ment and maintenance of the female reproductive
immediately postpartum. In general, the use of estrogen system and secondary sexual characteristics. Estradiol
and progestin as in combination hormonal contracep- is the principle intracellular human estrogen and is more
tives have not been associated with teratogenic effects potent than estrone and estriol at the receptor level; it is
when inadvertently taken early in pregnancy. the primary estrogen secreted prior to menopause.
527
ESTROGENS (CONJUGATED/EQUINE, TOPICAL)
Following menopause, estrone and estrone sulfate are flashes was observed after 4 weeks of therapy
more highly produced. Estrogens modulate the pituitary (Pinkerton, 2009).
secretion of gonadotropins, luteinizing hormone, and Osteoporosis: A significant increase in BMD meas-
follicle-stimulating hormone through a negative feed- ured at the lumbar spine and hip was observed at 12
back system; estrogen replacement reduces elevated months of therapy (Lindsay, 2009).
levels of these hormones in postmenopausal women. Half-life Elimination
Pharmacodynamics/Kinetics Bazedoxifene: ~30 hours
Time to Peak Total estrone: 6 hours Total estrone: ~17 hours
Pregnancy Considerations Time to Peak
Use is contraindicated during pregnancy. Bazedoxifene: ~2.5 hours
In general, the use of estrogen and progestin as in Total estrone: ~6.5 hours
combination hormonal contraceptives have not been Pregnancy Risk Factor X
associated with teratogenic effects when inadvertently Pregnancy Considerations
taken early in pregnancy. Use of the vaginal cream may Use is contraindicated in women who are or who may
weaken latex found in condoms, diaphragms, or cer- become pregnant.
vical caps. This combination product is approved for use in post-
menopausal women only.
Estrogens (Conjugated/Equine) and
Bazedoxifene Estrogens (Conjugated/Equine) and
(ES troe jenz, KON joo gate ed/EE kwine & ba ze DOX i feen)
Medroxyprogesterone
Brand Names: US Duavee (ES troe jenz KON joo gate ed/EE kwine & me DROKS ee proe JES
te rone)
Brand Names: Canada Duavive
Pharmacologic Category Estrogen Derivative; Selec- Related Information
tive Estrogen Receptor Modulator (SERM); Tissue- Endocrine Disorders and Pregnancy on page 1471
Selective Estrogen Complex (TSEC) Estrogens (Conjugated/Equine, Systemic) on page 526
Use MedroxyPROGESTERone on page 836
Postmenopausal osteoporosis prophylaxis: Preven- Brand Names: US Premphase; Prempro
tion of postmenopausal osteoporosis in women with a
Pharmacologic Category Estrogen and Progestin
uterus
Combination
Limitations of use: For use only in women at significant
risk of postmenopausal osteoporosis; consider use Use
of nonestrogen medications. Osteoporosis prevention (female): Prevention of
Vasomotor symptoms: Treatment of moderate-to- postmenopausal osteoporosis
severe vasomotor symptoms associated with meno- Limitations of use: For use only in women at significant
pause in women with a uterus risk of postmenopausal osteoporosis; consider use
Local Anesthetic/Vasoconstrictor Precautions of nonestrogen medications.
No information available to require special precautions Vasomotor symptoms associated with menopause:
Treatment of moderate to severe vasomotor symp-
complications reported toms associated with menopause.
Vulvar and vaginal atrophy associated with meno-
pause: Treatment of moderate to severe vulvar and
vaginal atrophy associated with menopause.
Adverse Reactions Percentages as reported with
Limitations of use: When used solely for the treatment
combination product.
of vulvar and vaginal atrophy, topical vaginal prod-
1% to 10%:
ucts should be considered.
Central nervous system: Dizziness (5%)
Note: The International Society for the Study of Wom-
Gastrointestinal: Diarrhea (8%), nausea (8%), dyspep-
sia (7%), upper abdominal pain (7%) en’s Sexual Health and The North American Meno-
Neuromuscular & skeletal: Muscle spasm (9%), neck pause Society have endorsed the term genitourinary
pain (5%) syndrome of menopause (GSM) as new terminology
Respiratory: Oropharyngeal pain (7%) for vulvovaginal atrophy. The term GSM encom-
passes all genital and urinary signs and symptoms
Mechanism of Action Conjugated estrogens contain a
mixture of estrone sulfate, equilin sulfate, 17 alpha- associated with a loss of estrogen due to menopause
dihydroequilin, 17 alpha-estradiol and 17 beta-dihy- (Portman 2014).
droequilin. Bazedoxifene is a selective estrogen recep- Guideline recommendations: Due to safety consider-
tor modulator (SERM). Conjugated estrogens act as an ations, when a progesterone is needed, use of micron-
estrogen agonist and bazedoxifene acts as an estrogen ized progesterone is preferred over
agonist/antagonist depending on the specific tissue. medroxyprogesterone acetate (AACE [Goodman
The combination of a SERM and estrogen [referred to 2011]; AACE/ACE [Cobin 2017]).
as a tissue-selective estrogen complex (TSEC)] pro- Local Anesthetic/Vasoconstrictor Precautions
vides relief of vasomotor symptoms and maintenance of No information available to require special precautions
bone mineral density in postmenopausal women with a Effects on Dental Treatment No significant effects or
uterus, while reducing the risk of endometrial hyper- complications reported
plasia observed with estrogen use alone (Pickar, 2009). Effects on Bleeding No information available to
Pharmacodynamics/Kinetics require special precautions related to hemostasis in
Onset of Action dental procedures.
Relief of vasomotor symptoms: A significant reduction Adverse Reactions
in the number and severity of moderate/severe hot Also see individual agents.
528
ESTROGENS (ESTERIFIED)
>10%:
Central nervous system: Headache (15% to 19%) Estrogens (Esterified) (ES troe jenz, es TER i fied)
Gastrointestinal: Abdominal pain (7% to 17%)
Related Information
Genitourinary: Mastalgia (13% to 36%), dysmenor-
rhea (3% to 13%)
1% to 10%:
Brand Names: US Menest
Cardiovascular: Edema (≤4%), peripheral edema (2% Brand Names: Canada Estragyn
to 3%), hypertension (2%), vasodilatation (≤2%), Pharmacologic Category Estrogen Derivative
chest pain (1%), palpitations (≤1%) Use
Central nervous system: Depression (7% to 8%), pain Breast cancer, metastatic: Treatment of metastatic
breast cancer (palliation) in appropriately selected
(5%), emotional lability (3%), dizziness (2% to 3%),
men and postmenopausal women
migraine (2% to 3%), nervousness (1% to 3%),
Hypoestrogenism (female): Treatment of hypoestro-
anxiety (2%), hypertonia (1% to 2%), insomnia (1% genism due to hypogonadism, castration, or primary
to 2%) ovarian failure
Dermatologic: Pruritus (2% to 6%), skin rash (2%), Prostate cancer: Palliative therapy of advanced pro-
acne vulgaris (≤2%), alopecia (≤2%), skin discolor- static carcinoma
ation (1% to 2%), diaphoresis (≤1%), xero- Vasomotor symptoms associated with menopause:
derma (≤1%) Treatment of moderate to severe vasomotor symp-
Endocrine & metabolic: Weight gain (3%), decreased toms associated with menopause
glucose tolerance (≤1%), hypermenorrhea (≤1%) Vulvar and vaginal atrophy associated with meno-
Gastrointestinal: Nausea (6% to 8%), flatulence (4% pause: Treatment of moderate to severe symptoms of
to 8%), diarrhea (≤6%), constipation (2%), increased vulvar and vaginal atrophy associated with meno-
appetite (≤2%), eructation (≤1%) pause
Genitourinary: Leukorrhea (3% to 8%), breast hyper- Limitations of use: When used solely for the treatment
trophy (2% to 5%), pelvic pain (2% to 5%), vaginal of vulvar and vaginal atrophy, topical vaginal prod-
hemorrhage (≤5%), vaginitis (2% to 4%), break- ucts should be considered
through bleeding (1% to 4%), uterine spasm (1% to Note: The International Society for the Study of Wom-
en’s Sexual Health and The North American Meno-
4%), vulvovaginal candidiasis (1% to 4%), cervical
changes (1% to 3%), abnormal Pap smear (≤2%),
syndrome of menopause (GSM) as new terminology
breast engorgement (≤1%), urinary inconti-
for vulvovaginal atrophy. The term GSM encom-
nence (≤1%) passes all genital and urinary signs and symptoms
Hematologic & oncologic: Malignant neoplasm of associated with a loss of estrogen due to menopause
breast (≤1%) (Portman 2014).
Infection: Candidiasis (≤2%), infection (≤1%) Local Anesthetic/Vasoconstrictor Precautions
Neuromuscular & skeletal: Weakness (3% to 6%), No information available to require special precautions
back pain (2% to 7%), leg cramps (2% to 4%) Effects on Dental Treatment No significant effects or
Respiratory: Pharyngitis (>5%), sinusitis (>5%), flu- complications reported
like symptoms (≤1%) Effects on Bleeding No information available to
<1%, postmarketing, and/or case reports: Abnormal require special precautions related to hemostasis in
uterine bleeding, amenorrhea, anaphylactoid reaction, dental procedures.
anaphylaxis, angioedema, bloating, breast tender- Adverse Reactions Frequency not defined.
ness, cerebrovascular accident, change in appetite, Cardiovascular: Cerebrovascular accident, edema,
change in cervical secretions, change in libido, hypertension, local thrombophlebitis, myocardial
chloasma, cholestatic jaundice, contact lens intoler- infarction, pulmonary embolism, retinal thrombosis,
ance, cough, deep vein thrombosis, dementia, endo- venous thromboembolism
metrial carcinoma, endometrial hyperplasia, erythema Central nervous system: Chorea, dementia (exacerba-
multiforme, erythema nodosum, exacerbation of tion), depression, dizziness, exacerbation of epilepsy,
asthma, exacerbation of epilepsy, exacerbation of tics, headache, irritability, migraine, mood disorder, nerv-
fibrocystic breast changes, galactorrhea, gallbladder ousness
Dermatologic: Chloasma, erythema multiforme, eryth-
disease, hirsutism, hypersensitivity reaction,
ema nodosum, pruritus, loss of scalp hair, skin rash,
increased serum triglycerides, irritability, ischemic col-
urticaria
itis, malignant neoplasm of ovary, meningioma Endocrine & metabolic: Change in libido, exacerbation
(benign; possible growth), myalgia, myocardial infarc- of porphyria, fibrocystic breast changes, galactorrhea,
tion, nipple discharge, pancreatitis, pulmonary embo- hirsutism, hypocalcemia, menstrual disease (altera-
lism, retinal thrombosis, rhinitis, superficial venous tions in frequency and flow of menstrual patterns),
thrombosis, thrombophlebitis, upper respiratory tract premenstrual-like syndrome, weight gain, weight loss
infection, urticaria, uterine fibroids (increase in size), Gastrointestinal: Abdominal cramps, bloating, carbohy-
vomiting, vulvovaginal candidiasis, weight loss drate intolerance, gallbladder disease, nausea, pan-
Mechanism of Action See individual agents. creatitis, vomiting
Pregnancy Considerations Genitourinary: Breakthrough bleeding, breast hypertro-
Use is contraindicated in pregnant women. phy, breast tenderness, change in cervical ectropion,
change in cervical secretions, cystitis-like syndrome,
In general, the use of estrogen and progestin as in dysmenorrhea, endometrial hyperplasia, nipple dis-
combination hormonal contraceptives have not been charge, vulvovaginal candidiasis, vaginitis
associated with teratogenic effects when inadvertently Hematologic & oncologic: Endometrial carcinoma, hem-
taken early in pregnancy. orrhagic eruption, malignant neoplasm of breast,
529
ESTROGENS (ESTERIFIED)
malignant neoplasm of ovary, uterine fibroids Pregnancy Considerations [US Boxed Warning]:
(increased size) Estrogens should not be used during pregnancy.
Hepatic: Cholestatic jaundice, exacerbation of hepatic This product is specifically contraindicated during preg-
hemangioma (enlargement) nancy.
Hypersensitivity: Anaphylactoid reaction, anaphylaxis,
Refer to the Estrogens (Esterified) monograph and the
angioedema
Testosterone monograph for additional information.
Neuromuscular & skeletal: Arthralgia, leg cramps
Ophthalmic: Contact lens intolerance, change in cor- Controlled Substance C-III or nonscheduled (DEA
neal curvature (steepening) exemption status dependent)
Respiratory: Exacerbation of asthma
Mechanism of Action Esterified estrogens contain a Estropipate (ES troe pih pate)
mixture of estrogenic substances; the principle compo-
nent is estrone. Preparations contain 75% to 85% Related Information
sodium estrone sulfate and 6% to 15% sodium equilin Endocrine Disorders and Pregnancy on page 1471
sulfate such that the total is not <90%. Estrogens are Brand Names: US Ortho-Est 0.625 [DSC]; Ortho-Est
responsible for the development and maintenance of 1.25 [DSC]
the female reproductive system and secondary sexual Brand Names: Canada Ogen [DSC]
characteristics. Estradiol is the principle intracellular Pharmacologic Category Estrogen Derivative
human estrogen and is more potent than estrone and Use
estriol at the receptor level; it is the primary estrogen Hypoestrogenism, female: Treatment of hypoestro-
secreted prior to menopause. In males and following genism due to hypogonadism, castration, or primary
menopause in females, estrone and estrone sulfate are ovarian failure.
more highly produced. Estrogens modulate the pituitary Osteoporosis prevention: Prevention of postmeno-
secretion of gonadotropins, luteinizing hormone, and pausal osteoporosis.
follicle-stimulating hormone through a negative feed- Limitations of use: For use only in women at significant
back system; estrogen replacement reduces elevated risk of postmenopausal osteoporosis; consider use
levels of these hormones. of nonestrogen medications.
Pregnancy Considerations Vasomotor symptoms associated with menopause:
Estrogens esterified are contraindicated for use during Treatment of moderate to severe vasomotor symp-
pregnancy. toms associated with menopause.
Vulval and vaginal atrophy associated with meno-
In general, the use of estrogen and progestin as in pause: Treatment of moderate to severe symptoms of
combination hormonal contraceptives have not been vulval and vaginal atrophy associated with meno-
associated with teratogenic effects when inadvertently pause.
taken early in pregnancy. Limitations of use: When used solely for the treatment
of vulvar and vaginal atrophy, topical vaginal prod-
Estrogens (Esterified) and ucts should be considered.
Note: The International Society for the Study of Wom-
Methyltestosterone en’s Sexual Health and The North American Meno-
(ES troe jenz es TER i fied & meth il tes TOS te rone)
Related Information syndrome of menopause (GSM) as new terminology
Endocrine Disorders and Pregnancy on page 1471 for vulvovaginal atrophy. The term GSM encom-
Estrogens (Esterified) on page 529 passes all genital and urinary signs and symptoms
MethylTESTOSTERone on page 884 associated with a loss of estrogen due to menopause
(Portman 2014).
Brand Names: US Covaryx; Covaryx H.S.; EEMT;
EEMT HS
Pharmacologic Category Estrogen and Androgen
Combination
Use Vasomotor symptoms associated with meno-
pause: Treatment of moderate to severe vasomotor
require special precautions related to hemostasis in
symptoms associated with menopause not improved
dental procedures.
by estrogens alone
Cardiovascular: Edema, hypertension, pulmonary
thromboembolism, venous thromboembolism
Effects on Dental Treatment No significant effects or Central nervous system: Chorea, depression, dizzi-
complications reported ness, headache, migraine
Effects on Bleeding No information available to Dermatologic: Chloasma, erythema multiforme, eryth-
require special precautions related to hemostasis in ema nodosum, loss of scalp hair
dental procedures. Endocrine & metabolic: Change in libido, exacerbation
Adverse Reactions Refer to the Estrogens (Esterified) of porphyria, hirsutism, hypercalcemia, impaired glu-
and the Testosterone monographs. cose tolerance, increased HDL cholesterol, decreased
Mechanism of Action LDL cholesterol, increased serum triglycerides,
Conjugated estrogens: Activate estrogen receptors increased T4, increased thyroxine binding globulin,
(DNA protein complex) located in estrogen-responsive menstrual disease (alterations in frequency and flow
tissues. Once activated, regulate transcription of cer- of menses), phospholipidemia, weight gain,
tain genes leading to observed effects. weight loss
Testosterone: Increases synthesis of DNA, RNA, and Gastrointestinal: Abdominal cramps, bloating, carbohy-
various proteins in target tissues drate intolerance, cholecystitis, cholelithiasis, gallblad-
Pregnancy Risk Factor X der disease, nausea, pancreatitis, vomiting
530
ETANERCEPT
Genitourinary: Breast hypertrophy, breast tenderness, Genitourinary: Dysmenorrhea (≤3%), urinary tract
vulvovaginal candidiasis infection (≤3%)
Hematologic & oncologic: Change in platelet count Infection: Infection (5% to 10%), viral infection (3%)
(increase), decreased antifactor Xa, decreased antith- Miscellaneous: Accidental injury (≤3%)
rombin III plasma level, endometrial carcinoma, hem- <1%, postmarketing, and/or case reports: Abnormal
orrhagic eruption, increased clotting factor VII, gait, abnormality in thinking, agitation, alopecia,
increased clotting factor VIII, increased clotting factor altered sense of smell, amenorrhea, anaphylaxis,
IX, increased clotting factor X, increased platelet anemia, angioedema, anorexia, apathy, aphthous sto-
aggregation, increased serum fibrinogen, prolonged matitis, arthritis, asthma, ataxia, blepharoptosis,
prothrombin time, uterine fibroids (increased size) breast hypertrophy, breast neoplasm, bronchitis, bur-
Hepatic: Cholestatic jaundice sitis, cholelithiasis, colitis, conjunctivitis, contact der-
Ophthalmic: Change in corneal curvature (steepening), matitis, cystitis, dehydration, diaphoresis, dry eye
contact lens intolerance syndrome, dysphagia, dyspnea, dysuria, eczema,
Mechanism of Action Estropipate is prepared from emotional lability, epistaxis, erythema multiforme,
naturally occurring estrone. Estrogens are responsible euphoria, facial edema, fever, gastric ulcer, gastritis,
for the development and maintenance of the female gout, halitosis, heatstroke, hematuria, hepatic dis-
reproductive system and secondary sexual character- ease, hepatitis, hepatomegaly, herpes zoster, hirsut-
istics. Estradiol is the principle intracellular human ism, hostility, hypercholesterolemia, hypermenorrhea,
estrogen and is more potent than estrone and estriol hypersensitivity reaction, hypertension, hypokalemia,
at the receptor level; it is the primary estrogen secreted hyporeflexia, increased appetite, increased thirst,
prior to menopause. In males and following menopause insomnia, laryngitis, lymphadenopathy, maculopapu-
in females, estrone and estrone sulfate are more highly lar rash, malaise, mastalgia, mastitis, melena, memory
produced. Estrogens modulate the pituitary secretion of impairment, myasthenia, mydriasis, myopathy, neck
gonadotropins, luteinizing hormone, and follicle-stimu- stiffness, nephrolithiasis, neuritis, neuropathy, nystag-
lating hormone through a negative feedback system; mus, oliguria, paresthesia, photophobia, psychoneu-
estrogen replacement reduces elevated levels of these rosis, pyelonephritis, rectal hemorrhage, reflexes
hormones. Estropipate is prepared from purified crys- decreased, renal pain, skin discoloration, skin photo-
talline estrone that has been solubilized as the sulfate sensitivity, sleep disorder (complex sleep-related
and stabilized with piperazine. behavior, including cooking or eating food, making
Pregnancy Considerations phone calls, sleep driving), swelling, thrombophlebitis,
Use is contraindicated in pregnant women. tinnitus, tongue edema, tremor, twitching, urethritis,
In general, the use of estrogen and progestin as in urinary frequency, urinary incontinence, urticaria, ute-
combination hormonal contraceptives has not been rine hemorrhage, vaginal hemorrhage, vaginitis, ver-
associated with teratogenic effects when inadvertently tigo, vesiculobullous dermatitis, vestibular disturbance
taken early in pregnancy. Mechanism of Action May interact with GABA-recep-
tor complexes at binding domains located close to or
allosterically coupled to benzodiazepine receptors.
Eszopiclone (es zoe PIK lone) Pharmacodynamics/Kinetics
Brand Names: US Lunesta Half-life Elimination ~6 hours; Elderly (≥65 years):
Pharmacologic Category Hypnotic, Miscellaneous ~9 hours
Use Insomnia: Treatment of insomnia Time to Peak ~1 hour
Local Anesthetic/Vasoconstrictor Precautions Pregnancy Considerations
No information available to require special precautions Eszopiclone is the S-isomer of the racemic derivative
Effects on Dental Treatment Key adverse event(s) zopiclone. Available data related to zopiclone (not
related to dental treatment: Unpleasant taste and xero- available in the United States) and similar medications
stomia (normal salivary flow resumes upon discontinu- note the potential for preterm birth, low birth weight,
ation). and/or small for gestational age infants following mater-
Effects on Bleeding No information available to nal use.
require special precautions Long-term use of medications in this class is not rec-
Adverse Reactions ommended during pregnancy and a planned discontin-
>10%: uation should be done to prevent rebound insomnia
Central nervous system: Headache (15% to 21%) (Okun 2015).
Gastrointestinal: Dysgeusia (8% to 34%) Controlled Substance C-IV
1% to 10%:
Cardiovascular: Chest pain (≥1%), peripheral
edema (≥1%) Etanercept (et a NER sept)
Central nervous system: Drowsiness (8% to 10%),
Related Information
dizziness (5% to 7%), pain (4% to 5%), nervousness
(≤5%), depression (1% to 4%), confusion (≤3%), Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
neuralgia (≤3%), abnormal dreams (1% to 3%), on page 1484
anxiety (1% to 3%), hallucination (1% to 3%), Brand Names: US Enbrel; Enbrel Mini; Enbrel Sure-
migraine Click
Dermatologic: Skin rash (3% to 4%), pruritus (1% Brand Names: Canada Brenzys; Enbrel; Erelzi
to 4%) Pharmacologic Category Antirheumatic, Disease
Endocrine & metabolic: Decreased libido (≤3%), gyne- Modifying; Tumor Necrosis Factor (TNF) Blocking
comastia (≤3%) Agent
Gastrointestinal: Xerostomia (3% to 7%), dyspepsia Use
(2% to 6%), nausea (4% to 5%), diarrhea (2% to Ankylosing spondylitis: Reducing signs and symp-
4%), vomiting (≤3%) toms in patients with active ankylosing spondylitis.
531
ETANERCEPT
Plaque psoriasis (Enbrel): Treatment of patients ≥4 (including pulmonary and extrapulmonary), uveitis,
years of age with chronic moderate to severe plaque varicella zoster infection, vasculitis (cutaneous and
psoriasis who are candidates for systemic therapy or systemic)
phototherapy. Mechanism of Action Etanercept is a recombinant
Polyarticular juvenile idiopathic arthritis: Reducing DNA-derived protein composed of tumor necrosis factor
signs and symptoms of moderately to severely active receptor (TNFR) linked to the Fc portion of human IgG1.
polyarticular juvenile idiopathic arthritis in patients ≥2 Etanercept binds tumor necrosis factor (TNF) and
years of age. blocks its interaction with cell surface receptors. TNF
Psoriatic arthritis (Enbrel): Reducing signs and symp- plays an important role in the inflammatory processes
toms, inhibiting the progression of structural damage and the resulting joint pathology of rheumatoid arthritis
of active arthritis, and improving physical function in (RA), polyarticular-course juvenile idiopathic arthritis
patients with psoriatic arthritis. Etanercept can be (JIA), ankylosing spondylitis (AS), and plaque psoriasis.
used with or without methotrexate. Pharmacodynamics/Kinetics
Rheumatoid arthritis: Reducing signs and symptoms, Onset of Action ~2 to 3 weeks; RA: 1 to 2 weeks;
inducing major clinical response, inhibiting the pro- Maximum effect: RA: Full effect is usually seen within
gression of structural damage, and improving physical 3 months
function in patients with moderately to severely active Half-life Elimination Half-life elimination: SubQ: Chil-
rheumatoid arthritis (RA). Etanercept can be initiated dren ≥4 years and Adolescents (JIA): Mean range: 70
in combination with methotrexate or used alone. to 94.8 hours (range: 31.2 to 104.8 hours) (Yim 2005);
Local Anesthetic/Vasoconstrictor Precautions Adults (RA): 102 ± 30 hours
No information available to require special precautions Time to Peak RA: SubQ: 69 ± 34 hours
Effects on Dental Treatment No significant effects or Pregnancy Considerations Adverse events have not
complications reported been observed in animal reproduction studies. Etaner-
Effects on Bleeding No information available to cept crosses the placenta. Following in utero exposure,
require special precautions concentrations in the newborn at delivery are 3% to
Adverse Reactions 32% of the maternal serum concentration.
>10%: Product Availability Erelzi (etanercept-szzs): FDA
Dermatologic: Skin rash (3% to 13%) approved August 2016; anticipated availability is cur-
Gastrointestinal: Diarrhea (3% to 16%) rently unknown. Erelzi is approved as biosimilar to
Infection: Infection (50% to 81%) Enbrel, but not as an interchangeable product.
Local: Injection site reaction (adults: 15% to 43%;
children: 7%; bleeding, bruising, erythema, itching,
pain, or swelling; mild to moderate and usually Ethacrynic Acid (eth a KRIN ik AS id)
decreases with subsequent injections) Brand Names: US Edecrin; Sodium Edecrin
Respiratory: Upper respiratory tract infection (38% to
Brand Names: Canada Edecrin; Sodium Edecrin
65%), respiratory tract infection (21% to 54%)
Miscellaneous: Antibody development (non-neutraliz- Pharmacologic Category Diuretic, Loop
ing; 4% to 16%), positive ANA titer (11%) Use
1% to 10%: Oral: Management of edema associated with conges-
Dermatologic: Pruritus (2% to 5%), urticaria (2%) tive heart failure; hepatic cirrhosis or renal disease;
Hypersensitivity: Hypersensitivity reaction (1%) short-term management of ascites due to malignancy,
Miscellaneous: Fever (2% to 3%) idiopathic edema, and lymphedema; short-term man-
Frequency not defined: agement of hospitalized pediatric patients, other than
Dermatologic: Cellulitis infants, with congenital heart disease or the nephrotic
Gastrointestinal: Gastroenteritis syndrome
Infection: Abscess, influenza, sepsis IV: Indicated when a rapid onset of diuresis is desired
Neuromuscular & skeletal: Osteomyelitis, septic (eg, in acute pulmonary edema, or when gastrointes-
arthritis tinal absorption is impaired or oral medication is not
Renal: Pyelonephritis feasible)
Respiratory: Bronchitis, pneumonia, sinusitis Local Anesthetic/Vasoconstrictor Precautions
<1%, postmarketing, and/or case reports: Anemia, No information available to require special precautions
angioedema, aplastic anemia, aseptic meningitis, Effects on Dental Treatment No significant effects or
aspergillosis, autoimmune hepatitis, cardiac failure, complications reported
chest pain, cutaneous lupus erythematous, demyeli- Effects on Bleeding No information available to
nating disease of the central nervous system, eryth- require special precautions
e m a m ul t if o r m e , fu n ga l i n fe c ti o n (i n c l ud i n g Adverse Reactions Frequency not defined.
histoplasmosis), Guillain-Barré syndrome, hepatotox- Cardiovascular: Thrombophlebitis (with intrave-
icity (idiosyncratic) (Chalasani 2014), herpes zoster, nous use)
increased serum transaminases, inflammatory bowel Central nervous system: Apprehension, brain disease
disease, interstitial pulmonary disease, leukemia, leu- (patients with preexisting liver disease), chills, confu-
kopenia, lupus-like syndrome, lymphadenopathy, sion, fatigue, headache, vertigo
malignant lymphoma, malignant melanoma, malignant Dermatologic: IgA vasculitis (in patient with rheumatic
neoplasm, Merkel cell carcinoma, multiple sclerosis, heart disease), skin rash
neutropenia, optic neuritis, pancytopenia, paresthesia, Endocrine & metabolic: Abnormal phosphorus levels
pneumonia due to Pneumocystis carinii, psoriasis (variations), abnormal serum calcium (variations),
(including new onset, palmoplantar, pustular, or exac- gout, hyperglycemia, hyperuricemia (reversible),
erbation), reactivation of HBV, sarcoidosis, scleritis, hypoglycemia (occurred in two uremic patients who
seizure, skin carcinoma, Stevens-Johnson syndrome, received doses above those recommended), hypona-
subcutaneous nodule, thrombocytopenia, toxic epider- tremia, variations in bicarbonate, variations in CO2
mal necrolysis, transverse myelitis, tuberculosis content
532
ETHINYL ESTRADIOL AND DESOGESTREL
Gastrointestinal: Abdominal distress, abdominal pain, Mechanism of Action Inhibits arabinosyl transferase
anorexia, diarrhea, dysphagia, gastrointestinal hemor- resulting in impaired mycobacterial cell wall synthesis
rhage, malaise, nausea, vomiting, acute pancreati- Pharmacodynamics/Kinetics
tis (rare) Half-life Elimination 2.5-3.6 hours; End-stage renal
Genitourinary: Hematuria disease: 7-15 hours
Hematologic & oncologic: Agranulocytosis, severe neu- Time to Peak Serum: 2-4 hours
tropenia, thrombocytopenia Pregnancy Risk Factor C
Hepatic: Abnormal hepatic function tests, jaundice Pregnancy Considerations Adverse events were
Local: Local irritation, local pain observed in animal reproduction studies. Ophthalmic
Ophthalmic: Blurred vision abnormalities have been reported in infants born to
Otic: Deafness (temporary or permanent), tinnitus women receiving ethambutol as a component of anti-
Renal: Increased serum creatinine tuberculous therapy. Due to the risk of untreated tuber-
Miscellaneous: Fever culosis to the mother and fetus, treatment is
Mechanism of Action Inhibits reabsorption of sodium recommended when the probability of maternal disease
and chloride in the ascending loop of Henle and distal is moderate to high. Ethambutol is one of the recom-
renal tubule, interfering with the chloride-binding cotran- mended agents to treat tuberculosis in pregnant women
sport system, thus causing increased excretion of (Nahid 2016).
water, sodium, chloride, magnesium, and calcium
Onset of Action Diuresis: Oral: ~30 minutes; IV: 5 Ethanolamine Oleate
(ETH a nol a meen OH lee ate)
minutes; Peak effect: Oral: 2 hours; IV: 30 minutes
Duration of Action Oral: 12 hours; IV: 2 hours Brand Names: US Ethamolin
Half-life Elimination Normal renal function: 2-4 hours Pharmacologic Category Sclerosing Agent
Pregnancy Risk Factor B Use Esophageal varices: Treatment of esophageal
Pregnancy Considerations Adverse events have not varices that have recently bled, to prevent rebleeding.
been observed in animal reproduction studies. Local Anesthetic/Vasoconstrictor Precautions
Ethambutol (e THAM byoo tole) Effects on Dental Treatment No significant effects or
Brand Names: US Myambutol Effects on Bleeding No information available to
Brand Names: Canada Etibi require special precautions
Pharmacologic Category Antitubercular Agent Adverse Reactions
Use Treatment of pulmonary tuberculosis in conjunction 1% to 10%:
with other antituberculosis agents Cardiovascular: Substernal pain (2%)
Local Anesthetic/Vasoconstrictor Precautions Gastrointestinal: Esophageal ulcer (2%), esophageal
No information available to require special precautions stenosis (1%)
Effects on Dental Treatment No significant effects or Respiratory: Pleural effusion (2%), pneumonia (1%)
complications reported Miscellaneous: Fever (2%)
Effects on Bleeding No information available to <1%, postmarketing, and/or case reports: Acute renal
require special precautions failure, anaphylaxis, esophageal perforation, esopha-
Adverse Reactions Frequency not defined. gitis, tissue necrosis at injection site
Cardiovascular: Myocarditis, pericarditis Mechanism of Action Ethanolamine oleate produces
Central nervous system: Confusion, disorientation, diz- a sterile dose-related inflammatory response resulting
ziness, hallucination, headache, malaise, peripheral in fibrosis and possible occlusion of the vein; a dose-
neuritis related extravascular inflammatory reaction occurs
Dermatologic: Dermatitis, erythema multiforme, exfolia- when the drug diffuses through the venous wall.
tive dermatitis, pruritus, skin rash Pregnancy Risk Factor C
Endocrine & metabolic: Acute gout attack, hyperuri- Pregnancy Considerations Animal reproduction
cemia studies have not been conducted.
Gastrointestinal: Abdominal pain, anorexia, gastric dis-
tress, nausea, vomiting Ethinyl Estradiol and Desogestrel
Hematologic & oncologic: Eosinophilia, leukopenia, (ETH in il es tra DYE ole & des oh JES trel)
lymphadenopathy, neutropenia, thrombocytopenia
Hepatic: Abnormal hepatic function tests, hepatitis, Brand Names: US Apri; Azurette; Bekyree; Caziant;
hepatotoxicity (possibly related to concurrent therapy) Cyclessa [DSC]; Cyred; Cyred EQ; Desogen [DSC];
Hypersensitivity: Anaphylaxis, anaphylactoid reaction, Emoquette; Enskyce; Isibloom; Juleber; Kariva; Kimi-
hypersensitivity reaction (syndrome includes cutane- dess [DSC]; Mircette; Ortho-Cept (28) [DSC]; Pimtrea;
ous reactions, eosinophilia, and organ-specific inflam- Reclipsen; Velivet; Viorele
mation) Brand Names: Canada Apri; Freya; Linessa; Mar-
Neuromuscular & skeletal: Arthralgia velon; Ortho-Cept; Reclipsen
Ophthalmic: Color blindness, decreased visual acuity, Pharmacologic Category Contraceptive; Estrogen
optic neuritis, scotoma, visual disturbance (usually and Progestin Combination
reversible with discontinuation; irreversible blindness Use Contraception: Prevention of pregnancy.
has been described) Local Anesthetic/Vasoconstrictor Precautions
Renal: Nephritis No information available to require special precautions
Respiratory: Pneumonitis, pulmonary infiltrates (with or Effects on Dental Treatment When prescribing anti-
without eosinophilia) biotics, patient must be warned to use additional meth-
Miscellaneous: Fever ods of birth control if on oral contraceptives.
533
ETHINYL ESTRADIOL AND DESOGESTREL

require special precautions Ethinyl Estradiol and Drospirenone
(ETH in il es tra DYE ole & droh SPYE re none)
Adverse Reactions Frequency not defined. Reactions
listed are based on reports in clinical trials or observa- Related Information
tional studies with ethinyl estradiol/desogestrel or other Endocrine Disorders and Pregnancy on page 1471
oral contraceptives. Brand Names: US Gianvi; Jasmiel; Loryna; Nikki;
Central nervous system: Depression, headache, Ocella; Syeda; Vestura [DSC]; Yasmin 28; YAZ; Zarah
migraine, mood changes Brand Names: Canada Mya; Yasmin; Yaz; Zamine;
Dermatologic: Erythema multiforme, erythema nodo- Zarah
sum, skin rash, urticaria Pharmacologic Category Contraceptive; Estrogen
Endocrine & metabolic: Decreased libido, fluid reten- and Progestin Combination
tion, increased libido, weight gain, weight loss Use
Acne vulgaris (Gianvi, Loryna, Nikki, Vestura, Yaz):
Gastrointestinal: Abdominal pain, diarrhea, nausea,
Treatment of moderate acne vulgaris in women 14
vomiting
years and older only if the patient desires an oral
Genitourinary: Breast hypertrophy, breast tenderness, contraceptive for birth control
mastalgia, vaginal discharge Contraception: Prevention of pregnancy
Hypersensitivity: Hypersensitivity reaction Premenstrual dysphoric disorder (Gianvi, Yaz):
Ophthalmic: Contact lens intolerance Treatment of premenstrual dysphoric disorder
Mechanism of Action Combination hormonal contra- (PMDD) for women who choose to use an oral contra-
ceptives inhibit ovulation via a negative feedback mech- ceptive for contraception
anism on the hypothalamus, which alters the normal Local Anesthetic/Vasoconstrictor Precautions
pattern of gonadotropin secretion of a follicle-stimulat- No information available to require special precautions
ing hormone (FSH) and luteinizing hormone by the Effects on Dental Treatment When prescribing anti-
anterior pituitary. The follicular phase FSH and midcycle biotics, patient must be warned to use additional meth-
surge of gonadotropins are inhibited. In addition, combi- ods of birth control if on oral contraceptives.
nation hormonal contraceptives produce alterations in
the genital tract, including changes in the cervical
mucus, rendering it unfavorable for sperm penetration
listed are based on reports for other agents in this same
even if ovulation occurs. Changes in the endometrium pharmacologic class (oral contraceptives) and may not
may also occur, producing an unfavorable environment be specifically reported for drospirenone/ethinyl estra-
for nidation. Combination hormonal contraceptive drugs diol.
may alter the tubal transport of the ova through the Increased risk or evidence of association with use:
fallopian tubes. Progestational agents may also alter Cardiovascular: Arterial thromboembolism, cerebral
sperm fertility. thrombosis, hypertension, local thrombophlebitis,
Pharmacodynamics/Kinetics mesenteric thrombosis, myocardial infarction, pulmo-
Half-life Elimination Monophasic preparations: Eto- nary embolism, retinal thrombosis
nogestrel: 38 ± 20 hours; Ethinyl estradiol: 26 ± 6.8 Central nervous system: Cerebral hemorrhage
hours Gastrointestinal: Gallbladder disease
Hepatic: Hepatic adenoma, hepatic neoplasm
Time to Peak Monophasic preparations: Etonogestrel:
(benign)
1.4 ± 0.8 hours; Ethinyl estradiol: 1.5 ± 0.8 hours; Time
Adverse reactions considered drug related:
to peak of etonogestrel and ethinyl estradiol varies by Cardiovascular: Edema, worsening of varicose veins
day in cycle for biphasic and triphasic preparations Central nervous system: Depression, exacerbation of
Pregnancy Considerations tics, migraine
Use is contraindicated in pregnant women. Combina- Dermatologic: Allergic skin rash, chloasma
tion hormonal contraceptives are used to prevent preg- Endocrine & metabolic: Amenorrhea, breast changes
nancy; treatment should be discontinued if pregnancy (breast hypertrophy, breast secretion, breast tender-
occurs. In general, the use of combination hormonal ness, mastalgia), decreased serum folate level,
contraceptives, when inadvertently used early in preg- exacerbation of porphyria, menstrual disease (men-
nancy, have not been associated adverse fetal or strual flow changes), weight changes
Gastrointestinal: Abdominal cramps, bloating, carbo-
maternal effects (Curtis 2016b).
hydrate intolerance, nausea, vomiting
Due to the increased risk of venous thromboembolism Genitourinary: Breakthrough bleeding, cervical ectro-
(VTE) postpartum, combination hormonal contracep- pion, cervical erosion, change in cervical secretions,
tives should not be started in any woman <21 days decreased lactation (with use immediately postpar-
following delivery. The risk decreases to baseline by tum), infertility (temporary), spotting, vulvovaginal
postpartum day 42. Use of combination hormonal con- candidiasis
Hepatic: Cholestatic jaundice
traceptives in women between 21 and 42 days after
Hypersensitivity: Anaphylaxis/anaphylactoid reaction
(including angioedema, circulatory shock, respiratory
woman's risk factors for VTE (eg, age ≥35 years, collapse, urticaria)
previous VTE, thrombophilia, immobility, preeclampsia, Neuromuscular & skeletal: Exacerbation of systemic
transfusion at delivery, cesarean delivery, peripartum lupus erythematosus
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- Ophthalmic: Change in corneal curvature (steepen-
rhage, or smoking) (Curtis 2016b). ing), contact lens intolerance
534
ETHINYL ESTRADIOL AND ETHYNODIOL DIACETATE
Adverse reactions in which association is not confirmed

or denied: Ethinyl Estradiol and Ethynodiol
Cardiovascular: Budd-Chiari syndrome Diacetate
Central nervous system: Dizziness, headache, nerv- (ETH in il es tra DYE ole & e thye noe DYE ole dye AS e tate)
ousness Related Information
Dermatologic: Acne vulgaris, erythema multiforme, Endocrine Disorders and Pregnancy on page 1471
erythema nodosum, loss of scalp hair Brand Names: US Kelnor 1/35; Kelnor 1/50; Zovia
Endocrine & metabolic: Change in libido, hirsutism, 1/35E (28); Zovia 1/50E (28) [DSC]
porphyria, premenstrual syndrome Brand Names: Canada Demulen 30
Gastrointestinal: Change in appetite, colitis, pancrea- Pharmacologic Category Contraceptive; Estrogen
titis and Progestin Combination
Genitourinary: Cystitis-like syndrome, dysmenorrhea, Use Contraception: For the prevention of pregnancy
vaginitis Limitation of use: Products containing the equivalent of
Hematologic & oncologic: Hemolytic-uremic syn- estrogen 50 mcg should not be used unless medically
drome, hemorrhagic eruption indicated.
Ophthalmic: Cataract, optic neuritis (with or without Local Anesthetic/Vasoconstrictor Precautions
partial or complete loss of vision)
Effects on Dental Treatment When prescribing anti-
Renal: Renal insufficiency biotics, patient must be warned to use additional meth-
Mechanism of Action Combination oral contracep- ods of birth control if on oral contraceptives.
tives inhibit ovulation via a negative feedback mecha- Effects on Bleeding No information available to
nism on the hypothalamus, which alters the normal require special precautions
pattern of gonadotropin secretion of a follicle-stimulat- Adverse Reactions Frequency not defined.
ing hormone (FSH) and luteinizing hormone by the Cardiovascular: Arterial thromboembolism, Budd-Chiari
anterior pituitary. The follicular phase FSH and midcycle syndrome, cerebral thrombosis, cerebrovascular acci-
surge of gonadotropins are inhibited. In addition, oral dent, edema, hypertension, local thrombophlebitis,
contraceptives produce alterations in the genital tract, mesenteric thrombosis, myocardial infarction, pulmo-
nary thromboembolism, retinal thrombosis
including changes in the cervical mucus, rendering it
Central nervous system: Cerebral hemorrhage, depres-
unfavorable for sperm penetration even if ovulation sion, dizziness, headache, migraine, nervousness
occurs. Changes in the endometrium may also occur, Dermatologic: Acne vulgaris, allergic skin rash,
producing an unfavorable environment for nidation. Oral chloasma (may persist), erythema multiforme, eryth-
contraceptive drugs may alter the tubal transport of the ema nodosum, loss of scalp hair
ova through the fallopian tubes. Progestational agents Endocrine & metabolic: Amenorrhea, change in libido,
may also alter sperm fertility. Drospirenone is a spiro- change in menstrual flow, decreased glucose toler-
nolactone analogue with antimineralocorticoid and anti- ance, decreased serum folate level, hirsutism,
androgenic activity. increased serum triglycerides, increased sex hormone
Pharmacodynamics/Kinetics binding globulins, increased thyroxine binding globu-
lin, porphyria, premenstrual syndrome, weight gain,
Half-life Elimination Terminal: Drospirenone: ~30
weight loss
hours; Ethinyl estradiol: ~24 hours Gastrointestinal: Abdominal cramps, bloating, carbohy-
Time to Peak 1 to 2 hours drate intolerance, change in appetite, cholestasis,
Pregnancy Considerations colitis, gallbladder disease, nausea, vomiting
Use is contraindicated in pregnant women. Combina- Genitourinary: Breakthrough bleeding, breast hypertro-
tion hormonal contraceptives are used to prevent preg- phy, breast secretion, breast tenderness, change in
nancy; treatment should be discontinued if pregnancy cervical erosion, change in cervical secretions, cys-
occurs. In general, the use of combination hormonal titis-like syndrome, decreased lactation (postpartum),
spotting, transient infertility (following discontinuation),
contraceptives, when inadvertently used early in preg-
vaginitis, vulvovaginal candidiasis
nancy, have not been associated adverse fetal or Hematologic & oncologic: Decreased antithrombin III
maternal effects (Curtis 2016b). plasma level, hemolytic-uremic syndrome, hemorrha-
The manufacturer states that combination hormonal gic eruption, increased clotting factor VII, increased
clotting factor VIII, increased clotting factor IX,
contraceptives should not be started until ≥4 weeks
increased clotting factor X, increased norepinephr-
after delivery in women who choose not to breastfeed, ine-induced platelet aggregation, prolonged prothrom-
or ≥4 weeks after a second trimester abortion or mis- bin time
carriage. Due to the increased risk of venous throm- Hepatic: Cholestatic jaundice, hepatic adenoma, hep-
boembolism (VTE) postpartum, combination hormonal atic neoplasm (benign), jaundice
contraceptives should not be started in any woman <21 Ophthalmic: Cataract, change in corneal curvature
days following delivery. The risk decreases to baseline (steepening), contact lens intolerance, optic neuritis
by postpartum day 42. Use of combination hormonal Renal: Renal insufficiency
contraceptives in women between 21 and 42 days after Mechanism of Action Combination hormonal contra-
ceptives inhibit ovulation via a negative feedback mech-
anism on the hypothalamus, which alters the normal
woman's risk factors for VTE (eg, age ≥35 years,
pattern of gonadotropin secretion of a follicle-stimulat-
previous VTE, thrombophilia, immobility, preeclampsia, ing hormone (FSH) and luteinizing hormone by the
transfusion at delivery, cesarean delivery, peripartum anterior pituitary. The follicular phase FSH and midcycle
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- surge of gonadotropins are inhibited. In addition, combi-
rhage, or smoking) (Curtis 2016b). nation hormonal contraceptives produce alterations in
535
ETHINYL ESTRADIOL AND ETHYNODIOL DIACETATE
the genital tract, including changes in the cervical Central nervous system: Anxiety
mucus, rendering it unfavorable for sperm penetration Gastrointestinal: Cholelithiasis
even if ovulation occurs. Changes in the endometrium <1%, postmarketing, and/or case reports: Anaphylaxis,
may also occur, producing an unfavorable environment angioedema, arterial thromboembolism, cerebrovas-
for nidation. Combination hormonal contraceptive drugs cular accident, chloasma, galactorrhea not associated
may alter the tubal transport of the ova through the with childbirth, hypersensitivity reaction, myocardial
fallopian tubes. Progestational agents may also alter infarction, toxic shock syndrome, urticaria, venous
sperm fertility. thromboembolism, worsening of varicose veins
Pregnancy Risk Factor X Mechanism of Action Combination hormonal contra-
Pregnancy Considerations ceptives inhibit ovulation via a negative feedback mech-
Use is contraindicated in pregnant women. Combina- anism on the hypothalamus, which alters the normal
tion hormonal contraceptives are used to prevent preg- pattern of gonadotropin secretion of a follicle-stimulat-
nancy; treatment should be discontinued if pregnancy ing hormone (FSH) and luteinizing hormone by the
occurs. In general, the use of combination hormonal anterior pituitary. The follicular phase FSH and midcycle
contraceptives, when inadvertently used early in preg- surge of gonadotropins are inhibited. In addition, combi-
nancy, have not been associated adverse fetal or nation hormonal contraceptives produce alterations in
maternal effects (Curtis 2016b). the genital tract, including changes in the cervical
The manufacturer states that combination hormonal
even if ovulation occurs. Changes in the endometrium
contraceptives should not be started until ≥4 to 6 weeks
may also occur, producing an unfavorable environment
after delivery in women who choose not to breastfeed.
for nidation. Combination hormonal contraceptive drugs
Due to the increased risk of venous thromboembolism
may alter the tubal transport of the ova through the
(VTE) postpartum, combination hormonal contracep-
fallopian tubes. Progestational agents may also alter
tives should not be started in any woman <21 days
sperm fertility (Rivera 1999).
following delivery. The risk decreases to baseline by
postpartum day 42. Use of combination hormonal con-
traceptives in women between 21 and 42 days after
Duration of Action Serum levels (contraceptive
effectiveness) decrease after 3 weeks of continuous
use
woman’s risk factors for VTE (eg, age ≥35 years,
previous VTE, thrombophilia, immobility, preeclampsia, Half-life Elimination Ethinyl estradiol: 45 hours; Eto-
transfusion at delivery, cesarean delivery, peripartum nogestrel: 29 hours
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- Time to Peak Vaginal: Ethinyl estradiol: 59 hours;
rhage, or smoking) (Curtis 2016b). Etonogestrel: 200 hours
Use is contraindicated in pregnant women. Combina-
Ethinyl Estradiol and Etonogestrel tion hormonal contraceptives are used to prevent preg-
(ETH in il es tra DYE ole & et oh noe JES trel)
nancy; treatment should be discontinued if pregnancy
Related Information occurs. In general, the use of combination hormonal
Endocrine Disorders and Pregnancy on page 1471 contraceptives, when inadvertently used early in preg-
Etonogestrel on page 548 nancy, have not been associated adverse fetal or
Brand Names: US NuvaRing maternal effects (Curtis 2016b).
Brand Names: Canada NuvaRing The manufacturer states that combination hormonal
Pharmacologic Category Contraceptive; Estrogen contraceptives should not be started until ≥4 weeks
and Progestin Combination after delivery in women who choose not to breastfeed,
Use Contraception: Prevention of pregnancy. or ≥4 weeks after a second trimester abortion or mis-
Local Anesthetic/Vasoconstrictor Precautions carriage. Due to the increased risk of venous throm-
No information available to require special precautions boembolism (VTE) postpartum, combination hormonal
Effects on Dental Treatment When prescribing anti- contraceptives should not be started in any woman <21
biotics, patient must be warned to use additional meth- days following delivery. The risk decreases to baseline
ods of birth control if on oral contraceptives. by postpartum day 42. Use of combination hormonal
Effects on Bleeding No information available to contraceptives in women between 21 and 42 days after
require special precautions delivery should take into consideration the individual
Adverse Reactions woman's risk factors for VTE (eg, age ≥35 years,
>10%: previous VTE, thrombophilia, immobility, preeclampsia,
Central nervous system: Headache (11%) transfusion at delivery, cesarean delivery, peripartum
Endocrine & metabolic: Intermenstrual bleeding (7% cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor-
to 12%) rhage, smoking) (Curtis 2016b).
Genitourinary: Vaginitis (14%)
1% to 10%: Ethinyl Estradiol and Levonorgestrel
Central nervous system: Mood changes (6%) (ETH in il es tra DYE ole & LEE voe nor jes trel)
Dermatologic: Acne vulgaris (2%)
Endocrine & metabolic: Weight gain (5%), amenor- Related Information
rhea (≤4%), decreased libido (2%) Endocrine Disorders and Pregnancy on page 1471
Gastrointestinal: Nausea (≤6%), vomiting (≤6%), Brand Names: US Altavera; Amethia; Amethia Lo;
abdominal pain (3%) Amethyst; Ashlyna; Aubra; Aubra EQ; Aviane; Balcol-
Genitourinary: Vaginal discharge (6%), dysmenorrhea tra; Camrese; Camrese Lo; Chateal; Chateal EQ; Day-
(4%), vaginal discomfort (4%), breast tenderness see; Delyla; Enpresse-28; FaLessa; Falmina; Fayosim;
(≤4%), mastalgia (≤4%) Introvale; Jolessa; Kurvelo; Larissia; Lessina; Levonest;
Frequency not defined: Levora 0.15/30 (28); Lillow; LoSeasonique; Lutera;
Cardiovascular: Deep vein thrombosis Marlissa; Myzilra; Orsythia; Portia-28; Quartette;
536
ETHINYL ESTRADIOL AND LEVONORGESTREL
Quasense [DSC]; Rivelsa; Seasonique; Setlakin; Sro- Adverse reactions in which association is not confirmed
nyx; Trivora (28); Vienva or denied:
Brand Names: Canada Alesse; Alysena; Aviane; Cardiovascular: Budd-Chiari syndrome
Esme; Lutera; Min-Ovral; Ovima; Portia; Seasonale; Central nervous system: Dizziness, headache, nerv-
Seasonique; Triquilar ousness
Pharmacologic Category Contraceptive; Estrogen Dermatologic: Acne vulgaris, erythema multiforme,
and Progestin Combination erythema nodosum, loss of scalp hair
Use Endocrine & metabolic: Change in libido, hirsutism,
Contraception: Prevention of pregnancy. premenstrual syndrome
Emergency contraception: Postcoital emergency Gastrointestinal: Colitis, pancreatitis
contraception. Genitourinary: Abnormal Pap smear, cystitis-like syn-
Limitations of use: Ethinyl estradiol in combination drome, dysmenorrhea
with levonorgestrel is effective and recommended Hematologic & oncologic: Hemolytic-uremic syn-
as an alternative method for the management of drome, hemorrhagic eruption
emergency contraception when other methods are Ophthalmic: Cataract, optic neuritis (with or without
not available. The use of other methods is preferred partial or complete loss of vision)
due to increased side effects and decreased efficacy Otic: Auditory disturbance
observed with this combination (AAP 2012; Renal: Renal insufficiency
ACOG 2015)
Mechanism of Action Combination hormonal contra-
Local Anesthetic/Vasoconstrictor Precautions ceptives inhibit ovulation via a negative feedback mech-
Effects on Dental Treatment When prescribing anti- pattern of gonadotropin secretion of a follicle-stimulat-
biotics, patient must be warned to use additional meth-
ing hormone (FSH) and luteinizing hormone by the
ods of birth control if on oral contraceptives.
anterior pituitary. The follicular phase FSH and midcycle
surge of gonadotropins are inhibited. In addition, combi-
nation hormonal contraceptives produce alterations in
the genital tract, including changes in the cervical
listed are based on reports for other agents in this same
pharmacologic class (oral contraceptives) and may not
be specifically reported for ethinyl estradiol/levonorges- even if ovulation occurs. Changes in the endometrium
trel. may also occur, producing an unfavorable environment
Increased risk or evidence of association with use: for nidation. Combination hormonal contraceptive drugs
Cardiovascular: Arterial thromboembolism, cerebral may alter the tubal transport of the ova through the
thrombosis, hypertension, local thrombophlebitis, fallopian tubes. Progestational agents may also alter
mesenteric thrombosis, myocardial infarction, pulmo- sperm fertility.
nary embolism, retinal thrombosis, venous thrombo- Pharmacodynamics/Kinetics
sis (with or without embolism) Half-life Elimination Ethinyl estradiol: 12-23 hours;
Central nervous system: Cerebral hemorrhage Levonorgestrel: 22-49 hours
Gastrointestinal: Gallbladder disease Pregnancy Risk Factor X
Hepatic: Hepatic adenoma, hepatic neoplasm Pregnancy Considerations
(benign) Use is contraindicated in pregnant women. Combina-
Adverse reactions considered drug related: tion hormonal contraceptives are used to prevent preg-
Cardiovascular: Edema, worsening of varicose veins nancy; treatment should be discontinued if pregnancy
Central nervous system: Depression, exacerbation of occurs. In general, the use of combination hormonal
tics, migraine, mood changes contraceptives, when inadvertently used early in preg-
Dermatologic: Allergic skin rash, chloasma nancy, have not been associated adverse fetal or
Endocrine & metabolic: Amenorrhea, breast changes maternal effects (Curtis 2016b).
(breast hypertrophy, breast secretion, breast tender-
ness, mastalgia), carbohydrate intolerance, Some manufacturers recommend waiting at least 4 to 6
decreased lactation (with use immediately postpar- weeks postpartum before starting this combination. Due
tum), decreased serum folate level, exacerbation of to the increased risk of venous thromboembolism (VTE)
porphyria, fluid retention, menstrual disease (men- postpartum, combination hormonal contraceptives
strual flow changes), weight changes should not be started in any woman <21 days following
Gastrointestinal: Abdominal cramps, abdominal pain, delivery. The risk decreases to baseline by postpartum
bloating, change in appetite, nausea, vomiting day 42. Use of combination hormonal contraceptives in
Genitourinary: Breakthrough bleeding, cervical ectro- women between 21 and 42 days after delivery should
pion, cervical erosion, change in cervical secretions, take into consideration the individual woman's risk
endocervical hyperplasia, infertility (temporary), factors for VTE (eg, age ≥35 years, previous VTE,
spotting, vulvovaginal candidiasis, vaginitis thrombophilia, immobility, preeclampsia, transfusion at
Hematologic & oncologic: Uterine fibroid enlargement delivery, cesarean delivery, peripartum cardiomyopathy,
Hepatic: Cholestatic jaundice, hepatic focal nodular BMI ≥30 kg/m2, postpartum hemorrhage, smoking)
hyperplasia (Curtis 2016b).
Hypersensitivity: Anaphylaxis/Anaphylactoid reaction
(including angioedema, circulatory shock, respiratory When used for emergency contraception, a barrier
collapse, urticaria) contraceptive is recommended immediately following
Neuromuscular & skeletal: Exacerbation of systemic use. Any regular (nonemergency) contraceptive method
lupus erythematosus can be started immediately after combined estrogen/
Ophthalmic: Change in corneal curvature (steepen- progestin emergency contraception; however, a barrier
ing), contact lens intolerance method (or abstinence from sexual intercourse) is also
Respiratory: Rhinitis needed for 7 days (ACOG 2015; Curtis 2016a).
537
ETHINYL ESTRADIOL AND NORELGESTROMIN
skin photosensitivity, skin rash, thrombosis, urticaria,

Ethinyl Estradiol and Norelgestromin uterine fibroids
(ETH in il es tra DYE ole & nor el JES troe min) Mechanism of Action Combination hormonal contra-
Brand Names: US Ortho Evra [DSC]; Xulane ceptives inhibit ovulation via a negative feedback mech-
Brand Names: Canada Evra
pattern of gonadotropin secretion of a follicle-stimulat-
Pharmacologic Category Contraceptive; Estrogen ing hormone (FSH) and luteinizing hormone by the
anterior pituitary. The follicular phase FSH and midcycle
Use surge of gonadotropins are inhibited. In addition, combi-
Contraception: For the prevention of pregnancy nation hormonal contraceptives produce alterations in
Limitations of use: The topical patch may be less the genital tract, including changes in the cervical
effective in patients weighing ≥90 kg. mucus, rendering it unfavorable for sperm penetration
Local Anesthetic/Vasoconstrictor Precautions even if ovulation occurs. Changes in the endometrium
No information available to require special precautions may also occur, producing an unfavorable environment
Effects on Dental Treatment When prescribing anti- for nidation. Combination hormonal contraceptive drugs
biotics, patient must be warned to use additional meth- may alter the tubal transport of the ova through the
ods of birth control if on oral contraceptives. fallopian tubes. Progestational agents may also alter
Effects on Bleeding No information available to sperm fertility.
require special precautions Pharmacodynamics/Kinetics
Adverse Reactions The following reactions have been Half-life Elimination Topical: Ethinyl estradiol: ~17
reported with the contraceptive patch. Adverse reac- hours; Norelgestromin: ~28 hours
tions associated with oral combination hormonal contra- Pregnancy Considerations
ceptive agents are also likely to appear with the topical Use is contraindicated in pregnant women. Combina-
contraceptive patch (frequency difficult to anticipate). tion hormonal contraceptives are used to prevent preg-
See individual oral contraceptive monographs for addi- nancy; treatment should be discontinued if pregnancy
tional information. occurs. In general, the use of combination hormonal
>10%: contraceptives, when inadvertently used early in preg-
Central nervous system: Headache (21%) nancy, have not been associated with adverse fetal or
Endocrine & metabolic: Breast changes (22%; includ- maternal effects (Curtis 2016b).
ing breast engorgement, discomfort, mastalgia) The manufacturer states that combination hormonal
Gastrointestinal: Nausea (17%) contraceptives should not be started until ≥4 weeks
Local: Application site reaction (17%) after delivery in women who choose not to breastfeed,
1% to 10%:
or ≥4 weeks after a second trimester abortion or mis-
Cardiovascular: Increased blood pressure (<3%), pul-
carriage. Due to the increased risk of venous throm-
monary embolism (<3%)
boembolism (VTE) postpartum, combination hormonal
Central nervous system: Anxiety (≤6%), mood disor-
contraceptives should not be started in any woman <21
der (≤6%), dizziness (3%), fatigue (3%), migraine
days following delivery. The risk decreases to baseline
(3%), insomnia (<3%), malaise (<3%)
by postpartum day 42. Use of combination hormonal
Dermatologic: Acne vulgaris (3%), pruritus (3%),
contraceptives in women between 21 and 42 days after
chloasma (<3%), contact dermatitis (<3%), erythema
(<3%), skin irritation (<3%)
woman's risk factors for VTE (eg, age ≥35 years,
Endocrine & metabolic: Menstrual disease (6%),
previous VTE, thrombophilia, immobility, preeclampsia,
weight gain (3%), change in libido (<3%), dyslipide-
transfusion at delivery, cesarean delivery, peripartum
mia (<3%), fluid retention (<3%), galactorrhea (<3%),
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor-
premenstrual syndrome (<3%)
rhage, smoking) (Curtis 2016b).
Gastrointestinal: Abdominal pain (8%), vomiting (5%),
diarrhea (4%), abdominal distention (<3%), chole-
cystitis (<3%) Ethinyl Estradiol and Norethindrone
Genitourinary: Dysmenorrhea (8%), vaginal hemor- (ETH in il es tra DYE ole & nor eth IN drone)
rhage (6%), vulvovaginal candidiasis (4%), genital
discharge (<3%), uterine spasm (<3%), vaginal dry- Related Information
ness (<3%), vulvar dryness (<3%) Endocrine Disorders and Pregnancy on page 1471
Neuromuscular & skeletal: Muscle spasm (<3%) Norethindrone on page 981
<1%, postmarketing, and/or case reports: Alopecia, Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
altered serum glucose, arterial thrombosis, benign on page 1484
mammary fibroadenoma, blood cholesterol abnormal, Brand Names: US Alyacen 1/35; Alyacen 7/7/7; Ara-
cerebrovascular accident, cervical dysplasia, choleli- nelle; Aurovela 24 FE; Balziva; Blisovi 24 Fe; Blisovi Fe
thiasis, cholestasis, cholestatic jaundice, colitis, con- 1.5/30; Blisovi FE 1/20; Brevicon (28) [DSC]; Briellyn;
tact lens intolerance (or complication), decreased Cyclafem 1/35; Cyclafem 7/7/7; Dasetta 1/35; Dasetta
lactation, deep vein thrombosis, dermatological reac- 7/7/7; Estrostep Fe; Femcon Fe [DSC]; Femhrt Low
tion, dysgeusia, eczema, edema, emotional disturb- Dose; Fyavolv; Generess FE; Gildagia [DSC]; Gildess
ance, erythema multiforme, erythema nodosum, 1.5/30 [DSC]; Gildess 1/20 [DSC]; Gildess 24 FE
hepatic adenoma, hepatic neoplasm, hyperglycemia, [DSC]; Gildess FE 1.5/30 [DSC]; Gildess FE 1/20
hyperirritability, hypersensitivity reaction, hyperten- [DSC]; Hailey 24 Fe; Jevantique Lo [DSC]; Jinteli; Junel
sion, hypertensive crisis, increased appetite, 1.5/30; Junel 1/20; Junel FE 1.5/30; Junel FE 1/20;
increased LDL cholesterol, insulin resistance, intra- Junel Fe 24; Kaitlib Fe; Larin 1.5/30; Larin 1/20; Larin
cranial hemorrhage, irritability, lesion (hepatic), malig- 24 FE; Larin Fe 1.5/30; Larin Fe 1/20; Layolis FE;
nant neoplasm of breast, malignant neoplasm of Leena; Lo Loestrin Fe; Loestrin 1.5/30 (21); Loestrin
cervix, mass (breast), migraine (with aura), myocardial 1/20 (21); Loestrin Fe 1.5/30; Loestrin Fe 1/20; Lomedia
infarction, outbursts of anger, seborrheic dermatitis, 24 FE [DSC]; Melodetta 24 Fe; Mibelas 24 Fe;
538
ETHINYL ESTRADIOL AND NORETHINDRONE
Microgestin 1.5/30; Microgestin 1/20; Microgestin 24 Fe 1% to 10%:

[DSC]; Microgestin FE 1.5/30; Microgestin FE 1/20; Central nervous system: Headache (≤8%), migraine
Minastrin 24 Fe; Modicon (28) [DSC]; Necon 0.5/35 (≤8%), depression (≤4%), mood changes (≤4%),
(28); Necon 1/35 (28) [DSC]; Necon 10/11 (28) [DSC]; mood disorder (≤3%), anxiety (≤2%)
Necon 7/7/7 [DSC]; Norinyl 1+35 (28) [DSC]; Nortrel Dermatologic: Acne vulgaris (3%)
0.5/35 (28); Nortrel 1/35 (21); Nortrel 1/35 (28); Nortrel Endocrine & metabolic: Heavy menstrual bleeding
7/7/7; Ortho-Novum 1/35 (28); Ortho-Novum 7/7/7 (28); (≤5%), weight changes (4%), weight gain (2%)
Ovcon-35 (28) [DSC]; Philith; Pirmella 1/35; Pirmella Gastrointestinal: Nausea (≤9%), vomiting (≤9%),
7/7/7; Tarina 24 Fe; Tarina FE 1/20; Tarina FE 1/20 EQ; abdominal pain (3%)
Taytulla; Tilia Fe; Tri-Legest Fe; Tri-Norinyl (28); Genitourinary: Vulvovaginal candidiasis (6%), abnor-
Vyfemla; Wera; Wymzya Fe; Zenchent FE [DSC]; Zen- mal uterine bleeding (≤5%), irregular menses
chent [DSC] (≤5%), vaginal hemorrhage (≤5%), dysmenorrhea
Brand Names: Canada Brevicon 0.5/35; Brevicon (4%), uterine cramps (4%), abnormal cervical or
1/35; FemHRT; Loestrin 1.5/30; Lolo; Minestrin 1/20; vaginal Papanicolaou smear (3%), bacterial vagi-
Ortho 0.5/35; Ortho 1/35; Ortho 7/7/7; Select 1/35; nosis (3%), breast tenderness (≤3%), mastal-
Synphasic gia (≤2%)
Cardiovascular: Hypertension
Endocrine & metabolic: Decreased libido
Use
Acne vulgaris (Estrostep Fe, Tilia Fe, Tri-Legest Fe):
cramps, abnormal sensory symptoms, allergic skin
Treatment of moderate acne vulgaris in females at
rash, alopecia, altered serum glucose, anaphylaxis,
least 15 years.
anemia, angina pectoris, angioedema, arthralgia, back
Limitations of use: When used for acne, use only in
pain, benign breast nodule, bipolar mood disorder,
females ≥15 years who have achieved menarche,
bloating, blurred vision, breast changes, breast dis-
who also desire combination hormonal contraceptive ease, breast hypertrophy, breast secretion, burning
therapy, are unresponsive to topical treatments, have sensation of skin, cerebral embolism, cerebral throm-
no contraindications to combination hormonal con- bosis, cerebrovascular accident, change in appetite,
traceptive use, and plan to stay on therapy for ≥6 change in cervical ectropion, change in cervical secre-
months. tions, change in corneal curvature (steepening),
Contraception: Prevention of pregnancy. change in libido, chest pain, chloasma, cholecystitis,
Limitations of use: The efficacy of some products has cholelithiasis, cholestatic jaundice, chorea, constipa-
not been established in women with a BMI >35 tion, contact lens intolerance, corneal thinning, coro-
kg/m2. nary thrombosis, cystitis-like syndrome, deep vein
Osteoporosis prevention (female) (femhrt, Jevan- thrombosis, dementia, diabetes mellitus, dissociative
tique Lo, Jinteli): Prevention of postmenopausal reaction, dizziness, drowsiness, dyspnea, dysuria,
osteoporosis. embolism, endometrial carcinoma, erythema, eryth-
Limitations of use: For use only in women at significant ema multiforme, erythema nodosum, exacerbation of
risk of postmenopausal osteoporosis; consider use asthma, exacerbation of epilepsy, exacerbation of
of nonestrogen medications. hepatic hemangioma, exacerbation of porphyria, facial
Vasomotor symptoms associated with menopause swelling, fatigue, fibrocystic breast changes, fungal
(femhrt, Jevantique Lo, Jinteli): Treatment of mod- infection, galactorrhea not associated with childbirth,
erate to severe vasomotor symptoms associated with gallbladder disease, hemangioma (hepatic), hemipa-
menopause. resis, hemorrhagic eruption, hepatic adenoma, hirsut-
Local Anesthetic/Vasoconstrictor Precautions ism, homicidal ideation, hot flash, hyperesthesia,
No information available to require special precautions hypersensitivity reaction, hyperthyroidism, hypocalce-
Effects on Dental Treatment When prescribing anti- mia, hypoesthesia, hypoglycemia, hypothyroidism,
biotics, patient must be warned to use additional meth- impaired glucose tolerance/prediabetes, increased
ods of birth control if on oral contraceptives. blood pressure, increased serum triglycerides, insom-
Effects on Bleeding No information available to nia, irregular pulse, irritability, ischemic stroke, local-
require special precautions ized edema (pelvic), loss of consciousness, loss of
scalp hair, lower limb cramp, malaise, malignant neo-
Adverse Reactions
plasm of breast, malignant neoplasm of ovary, malig-
Menopausal vasomotor symptoms and osteoporo-
nant neoplasm of uterus, myalgia, myocardial
sis prevention:
infarction, nervousness, night sweats, nipple dis-
>10%: Endocrine & metabolic: Increased sex hor-
charge, nipple pain, nonimmune anaphylaxis, ovarian
mone binding globulin (22%)
cyst, palpitations, pancreatitis, panic attack, paresthe-
1% to 10%: sia, pelvic pain, peripheral edema, pollakiuria, pre-
Cardiovascular: Edema (5%) menstrual syndrome, pruritus, pulmonary embolism,
Central nervous system: Headache (6%) retinal thrombosis, rupture of ovarian cyst, skin dis-
Gastrointestinal: Abdominal pain (5% to 7%) coloration, skin rash, suicidal ideation, superficial
Genitourinary: Mastalgia (8% to 9%), endometrial venous thrombosis, swelling of lips, tachycardia,
hyperplasia (≤1%) thrombophlebitis, thrombosis (including ovarian), tran-
Contraception and Acne: sient blindness, transient ischemic attacks, urticaria,
>10%: uterine fibroid enlargement, uterine hypertrophy, vag-
Endocrine & metabolic: Change in menstrual flow inal infection, vaginitis, visual impairment, weight loss
(including absence of withdrawal bleeding: 31% to
Mechanism of Action Combination oral contracep-
41%), amenorrhea (8% to 36%) tives inhibit ovulation via a negative feedback mecha-
Genitourinary: Breakthrough bleeding (≤86%), spot- nism on the hypothalamus, which alters the normal
ting (≤86%)
539
ETHINYL ESTRADIOL AND NORETHINDRONE
pattern of gonadotropin secretion of a follicle-stimulat- Limitations of use: When used for acne, use only in
ing hormone (FSH) and luteinizing hormone by the females ≥15 years of age who achieved menarche,
anterior pituitary. The follicular phase FSH and midcycle who also desire combination hormonal contraceptive
surge of gonadotropins are inhibited. In addition, combi- therapy, and have no contraindications to combina-
nation hormonal contraceptives produce alterations in tion hormonal contraceptive use
the genital tract, including changes in the cervical Contraception: Prevention of pregnancy.
mucus, rendering it unfavorable for sperm penetration Local Anesthetic/Vasoconstrictor Precautions
even if ovulation occurs. Changes in the endometrium No information available to require special precautions
may also occur, producing an unfavorable environment Effects on Dental Treatment When prescribing anti-
for nidation. Combination hormonal contraceptive drugs biotics, patient must be warned to use additional meth-
may alter the tubal transport of the ova through the ods of birth control if on oral contraceptives.
fallopian tubes. Progestational agents may also alter Effects on Bleeding No information available to
sperm fertility. require special precautions
In postmenopausal women, exogenous estrogen is
Adverse Reactions
used to replace decreased endogenous production. >10%:
Central nervous system: Headache (≤34%),
The addition of progestin reduces the incidence of
migraine (≤34%)
endometrial hyperplasia and risk of endometrial cancer
Gastrointestinal: Nausea (≤16%), vomiting (≤16%)
in women with an intact uterus.
Pharmacodynamics/Kinetics Genitourinary: Breakthrough bleeding (7% to 38%)
1% to 10%:
Half-life Elimination Ethinyl estradiol: 19 to 24 hours
Central nervous system: Nipple pain (≤10%), depres-
Pregnancy Risk Factor X sion (≤8%), emotional lability (≤8%), mood changes
Pregnancy Considerations (≤8%), mood disorder (≤8%), nervousness (3%),
Use is contraindicated in pregnant women. Combina- fatigue (2%)
tion hormonal contraceptives are used to prevent preg- Dermatologic: Acne vulgaris (5%), skin rash (3%)
nancy; treatment should be discontinued if pregnancy Endocrine & metabolic: Menstrual disease (≤9%),
occurs. In general, the use of combination hormonal weight changes (≤3%), weight gain (≤3%), weight
contraceptives, when inadvertently used early in preg- loss (≤3%)
nancy, have not been associated adverse fetal or Gastrointestinal: Abdominal pain (≤9%), gastrointesti-
maternal effects (Curtis 2016b). nal pain (≤8%), abdominal distention (3%), flatu-
The manufacturer states that combination hormonal lence (3%)
contraceptives should not be started until ≥4 weeks Genitourinary: Breast cyst (≤10%), breast hypertrophy
after delivery in women who choose not to breastfeed. (≤10%), breast swelling (≤10%), breast tenderness
Due to the increased risk of venous thromboembolism (≤10%), mastalgia (≤10%), nipple discharge (≤10%),
(VTE) postpartum, combination hormonal contracep- dysmenorrhea (≤9%), vaginal infection (7% to 8%),
tives should not be started in any woman <21 days genital discharge (3% to 7%), vulvovaginal infec-
following delivery. The risk decreases to baseline by tion (4%)
postpartum day 42. Use of combination hormonal con- Frequency not defined:
traceptives in women between 21 and 42 days after Cardiovascular: Hypertension, venous thromboemb-
delivery should take into consideration the individual olism
woman's risk factors for VTE (eg, age ≥35 years, Central nervous system: Irritability
previous VTE, thrombophilia, immobility, preeclampsia, Endocrine & metabolic: Amenorrhea, premenstrual
transfusion at delivery, cesarean delivery, peripartum syndrome
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- Genitourinary: Abnormal uterine bleeding, cervical
rhage, smoking) (Curtis 2016b). carcinoma (in situ), cervical dysplasia
<1%, postmarketing, and/or case reports: Angioedema,
Dental Health Professional Considerations Cur-
anxiety, arterial thromboembolism, asthenia, back
rent hormone contraceptives should not be considered
pain, breast neoplasm (benign), cerebrovascular acci-
a risk factor for gingival or periodontal disease (Pre-
dent, chest pain, constipation, contact lens intoler-
shaw 2013).
ance, deep vein thrombosis, diarrhea, dizziness,
dyslipidemia, dyspnea, erythema nodosum, hepatic
Ethinyl Estradiol and Norgestimate adenoma, hepatic focal nodular hyperplasia, hepatitis,
(ETH in il es tra DYE ole & nor JES ti mate) hirsutism, hot flash, hyperhidrosis, hypersensitivity
reaction, insomnia, lactation insufficiency, limb pain,
Related Information malignant neoplasm of breast, muscle spasm, myal-
Endocrine Disorders and Pregnancy on page 1471 gia, myocardial infarction, night sweats, ovarian cyst,
Brand Names: US Estarylla; Femynor; Mili; Mono- palpitations, pancreatitis, paresthesia, pruritus, pulmo-
Linyah; MonoNessa; Ortho Tri-Cyclen (28); Ortho Tri- nary embolism, retinal thrombosis, seizure, skin pho-
Cyclen Lo; Ortho-Cyclen (28); Previfem; Sprintec 28; Tri tosensitivity, syncope, tachycardia, urinary tract
Femynor; Tri-Estarylla; Tri-Linyah; Tri-Lo-Estarylla; Tri- infection, urticaria, vaginal dryness, vertigo, visual
Lo-Marzia; Tri-Lo-Sprintec; Tri-Mili; Tri-Previfem; Tri- impairment, vulvar dryness, xerophthalmia
Sprintec; Tri-VyLibra; Tri-VyLibra Lo; TriNessa (28) Mechanism of Action Combination hormonal contra-
[DSC]; TriNessa Lo [DSC]; VyLibra ceptives inhibit ovulation via a negative feedback mech-
Brand Names: Canada Cyclen; Tri-Cyclen; Tri-Cyclen anism on the hypothalamus, which alters the normal
Lo; Tricira Lo pattern of gonadotropin secretion of a follicle-stimulat-
Pharmacologic Category Contraceptive; Estrogen ing hormone (FSH) and luteinizing hormone by the
and Progestin Combination anterior pituitary. The follicular phase FSH and midcycle
Use surge of gonadotropins are inhibited. In addition, combi-
Acne vulgaris: Treatment of moderate acne vulgaris in nation hormonal contraceptives produce alterations in
females at least 15 years of age the genital tract, including changes in the cervical
540
ETHINYL ESTRADIOL AND NORGESTREL
mucus, rendering it unfavorable for sperm penetration level, hirsutism, increased serum triglycerides,
even if ovulation occurs. Changes in the endometrium increased sex hormone binding globulin, increased
may also occur, producing an unfavorable environment thyroxine binding globulin, menstrual disease (flow
for nidation. Combination hormonal contraceptive drugs changes), porphyria, premenstrual syndrome, weight
may alter the tubal transport of the ova through the gain, weight loss
fallopian tubes. Progestational agents may also alter Gastrointestinal: Abdominal cramps, bloating, carbohy-
sperm fertility. drate intolerance, change in appetite, cholestasis,
Pharmacodynamics/Kinetics colitis, gallbladder disease, nausea, vomiting
Half-life Elimination EE: 10-16 hours; NGMN: 18-25 Genitourinary: Breakthrough bleeding, breast hypertro-
hours; NG: 38-45 hours phy, breast secretion, breast tenderness, change in
Time to Peak EE and NGM: ~2 hours cervical erosion, change in cervical secretions, cys-
Pregnancy Considerations titis-like syndrome, decreased lactation (postpartum),
Use is contraindicated in pregnant women. Combina- spotting, transient infertility (following discontinuation),
tion hormonal contraceptives are used to prevent preg- vaginitis, vulvovaginal candidiasis
nancy; treatment should be discontinued if pregnancy Hematologic & oncologic: Decreased antithrombin III
occurs. In general, the use of combination hormonal plasma level, hemolytic-uremic syndrome, hemorrha-
contraceptives, when inadvertently used early in preg- gic eruption, increased clotting factor VII, increased
nancy, have not been associated adverse fetal or clotting factor VIII, increased clotting factor IX,
maternal effects (Curtis 2016b). increased clotting factor X, increased norepinephr-
The manufacturer states that combination hormonal ine-induced platelet aggregation, prolonged prothrom-
contraceptives should not be started until ≥4 weeks bin time
after delivery in women who choose not to breastfeed. Hepatic: Cholestatic jaundice, hepatic adenoma, hep-
Due to the increased risk of venous thromboembolism atic neoplasm (benign), jaundice
(VTE) postpartum, combination hormonal contracep- Ophthalmic: Cataract, change in corneal curvature
tives should not be started in any woman <21 days (steepening), contact lens intolerance, optic neuritis
following delivery. The risk decreases to baseline by Renal: Renal insufficiency
postpartum day 42. Use of combination hormonal con- Mechanism of Action Combination hormonal contra-
traceptives in women between 21 and 42 days after ceptives inhibit ovulation via a negative feedback mech-
delivery should take into consideration the individual anism on the hypothalamus, which alters the normal
woman's risk factors for VTE (eg, age ≥35 years, pattern of gonadotropin secretion of a follicle-stimulat-
previous VTE, thrombophilia, immobility, preeclampsia, ing hormone (FSH) and luteinizing hormone by the
transfusion at delivery, cesarean delivery, peripartum anterior pituitary. The follicular phase FSH and midcycle
cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor- surge of gonadotropins are inhibited. In addition, combi-
rhage, smoking) (Curtis 2016b). nation hormonal contraceptives produce alterations in
Dental Health Professional Considerations Cur- the genital tract, including changes in the cervical
rent hormone contraceptives should not be considered mucus, rendering it unfavorable for sperm penetration
a risk factor for gingival or periodontal disease (Pre- even if ovulation occurs. Changes in the endometrium
shaw, 2013). may also occur, producing an unfavorable environment
for nidation. Combination hormonal contraceptive drugs
Ethinyl Estradiol and Norgestrel may alter the tubal transport of the ova through the
(ETH in il es tra DYE ole & nor JES trel) fallopian tubes. Progestational agents may also alter
sperm fertility.
Related Information Pregnancy Risk Factor X
Endocrine Disorders and Pregnancy on page 1471 Pregnancy Considerations
Brand Names: US Cryselle-28; Elinest; Low-Ogestrel; Use is contraindicated in pregnant women. Combina-
Ogestrel tion hormonal contraceptives are used to prevent preg-
Pharmacologic Category Contraceptive; Estrogen nancy; treatment should be discontinued if pregnancy
and Progestin Combination occurs. In general, the use of combination hormonal
Use Contraception: Prevention of pregnancy contraceptives, when inadvertently used early in preg-
Local Anesthetic/Vasoconstrictor Precautions nancy, have not been associated adverse fetal or
No information available to require special precautions maternal effects (Curtis 2016b).
Effects on Dental Treatment When prescribing anti-
biotics, patient must be warned to use additional meth- The manufacturer states that combination hormonal
ods of birth control if on oral contraceptives. contraceptives should not be started until ≥4 to 6 weeks
Effects on Bleeding No information available to after delivery in women who choose not to breastfeed.
require special precautions Due to the increased risk of venous thromboembolism
Adverse Reactions Frequency not defined. (VTE) postpartum, combination hormonal contracep-
Cardiovascular: Arterial thromboembolism, Budd-Chiari tives should not be started in any woman <21 days
syndrome, cerebral thrombosis, cerebrovascular acci- following delivery. The risk decreases to baseline by
dent, edema, hypertension, local thrombophlebitis, postpartum day 42. Use of combination hormonal con-
mesenteric thrombosis, myocardial infarction, pulmo- traceptives in women between 21 and 42 days after
nary thromboembolism, retinal thrombosis delivery should take into consideration the individual
Central nervous system: Cerebral hemorrhage, depres- woman's risk factors for VTE (eg, age ≥35 years,
sion, dizziness, headache, migraine, nervousness previous VTE, thrombophilia, immobility, preeclampsia,
Dermatologic: Acne vulgaris, allergic skin rash, transfusion at delivery, cesarean delivery, peripartum
chloasma (may persist), erythema multiforme, eryth- cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor-
ema nodosum, loss of scalp hair rhage, smoking) (Curtis 2016b).
Endocrine & metabolic: Amenorrhea, change in libido, Dental Health Professional Considerations Cur-
decreased glucose tolerance, decreased serum folate rent hormone contraceptives should not be considered
541
ETHINYL ESTRADIOL AND NORGESTREL
a risk factor for gingival or periodontal disease (Pre- producing an unfavorable environment for nidation. Oral
shaw, 2013). contraceptive drugs may alter the tubal transport of the
ova through the fallopian tubes. Progestational agents
may also alter sperm fertility. Drospirenone is a spiro-
Ethinyl Estradiol, Drospirenone, and nolactone analogue with antimineralocorticoid and anti-
Levomefolate androgenic activity.
(ETH in il es tra DYE ole, droh SPYE re none, & lee voe me FOE Pharmacodynamics/Kinetics
late)
Half-life Elimination Terminal: Drospirenone: ~31
Related Information hours; Ethinyl estradiol: ~24 hours; levomefolate cal-
Endocrine Disorders and Pregnancy on page 1471 cium: ~4-5 hours
Brand Names: US Beyaz; Rajani [DSC]; Safyral; Time to Peak Drospirenone, ethinyl estradiol: 1-2
Tydemy hours; Levomefolate calcium: 0.5-1.5 hours
Brand Names: Canada Yasmin Plus; Yaz Plus Pregnancy Considerations
Use is contraindicated in pregnant women. Combina-
tion hormonal contraceptives are used to prevent preg-
nancy; treatment should be discontinued if pregnancy
Use
occurs. In general, the use of combination hormonal
Acne vulgaris (Beyaz, Rajani): Treatment of moderate
acne vulgaris in women 14 years and older who have
nancy, have not been associated adverse fetal or
achieved menarche and who desire an oral contra- maternal effects (Curtis 2016b). The addition of levo-
ceptive for birth control. mefolate in this product is intended to decrease the risk
Contraception: Prevention of pregnancy. of neural tube defects if pregnancy inadvertently occurs
Folate supplementation: To increase folate concen- during therapy or shortly after discontinuation.
trations in women choosing an oral contraceptive for
birth control, in order to reduce the risk of neural tube The manufacturer states that combination hormonal
defects in pregnancies conceived during therapy or contraceptives should not be started until ≥4 weeks
soon after treatment is discontinued. after delivery in women who choose not to breastfeed,
Premenstrual dysphoric disorder (Beyaz, Rajani): or ≥4 weeks after a second trimester abortion or mis-
Treatment of symptoms of premenstrual dysphoric carriage. Due to the increased risk of venous throm-
disorder (PMDD) in women who choose to use an boembolism (VTE) postpartum, combination hormonal
oral contraceptive for contraception. contraceptives should not be started in any woman <21
Limitations of use: The effectiveness of use for more days following delivery. The risk decreases to baseline
than 3 menstrual cycles has not been evaluated. Has by postpartum day 42. Use of combination hormonal
not been evaluated for the treatment of premenstrual contraceptives in women between 21 and 42 days after
syndrome (PMS). delivery should take into consideration the individual
Local Anesthetic/Vasoconstrictor Precautions woman's risk factors for VTE (eg, age ≥35 years,
No information available to require special precautions previous VTE, thrombophilia, immobility, preeclampsia,
Effects on Dental Treatment When prescribing anti- transfusion at delivery, cesarean delivery, peripartum
biotics, patient must be warned to use additional meth- cardiomyopathy, BMI ≥30 kg/m2, postpartum hemor-
ods of birth control if on oral contraceptives. rhage, smoking) (Curtis 2016b).
require special precautions Ethosuximide (eth oh SUKS i mide)
Percentages reported with Beyaz. For additional Brand Names: US Zarontin
adverse events and postmarketing reports, refer to the Brand Names: Canada Zarontin
Ethinyl Estradiol and Drospirenone (Yasmin, Yaz) Pharmacologic Category Anticonvulsant, Succini-
monograph. mide
Central nervous system: Headache (≤6% to 13%), Use Absence (petit mal) seizures: Management of
migraine (≤6% to 13%), fatigue (4%), irritability absence (petit mal) seizures
(3%), emotional lability (2%) Local Anesthetic/Vasoconstrictor Precautions
Endocrine & metabolic: Menstrual disease (4% to No information available to require special precautions
25%, including menorrhagia, spotting, uterine hem- Effects on Dental Treatment No significant effects or
orrhage, vaginal hemorrhage), decreased libido complications reported
(3%), weight gain (3%) Effects on Bleeding No information available to
Gastrointestinal: Nausea (≤4% to 16%), vomiting require special precautions
(≤4% to 16%) Adverse Reactions Frequency not defined.
Genitourinary: Breast tenderness (≤3% to 11%), mas- Central nervous system: Aggressive behavior, ataxia,
talgia (≤3% to 11%), cervical carcinoma (stage 0), delusional paranoid disorder, depression (with cases
cervical dysplasia of overt suicidal intentions), disturbed sleep dizziness,
Mechanism of Action Combination oral contracep- drowsiness, euphoria, fatigue, headache, hyperactiv-
tives inhibit ovulation via a negative feedback mecha- ity, irritability, lack of concentration, lethargy, night
nism on the hypothalamus, which alters the normal terrors
pattern of gonadotropin secretion of a follicle-stimulat- Dermatologic: Pruritus, skin rash, Stevens-Johnson
ing hormone (FSH) and luteinizing hormone by the syndrome, urticaria
anterior pituitary. The follicular phase FSH and midcycle Endocrine & metabolic: Hirsutism, increased libido,
surge of gonadotropins are inhibited. In addition, oral weight loss
contraceptives produce alterations in the genital tract, Gastrointestinal: Abdominal pain, anorexia, abdominal
including changes in the cervical mucus, rendering it cramps, diarrhea, epigastric pain, gastric distress,
unfavorable for sperm penetration even if ovulation gingival hyperplasia, hiccups, nausea, swollen tongue,
occurs. Changes in the endometrium may also occur, vomiting
542
ETIDRONATE
Genitourinary: Occult blood in urine, vaginal hemor- been reported following in utero exposure to ethotoin
rhage (Zablen 1977). Maternal ingestion of antiepileptic
Hematologic & oncologic: Agranulocytosis, eosino- agents has been associated with neonatal coagulation
philia, leukopenia, pancytopenia defects/bleeding usually within 24 hours of birth..
Hypersensitivity: Hypersensitivity reaction
Immunologic: DRESS syndrome (drug rash with eosi- Patients exposed to ethotoin during pregnancy are
nophilia and systemic symptoms) encouraged to enroll themselves into the AED Preg-
Neuromuscular & skeletal: Systemic lupus erythema- nancy Registry by calling 1-888-233-2334. Additional
tosus information is available at www.-
Ophthalmic: Myopia aedpregnancyregistry.org.
Mechanism of Action Increases the seizure threshold
and suppresses paroxysmal spike-and-wave pattern in Etidronate (e ti DROE nate)
absence seizures; depresses nerve transmission in the
motor cortex Related Information
Pharmacodynamics/Kinetics Osteonecrosis of the Jaw on page 1486
Half-life Elimination Serum: Children: 30 hours; Brand Names: Canada ACT Etidronate; Mylan-Etidr-
Adults: 50 to 60 hours onate
Time to Peak Serum: 1 to 7 hours Pharmacologic Category Bisphosphonate Derivative
Pregnancy Considerations Ethosuximide crosses Use
the placenta. Birth defects have been reported in Paget disease: Symptomatic treatment of Paget dis-
infants. Epilepsy itself, the number of medications, ease of bone
genetic factors, or a combination of these may influence Heterotopic ossification: Prevention and treatment of
the teratogenicity of anticonvulsant therapy. In general, heterotopic ossification due to spinal cord injury or
polytherapy may increase the risk of congenital malfor- after total hip replacement
mations; monotherapy with the lowest effective dose is Local Anesthetic/Vasoconstrictor Precautions
recommended (Harden 2009). For women with epilepsy No information available to require special precautions
who are planning a pregnancy in advance, baseline Effects on Dental Treatment Key adverse event(s)
serum concentrations should be measured once or related to dental treatment: Abnormal taste.
twice prior to pregnancy during a period when seizure Osteonecrosis of the jaw (ONJ), generally associated
control is optimal. Monitoring can then be continued up with local infection and/or tooth extraction and often
to once a month during pregnancy in women with stable with delayed healing, has been reported in patients
seizure control (Patsalos 2008). taking bisphosphonates. Symptoms included nonheal-
Patients exposed to ethosuximide during pregnancy are ing extraction socket or an exposed jawbone. Most
encouraged to enroll themselves into the NAAED Preg- reported cases of bisphosphonate-associated osteo-
nancy Registry by calling 1-888-233-2334. Additional necrosis have been in cancer patients treated with
information is available at www.- intravenous bisphosphonates. However, some have
aedpregnancyregistry.org. occurred in patients with postmenopausal osteoporo-
sis taking oral bisphosphonates. Dental surgery, par-
ticularly tooth extraction, may increase the risk for
Ethotoin (ETH oh toyn)
ONJ. Patients who develop ONJ while on bisphosph-
Brand Names: US Peganone onate therapy should receive care by an oral surgeon.
Pharmacologic Category Anticonvulsant, Hydantoin See Dental Health Professional Considerations.
Use Seizures: Control of generalized tonic-clonic (grand Effects on Bleeding No information available to
mal) and complex-partial (psychomotor) seizures require special precautions
No information available to require special precautions Gastrointestinal: Diarrhea (≤30%; dose dependent),
Effects on Dental Treatment No significant effects or nausea (≤30%; dose dependent)
complications reported Neuromuscular & skeletal: Ostealgia (10% to 20%;
Effects on Bleeding No information available to dose dependent)
require special precautions Postmarketing and/or case reports: Agranulocytosis,
Adverse Reactions Frequency not defined. alopecia, amnesia, angioedema, arthralgia, arthritis,
Cardiovascular: Chest pain bone fracture, confusion, depression, erythema multi-
Central nervous system: Ataxia, dizziness, fatigue, forme, esophagitis, exacerbation of asthma, exacer-
headache, insomnia, numbness bation of peptic ulcer, folliculitis, gastritis, glossitis,
Dermatologic: Skin rash, Stevens-Johnson syndrome glossopyrosis, hallucination, headache, hypersensitiv-
Gastrointestinal: Diarrhea, gingival hyperplasia, nau- ity reaction, leg cramps, leukemia, leukopenia, mac-
sea, vomiting ulopapular rash, osteomalacia, osteonecrosis of the
Hematologic & oncologic: Hematologic disease, lym- jaw, pancytopenia, paresthesia, pruritus, skin rash
phadenopathy (macular), Stevens-Johnson syndrome, toxic epider-
Neuromuscular & skeletal: Lupus-like syndrome mal necrolysis, urticaria
Ophthalmic: Diplopia, nystagmus Mechanism of Action Decreases bone resorption by
Miscellaneous: Fever inhibiting osteocystic osteolysis; decreases mineral
Mechanism of Action Stabilizes the seizure threshold release and matrix or collagen breakdown in bone
and prevents the spread of seizure activity Pharmacodynamics/Kinetics
Pharmacodynamics/Kinetics Onset of Action 1 to 3 months
Half-life Elimination 3 to 9 hours Duration of Action Can persist for 12 months without
Pregnancy Considerations Adverse fetal effects may continuous therapy
occur following maternal use of ethotoin. Cleft lip and Half-life Elimination 1 to 6 hours
cleft palate observed with other hydantoins has also Pregnancy Risk Factor C
543
ETIDRONATE
Pregnancy Considerations Adverse events were The most comprehensive review to date on osteonec-
observed in some animal reproduction studies. It is rosis of the jaw bone (ONJ) has been published in the
not known if bisphosphonates cross the placenta, but Journal of Bone and Mineral Research (Khan 2015),
fetal exposure is expected (Djokanovic 2008; Statho- and written by an International Task Force of authors,
poulos 2011). Bisphosphonates are incorporated into totaling 34, from academe; industry; clinical medical
the bone matrix and gradually released over time. The and dental practice; oral and maxillofacial surgery; bone
amount available in the systemic circulation varies by and mineral research; epidemiology; medical and den-
dose and duration of therapy. Theoretically, there may tal oncology; orthopedic surgery; osteoporosis
be a risk of fetal harm when pregnancy follows the research; muscle and bone research; endocrinology
completion of therapy; however, available data have and diagnostic sciences. The work provides a system-
not shown that exposure to bisphosphonates during atic review of the literature and international consensus
pregnancy significantly increases the risk of adverse on the classification, incidence, pathophysiology, diag-
fetal events (Djokanovic 2008; Levy 2009; Stathopoulos nosis, and management of ONJ in both oncology and
2011). Until additional data is available, most sources osteoporosis patient populations. This review of the
recommend discontinuing bisphosphonate therapy in literature from January 2003 to April 2014, with 299
women of reproductive potential as early as possible references, offers recommendations for management of
prior to a planned pregnancy; use in premenopausal ONJ based on multidisciplinary international con-
women should be reserved for special circumstances sensus.
when rapid bone loss is occurring (Bhalla 2010; Pereira Prevalence and incidence of ONJ in osteoporosis
2012; Stathopoulos 2011). Because hypocalcemia has patients from the Task Force report:
been described following in utero bisphosphonate
Prevalence – the percent of osteoporotic population
exposure, exposed infants should be monitored for
affected with ONJ
hypocalcemia after birth (Djokanovic 2008; Stathopou-
los 2011). After reviewing all literature reports on this subject, the
Dental Health Professional Considerations A Task Force concluded that the prevalence of ONJ in
review of 2,408 published cases of bisphosphonate- patients prescribed oral BPs for the treatment of osteo-
associated osteonecrosis of the jaw bone (BP-associ- porosis ranges from 0% to 0.04% with the majority
ated ONJ) was done by Filleul 2010. BP therapy was being below 0.001%. However, the Task Force does
associated with 89% of the cases to treat malignancies cite the study of (Lo et al) that evaluated the Kaiser
and 11% of the cases to treat nonmalignant conditions. Permanente database and found the prevalence of
Information on the specific bisphosphonate used was ONJ in those receiving BPs for more than 2 years to
available for 1,694 of the patients. Intravenous therapy range from 0.05% to 0.21% and appeared to be related
(primarily zoledronic acid) was received by 88% of the to duration of exposure. As mentioned above, the
patients and 12% received oral treatment (primarily American Dental Association has previously reported
alendronate). Of all the cases of BP-associated ONJ, that the prevalence of ONJ in osteoporosis patients
67% were preceded by tooth extraction and for 26% of using oral BPs to be 1 out of 1,000 or 0.1% (Hell-
patients, there was no predisposing factor identified. stein 2011).
A 2010 retrospective case review reported the preva- Incidence - the rate at which ONJ occurs or the number
lence of BP-associated ONJ in patients using alendro- of times it happens
nate-type drugs was one out of 952 patients or ~0.1% From currently available data, the incidence of ONJ in
(Lo 2010). Of the 8,572 respondents, nine cases of ONJ the osteoporosis patient population appears to be low
were identified; five had developed ONJ spontaneously ranging from 0.15% to less than 0.001% person-years
and four developed ONJ after tooth extraction. When drug exposure. In terms of the osteoporosis patient
extrapolated to patient-years of bisphosphonate expo- population taking oral BPs, the incidence ranges from
sure, this prevalence rate of 0.1% equates to a fre- 1.04 to 69 per 100,000 patient years of drug exposure.
quency of 28 cases per 100,000 person-years of oral
bisphosphonate treatment. An Australian group (Mav-
rokokki 2007), identified the frequency of BP-associated
Etidronate and Calcium Carbonate
(e ti DROE nate & KAL see um KAR bun ate)
ONJ in osteoporotic patients, mainly taking weekly oral
alendronate, was 1 in 8,470 to 1 in 2,260 (0.01% to Related Information
0.04%) patients. If extractions were carried out, the Etidronate on page 543
calculated frequency was 1 in 1,130 to 1 in 296 Brand Names: Canada ACT Etidrocal
(0.09% to 0.34%) patients. The median time to onset Pharmacologic Category Bisphosphonate Deriva-
of ONJ in alendronate patients was 24 months. tive; Calcium Salt
According to the 2011 report by the American Dental Use Note: Not approved in the US
Association (ADA), the incidence of BP-associated ONJ Corticosteroid-induced osteoporosis: Prevention of
remains low and the benefits of using oral bisphosph- corticosteroid-induced osteoporosis
onates significantly outweighs the risk of developing Postmenopausal osteoporosis: Treatment and pre-
BP-associated ONJ for treatment and prevention of vention of established postmenopausal osteoporosis
osteoporosis and cancer treatment (Hellstein 2011). Local Anesthetic/Vasoconstrictor Precautions
The full 47-page report can be accessed at http://www.- No information available to require special precautions
ada.org/~/media/ADA/Member%20Center/FIles/ Effects on Dental Treatment Osteonecrosis of the
topics_ARONJ_report.ashx. jaw (ONJ), generally associated with local infection and/
or tooth extraction and often with delayed healing, has
The ADA review of 2011 stated the incidence of oral been reported in patients taking bisphosphonates.
BP-associated ONJ was one case for every 1,000 Symptoms included nonhealing extraction socket or
individuals exposed to oral bisphosphonates (0.1%) an exposed jawbone. Most reported cases of
(Hellstein 2011). bisphosphonate-associated osteonecrosis have been
544
ETODOLAC
in cancer patients treated with intravenous bisphosph- Adverse Reactions

onates. However, some have occurred in patients with 1% to 10%:
postmenopausal osteoporosis taking oral bisphospho- Central nervous system: Dizziness (3% to 9%), chills
nates. Dental surgery, particularly tooth extraction, may (≤3%), depression (1% to 3%), nervousness (1%
increase the risk for ONJ. Patients who develop ONJ to 3%)
while on bisphosphonate therapy should receive care Dermatologic: Skin rash (1% to 3%), pruritus (1%
by an oral surgeon. See Dental Health Professional to 3%)
Considerations. Gastrointestinal: Dyspepsia (10%), abdominal cramps
Effects on Bleeding No information available to (3% to 9%), diarrhea (3% to 9%), flatulence (3% to
require special precautions 9%), nausea (3% to 9%), vomiting (1% to 3%),
Adverse Reactions constipation (1% to 3%), melena (1% to 3%), gas-
>10%: tritis (1% to 3%)
Central nervous system: Dizziness (16%), head- Genitourinary: Dysuria (1% to 3%)
ache (13%) Neuromuscular & skeletal: Weakness (3% to 9%)
Gastrointestinal: Diarrhea (37%), nausea (18%), flat- Ophthalmic: Blurred vision (1% to 3%)
ulence (17%), constipation (13%), dyspepsia (12%), Otic: Tinnitus (1% to 3%)
vomiting (11%) Renal: Polyuria (1% to 3%)
<1%, postmarketing, and/or case reports: Agranulocy- Miscellaneous: Fever (≤3%)
tosis, alopecia, amnesia, angioedema, arthropathy, <1%: Abnormal uterine bleeding, agranulocytosis, alo-
bone fracture, confusion, depression, erythema multi- pecia, anaphylactoid reaction, anaphylaxis, anemia,
forme, esophagitis, exacerbation of asthma, exacer- angioedema, anorexia, aphthous stomatitis, aseptic
ba ti on of p ep tic ul ce r, fol lic ul it is, gl os si tis , meningitis, asthma, cardiac arrhythmia, cardiac fail-
glossopyrosis, hallucination, leukemia (1 in 100,000 ure, cerebrovascular accident, confusion, conjunctivi-
patients), leukopenia, maculopapular rash, malignant tis, cystitis, duodenitis, dyspnea, ecchymosis, edema,
neoplasm of esophagus, musculoskeletal pain, pan- erythema multiforme, esophagitis (+/- stricture or car-
cytopenia, paresthesia, Stevens-Johnson syndrome, diospasm), exfoliative dermatitis, gastrointestinal
urticaria ulceration, hallucination, headache, hearing loss,
Mechanism of Action See individual agents. hematemesis, hematuria, hepatic failure, hepatitis,
Pregnancy Considerations Adverse events were hepatotoxicity (idiosyncratic) (Chalasani, 2014),
observed in some animal reproduction studies. Refer hyperglycemia (in controlled patients with diabetes),
to individual agents. According to the manufacturer, this hyperpigmentation, hypersensitivity angiitis, hyper-
product is not intended for use in pregnant women. sensitivity reaction, hypertension, increased liver func-
Product Availability Not available in the US tion tests, infection, insomnia, interstitial nephritis,
Dental Health Professional Considerations See jaundice, leukopenia, myocardial infarction, necrotiz-
Etidronate monograph. ing angiitis, nephrolithiasis, palpitations, pancreatitis,
pancytopenia, paresthesia, peptic ulcer (+/- bleeding/
perforation), peripheral neuropathy, photophobia, pro-
Etodolac (ee toe DOE lak) longed bleeding time, pulmonary infiltrates (eosino-
p hi li a) , r ec ta l b le e di ng , r e na l f ai lu r e, re na l
Related Information
insufficiency, shock, skin photosensitivity, Stevens-
Johnson syndrome, syncope, thrombocytopenia, toxic
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis epidermal necrolysis, urticaria, vesiculobullous derma-
on page 1484 titis, renal papillary necrosis, visual disturbance
Temporomandibular Dysfunction (TMD), Chronic Pain, Dental Usual Dosage Acute pain: Adults: Oral: Imme-
and Fibromyalgia on page 1559 diate release formulation: 200 to 400 mg every 6 to 8
Brand Names: US Lodine hours, as needed, not to exceed total daily doses of
Brand Names: Canada Etodolac 1000 mg
Generic Availability (US) Yes Dosing
Pharmacologic Category Analgesic, Nonopioid; Non- Adult Note: For chronic conditions, response is usually
steroidal Anti-inflammatory Drug (NSAID), Oral observed within 1 to 2 weeks.
Dental Use Management of postoperative pain Acute pain: Oral: Immediate release: 200 to 400 mg
Use every 6 to 8 hours; maximum: 1,000 mg daily.
Acute pain: Management of acute pain (immediate Osteoarthritis, rheumatoid arthritis: Oral:
release only). Immediate release: 400 mg 2 times daily or 300 mg
Arthritis: Relief of the signs and symptoms of osteo- 2 to 3 times daily or 500 mg 2 times daily.
arthritis, rheumatoid arthritis, and juvenile arthritis Extended release: Initial: 400 to 1,000 mg once daily.
(ER only). Geriatric Refer to adult dosing, use with caution. The
Local Anesthetic/Vasoconstrictor Precautions elderly are more sensitive to antiprostaglandin effects
No information available to require special precautions and may need dosage adjustments.
Effects on Dental Treatment The dentist should be Renal Impairment: Adult
aware of the potential of abnormal coagulation. Caution CrCl >88 mL/minute: No dosage adjustment neces-
should also be exercised in the use of NSAIDs in sary.
patients already on anticoagulant therapy with drugs CrCl 37 to 88 mL/minute: No dosage adjustment
such as warfarin (Coumadin®). See Effects on Bleed- necessary; however, use with caution.
ing. CrCl <37 mL/minute: There are no specific dosage
Effects on Bleeding Nonselective NSAIDs such as adjustments provided in the manufacturer’s labeling;
etodolac inhibit platelet aggregation and prolong bleed- if use must be initiated, use with caution. Avoid use in
ing time in some patients. Unlike aspirin, the NSAID patients with advanced renal disease unless benefits
effect on platelet function is quantitatively less, of are expected to outweigh risk of worsening renal
shorter duration, and reversible. function.
545
ETODOLAC
Hemodialysis: Not significantly removed. Other proposed mechanisms not fully elucidated (and
KDIGO 2012 guidelines provide the following recom- possibly contributing to the anti-inflammatory effect to
mendations for NSAIDs: varying degrees), include inhibiting chemotaxis, altering
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily lymphocyte activity, inhibiting neutrophil aggregation/
discontinue in patients with intercurrent disease activation, and decreasing proinflammatory cytokine
that increases risk of acute kidney injury. levels.
eGFR <30 mL/minute/1.73 m2: Avoid use. Contraindications
Hepatic Impairment: Adult No dosage adjustment Hypersensitivity to etodolac, or any component of the
necessary. However, reduced doses may be required formulation; history of asthma, urticaria, or allergic-
due to extensive hepatic metabolism. type reactions after taking aspirin or other NSAID
Pediatric Note: Dosage should be titrated to the low- agents; use in the setting of coronary artery bypass
est effective dose for the shortest duration possible. graft (CABG) surgery.
For chronic conditions, therapeutic response may take Canadian labeling: Additional contraindications (not in
1 to 2 weeks of treatment. US labeling): Active peptic ulcer; inflammatory dis-
Analgesia, acute pain: eases of the GI tract
Children and Adolescents <18 years: Limited data Warnings/Precautions [US Boxed Warning]:
available (American Pain Society 2016): Oral: NSAIDs cause an increased risk of serious (and
Immediate release: potentially fatal) adverse cardiovascular thrombotic
Patient weight <50 kg: 7.5 to 10 mg/kg/dose every events, including MI and stroke. Risk may occur
12 hours; maximum daily dose: 1,000 mg/day early during treatment and may increase with dura-
Patient weight ≥50 kg: 300 to 400 mg every 8 to 12 tion of use. Relative risk appears to be similar in those
hours; maximum daily dose: 1,000 mg/day with and without known cardiovascular disease or risk
Adolescents ≥18 years: Oral: Immediate release: factors for cardiovascular disease; however, absolute
200 to 400 mg every 6 to 8 hours, as needed; incidence of serious cardiovascular thrombotic events
maximum daily dose: 1,000 mg/day (which may occur early during treatment) was higher in
Juvenile idiopathic arthritis: Children ≥6 years patients with known cardiovascular disease or risk
weighing at least 20 kg and Adolescents: Oral: factors and in those receiving higher doses. New onset
Extended-release tablets: hypertension or exacerbation of hypertension may
20 to 30 kg: 400 mg once daily occur (NSAIDs may also impair response to ACE
31 to 45 kg: 600 mg once daily inhibitors, thiazide diuretics, or loop diuretics); may
46 to 60 kg: 800 mg once daily contribute to cardiovascular events; monitor blood pres-
>60 kg: 1,000 mg once daily sure; use with caution in patients with hypertension.
Rheumatoid arthritis, osteoarthritis: Adolescents May cause sodium and fluid retention; use with caution
≥18 years: Oral: in patients with edema. Avoid use in heart failure
Immediate release: 300 to 500 mg twice daily or (ACCF/AHA [Yancy, 2013]). Avoid use in patients with
recent MI unless benefits outweigh risk of cardiovascu-
300 mg 3 times daily; maximum daily dose:
lar thrombotic events. Use the lowest effective dose for
1,000 mg/day
the shortest duration of time, consistent with individual
Extended-release tablets: 400 to 1,000 mg once
patient goals, to reduce risk of cardiovascular events;
daily
alternate therapies should be considered for patients at
Renal Impairment: Pediatric high risk. [US Boxed Warning]: Use is contraindi-
KDIGO 2012 guidelines provide the following recom- cated in the setting of coronary artery bypass graft
mendations for NSAIDs (KDIGO 2013): Children and (CABG) surgery. Risk of MI and stroke may be
Adolescents: increased with use following CABG surgery.
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily
discontinue in patients with intercurrent disease [US Boxed Warning]: NSAIDs cause increased risk
that increases risk of acute kidney injury of serious GI inflammation, ulceration, bleeding,
eGFR <30 mL/minute/1.73 m2: Avoid use and perforation (may be fatal); elderly patients and
Manufacturer's labeling: patients with history of peptic ulcer disease and/or
Adolescents ≥18 years: Immediate release: GI bleeding are at greater risk for serious GI events.
CrCl >88 mL/minute: No adjustment required These events may occur at any time during therapy
CrCl 37 to 88 mL/minute: No dosage adjustment and without warning. Avoid use in patients with active
necessary; however, use with caution. GI bleeding. In patients with a history of acute lower GI
CrCl <37 mL/minute: There are no specific dosage bleeding, avoid use of non-aspirin NSAIDs, especially if
adjustments provided in the manufacturer's label- due to angioectasia or diverticulosis (Strate 2016). Use
ing; if use must be initiated, use with caution. caution with a history of GI ulcers, concurrent therapy
Avoid use in patients with advanced renal disease known to increase the risk of GI bleeding (eg, aspirin,
unless benefits are expected to outweigh risk of anticoagulants and/or corticosteroids, selective seroto-
worsening renal function. nin reuptake inhibitors), advanced hepatic disease,
Hemodialysis: Not significantly removed coagulopathy, smoking, use of alcohol, or in elderly or
Extended release: There are no dosing adjustments debilitated patients. Use the lowest effective dose for
provided in the manufacturer's labeling; has not the shortest duration of time, consistent with individual
been studied patient goals, to reduce risk of GI adverse events;
Hepatic Impairment: Pediatric No adjustment alternate therapies should be considered for patients
required; in adult patients, reduced doses may be at high risk. When used concomitantly with aspirin, a
required due to extensive hepatic metabolism. substantial increase in the risk of GI complications (eg,
ulcer) occurs; concomitant gastroprotective therapy (eg,
Mechanism of Action Reversibly inhibits cyclooxyge-
proton pump inhibitors) is recommended (Bhatt, 2008).
decreased formation of prostaglandin precursors; has Platelet adhesion and aggregation may be decreased;
antipyretic, analgesic, and anti-inflammatory properties may prolong bleeding time; patients with coagulation
546
ETODOLAC
disorders or who are receiving anticoagulants should be Avoid Concomitant Use

monitored closely. Anemia may occur; patients on long- Avoid concomitant use of Etodolac with any of the
term NSAID therapy should be monitored for anemia. following: Acemetacin; Aminolevulinic Acid (Sys-
Rarely, NSAID use may cause severe blood dyscrasias temic); Dexibuprofen; Dexketoprofen; Floctafenine;
(eg, agranulocytosis, aplastic anemia, thrombocytope- Ketorolac (Nasal); Ketorolac (Systemic); Macimorelin;
nia). May increase the risk of aseptic meningitis, espe- Mifamurtide; Morniflumate; Nonsteroidal Anti-Inflam-
cially in patients with systemic lupus erythematosus matory Agents (COX-2 Selective); Omacetaxine;
(SLE) and mixed connective tissue disorders. Pelubiprofen; Phenylbutazone; Talniflumate; Tenoxi-
NSAID use may compromise existing renal function; cam; Urokinase; Zaltoprofen
dose-dependent decreases in prostaglandin synthesis Increased Effect/Toxicity
may result from NSAID use, reducing renal blood flow Etodolac may increase the levels/effects of: 5-Amino-
which may cause renal decompensation (usually rever- salicylic Acid Derivatives; Agents with Antiplatelet
sible). Patients with impaired renal function, dehydra- Properties; Aliskiren; Aminoglycosides; Aminolevulinic
tion, hypovolemia, heart failure, hepatic impairment, Acid (Systemic); Aminolevulinic Acid (Topical); Anti-
those taking diuretics, and ACE inhibitors, and the coagulants; Apixaban; Bisphosphonate Derivatives;
elderly are at greater risk of renal toxicity. Rehydrate Cephalothin; Collagenase (Systemic); CycloSPOR-
patient before starting therapy; monitor renal function INE (Systemic); Dabigatran Etexilate; Deferasirox;
closely. Long-term NSAID use may result in renal Deoxycholic Acid; Desmopressin; Dexibuprofen;
papillary necrosis and other renal injury. Avoid use in Digoxin; Drospirenone; Edoxaban; Eplerenone; Halo-
patients with advanced renal disease unless benefits peridol; Ibritumomab Tiuxetan; Lithium; Methotrexate;
are expected to outweigh risk of worsening renal func- Nonsteroidal Anti-Inflammatory Agents (COX-2 Selec-
tion; monitor closely if therapy must be initiated. tive); Obinutuzumab; Omacetaxine; Porfimer; Potas-
sium-Sparing Diuretics; PRALAtrexate; Quinolones;
Elderly patients are at greater risk for serious GI, Rivaroxaban; Salicylates; Tacrolimus (Systemic);
cardiovascular, and/or renal events; use with caution. Tenofovir Products; Thrombolytic Agents; Tolperisone;
NSAIDs may cause potentially fatal serious skin Urokinase; Vancomycin; Verteporfin; Vitamin K Antag-
adverse events including exfoliative dermatitis, Ste- onists
vens-Johnson syndrome (SJS), and toxic epidermal
The levels/effects of Etodolac may be increased by:
necrolysis (TEN); may occur without warning; discon-
Acemetacin; Alcohol (Ethyl); Angiotensin II Receptor
tinue use at first sign of skin rash (or any other hyper-
Blockers; Angiotensin-Converting Enzyme Inhibitors;
sensitivity). Even in patients without prior exposure
Corticosteroids (Systemic); CycloSPORINE (Sys-
anaphylactoid reactions may occur; patients with
temic); Dasatinib; Dexketoprofen; Diclofenac (Sys-
"aspirin triad" (bronchial asthma, aspirin intolerance,
temic); Fat Emulsion (Fish Oil Based); Felbinac;
rhinitis) may be at increased risk. Contraindicated in
Floctafenine; Glucosamine; Herbs (Anticoagulant/
patients who experience bronchospasm, asthma, rhini-
Antiplatelet Properties); Ibrutinib; Inotersen; Ketorolac
tis, or urticaria with NSAID or aspirin therapy. Contra-
(Nasal); Ketorolac (Systemic); Limaprost; Loop Diu-
indicated in patients with aspirin-sensitive asthma;
retics; Morniflumate; Multivitamins/Fluoride (with
severe and potentially fatal bronchospasm may occur.
ADE); Multivitamins/Minerals (with ADEK, Folate,
Use caution in patients with other forms of asthma.
Iron); Multivitamins/Minerals (with AE, No Iron); Nafta-
Transaminase elevations have been reported with use; zone; Omega-3 Fatty Acids; Pelubiprofen; Pentosan
closely monitor patients with any abnormal LFT. Rare Polysulfate Sodium; Pentoxifylline; Phenylbutazone;
(sometimes fatal) severe hepatic reactions (eg, fulmi- Probenecid; Prostacyclin Analogues; Selective Sero-
nant hepatitis, hepatic necrosis, hepatic failure) have tonin Reuptake Inhibitors; Serotonin/Norepinephrine
occurred with NSAID use; discontinue immediately if Reuptake Inhibitors; Sodium Phosphates; Talniflu-
clinical signs or symptoms of liver disease develop or if mate; Tenoxicam; Thiazide and Thiazide-Like Diu-
systemic manifestations occur. Use with caution in r e t i c s ; T i p r a n a v i r ; To l p e r i s o n e ; T r i c y c l i c
patients with hepatic impairment; reduced doses may Antidepressants (Tertiary Amine); Vitamin E (Sys-
be required due to extensive hepatic metabolism. temic); Zaltoprofen
Patients with advanced hepatic disease are at an Decreased Effect
increased risk of GI bleeding with NSAIDs. NSAIDS Etodolac may decrease the levels/effects of: Aliskiren;
may cause drowsiness, dizziness, blurred vision and Angiotensin II Receptor Blockers; Angiotensin-Con-
other neurologic effects which may impair physical or verting Enzyme Inhibitors; Beta-Blockers; Eplerenone;
mental abilities; patients must be cautioned about per- HydrALAZINE; Loop Diuretics; Macimorelin; Mifamur-
forming tasks which require mental alertness (eg, oper- tide; Potassium-Sparing Diuretics; Prostaglandins
ating machinery or driving). (Ophthalmic); Salicylates; Selective Serotonin Reup-
Withhold for at least 4 to 6 half-lives prior to surgical or take Inhibitors; Sincalide; Thiazide and Thiazide-Like
dental procedures. Potentially significant interactions Diuretics
may exist, requiring dose or frequency adjustment, The levels/effects of Etodolac may be decreased by:
additional monitoring, and/or selection of alternative Bile Acid Sequestrants; Salicylates
therapy. Food Interactions Etodolac peak serum levels may be
Use of extended release product consisting of a non- decreased if taken with food. Management: Administer
deformable matrix should be avoided in patients with with food to decrease GI upset.
stricture/narrowing of the GI tract; symptoms of obstruc- Pharmacodynamics/Kinetics
tion have been associated with nondeformable Onset of Action Analgesia: Immediate release: ~0.5
products. hour; Arthritis (chronic management): Typically within
Drug Interactions 2 weeks; Maximum effect: Analgesia: 1 to 2 hours
Metabolism/Transport Effects None known. Duration of Action Mean range: 4 to 6 hours
547
ETODOLAC
Half-life Elimination Terminal: antibiotics to female patients taking progestin-only con-

Immediate release: Children (6 to 16 years, n=11): 6.5 traceptives.
hours (Boni 1999); Adults: 6.4 hours Effects on Bleeding No information available to
Extended release: Children (6 to 16 years, n=72): 12 require special precautions
hours; Adults: 8.4 hours Adverse Reactions
Time to Peak Serum: >10%:
Immediate release: Children (6 to 16 years, n=11): 1.4 Central nervous system: Headache (25%)
hours (Boni 1999); Adults: ~1 to 2 hours, increased Dermatologic: Acne vulgaris (14%)
1.4 to 3.8 hours with food Endocrine & metabolic: Menstrual disease (<3 epi-
Extended release: ~5 to 7 hours sodes/90 days: 34%; prolonged menstrual bleeding
Pregnancy Risk Factor C lasting >14 days: 18%; >5 episodes/90 days: 7%),
Pregnancy Considerations Birth defects have been amenorrhea (no bleeding in 90 days: 22%), weight
observed following in utero NSAID exposure in some gain (14%)
studies; however, data is conflicting (Bloor 2013). Non- Gastrointestinal: Abdominal pain (11%)
teratogenic effects, including prenatal constriction of the Genitourinary: Vaginitis (15%), mastalgia (13%)
ductus arteriosus, persistent pulmonary hypertension of Respiratory: Pharyngitis (11%)
the newborn, oligohydramnios, necrotizing enterocolitis, 1% to 10%:
renal dysfunction or failure, and intracranial hemor- Central nervous system: Dizziness (7%), emotional
rhage have been observed in the fetus/neonate follow- lability (7%), depression (6%), nervousness (6%),
ing in utero NSAID exposure. In addition, nonclosure of pain (6%)
the ductus arteriosus postnatally may occur and be Dermatologic: Localized erythema (implant site: ≤3%)
resistant to medical management (Bermas 2014; Bloor Endocrine & metabolic: Dysmenorrhea (7%)
2013). Because they may cause premature closure of Gastrointestinal: Nausea (6%)
the ductus arteriosus, the use of NSAIDs late in preg- Genitourinary: Leukorrhea (10%)
nancy (the third trimester) should be avoided. Use of Hypersensitivity: Hypersensitivity reaction (5%)
NSAIDs can be considered for the treatment of mild Local: Application site reaction (implant site: 4% to
rheumatoid arthritis flares in pregnant women; however, 9%), local pain (implant site: 1% to 5%), hematoma
use should be minimized or avoided early and late in at injection site (implant site: ≤3%), bruising at injec-
pregnancy (Bermas 2014; Saavedra Salinas 2015). tion site (implant site: 2%)
Neuromuscular & skeletal: Back pain (7%)
The chronic use of NSAIDs in women of reproductive Respiratory: Flu-like symptoms (8%)
age may be associated with infertility that is reversible <1%, postmarketing, and/or case reports: Abscess,
upon discontinuation of the medication (Micu 2011). alopecia, anaphylaxis, angioedema (including exacer-
The use of NSAIDs close to conception may be asso- bation of hereditary angioedema), anxiety, arthralgia,
ciated with an increased risk of miscarriage (Bloor breast hypertrophy, cerebrovascular accident,
2013; Bermas 2014). chloasma, constipation, convulsions, decreased
Breastfeeding Considerations It is not known if libido, deep vein thrombosis, diarrhea, drowsiness,
etodolac is present in breast milk. In general, NSAIDs dysuria, edema, fatigue, fever, fibrosis (implant site),
may be used in postpartum women who wish to breast- flatulence, genital pruritus, hot flash, hypertension,
feed; however, agents other than etodolac are preferred hypertrichosis, increased appetite, insomnia,
(Montgomery 2012) and use should be avoided in migraine, musculoskeletal pain, myalgia, myocardial
women breastfeeding infants with platelet dysfunction infarction, nipple discharge, ovarian cyst, paresthesia,
or thrombocytopenia (Bloor 2013; Sammaritano 2014). pruritus, pulmonary embolism, rhinitis, scarring, sebor-
Due to the potential for serious adverse reactions in the rhea, seizure, skin rash, swelling (implant site), urinary
breastfeeding infant, the manufacturer recommends a tract infection, urticaria, vaginal discomfort, vomiting,
decision be made whether to discontinue breastfeeding weight loss
or to discontinue the drug, taking into account the Mechanism of Action Etonogestrel is the active
importance of treatment to the mother. metabolite of desogestrel. It prevents pregnancy by
Dosage Forms: US suppressing ovulation, increasing the viscosity of cer-
Capsule, Oral: vical mucous, and inhibiting endometrial proliferation.
Generic: 200 mg, 300 mg Pharmacodynamics/Kinetics
Tablet, Oral: Duration of Action Each implant maintains etono-
Lodine: 400 mg gestrel levels sufficient to inhibit ovulation for 3 years
Generic: 400 mg, 500 mg Half-life Elimination ~25 hours
Use is contraindicated in pregnant women.
Dosage Forms: Canada Refer to Dosage Forms.
Note: Tablets and Extended Release tablets are not Pregnancy status should be evaluated prior to prescrib-
available in Canada. ing and the implant should be removed if pregnancy
occurs. In general, the use of combination hormonal
Etonogestrel (e toe noe JES trel)
nancy, have not been associated with teratogenic
Brand Names: US Nexplanon effects. There is no evidence that the risk is different
Pharmacologic Category Contraceptive; Progestin with etonogestrel.
Use Contraception: Prevention of pregnancy Due to the risk of thromboembolism associated with
Local Anesthetic/Vasoconstrictor Precautions pregnancy and the immediate postpartum period, the
No information available to require special precautions manufacturer does not recommend insertion <21 days'
Effects on Dental Treatment Key adverse event(s) postpartum. However, available guidelines state that
related to dental treatment: Until more is known about progestin only implants may be inserted at any time if
the mechanism of interaction, use caution in prescribing it is reasonably certain the woman is not pregnant,
548
ETOPOSIDE PHOSPHATE
including immediately postpartum or post abortion (Cur- optic neuritis, ovarian failure, pruritic erythematous
tis 2016a). Administration immediately postpartum rash, pruritus, pulmonary fibrosis, radiation-recall phe-
(prior to hospital discharge) may be offered regardless nomenon (dermatitis), reversible posterior leukoence-
of breastfeeding status and may help prevent rapid phalopathy syndrome (RPLS), seizure, skin rash,
repeat and unintended pregnancies (ACOG 186 2017). Stevens-Johnson syndrome, tongue edema, toxic epi-
Etonogestrel serum concentrations decrease by 1 week dermal necrolysis, toxic megacolon, urticaria, vaso-
after removal of the implant; pregnancies have been spasm, weakness
reported as early as 7 to 14 days after removal. Restart Mechanism of Action Etoposide has been shown to
contraception immediately after removal if continued delay transit of cells through the S phase and arrest
contraception is desired. cells in late S or early G2 phase. The drug may inhibit
mitochondrial transport at the NADH dehydrogenase
level or inhibit uptake of nucleosides into HeLa cells.
Etoposide (e toe POE side)
It is a topoisomerase II inhibitor and appears to cause
Brand Names: US Toposar DNA strand breaks. Etoposide does not inhibit micro-
Brand Names: Canada Etoposide Injection; Etopo- tubular assembly.
side Injection USP; Vepesid Pharmacodynamics/Kinetics
Pharmacologic Category Antineoplastic Agent, Half-life Elimination Terminal: IV: Normal renal/
Podophyllotoxin Derivative; Antineoplastic Agent, Top- hepatic function: Children: 6 to 8 hours: Adults: 4 to
oisomerase II Inhibitor 11 hours
Use Pregnancy Risk Factor D
Small cell lung cancer (oral and IV): Treatment (first- Pregnancy Considerations
line) of small cell lung cancer (SCLC) Adverse events were observed in animal reproduction
Testicular cancer (IV): Treatment of refractory testicu- studies. Fetal growth restriction and newborn myelo-
lar tumors (injectable formulation) suppression have been observed following maternal
Local Anesthetic/Vasoconstrictor Precautions use of regimens containing etoposide during pregnancy
No information available to require special precautions (NTP 2013; Peccatori 2013).
related to dental treatment: Mucositis (especially at high The European Society for Medical Oncology has pub-
doses) and stomatitis. lished guidelines for diagnosis, treatment, and follow-up
Effects on Bleeding Myelosuppression is dose of cancer during pregnancy. The guidelines recommend
related. When thrombocytopenia occurs, platelet nadirs referral to a facility with expertise in cancer during
develop 9-16 days after drug administration. Bone pregnancy and encourage a multidisciplinary team
marrow recovery is usually complete by day 20, and (obstetrician, neonatologist, oncology team). In general,
no cumulative toxicity has been reported. if chemotherapy is indicated, it should be avoided
Adverse Reactions The following may occur with during in the first trimester, there should be a 3-week
higher doses used in stem cell transplantation: Alope- time period between the last chemotherapy dose and
cia, ethanol intoxication, hepatitis, hypotension (infu- anticipated delivery, and chemotherapy should not be
sion-related), metabolic acidosis, mucositis, nausea administered beyond week 33 of gestation. Guidelines
and vomiting (severe), secondary malignancy, skin for the treatment of SCLC are not provided (Pecca-
lesions (resembling Stevens-Johnson syndrome). tori 2013).
>10%:
In females of reproductive potential, product labeling for
Dermatologic: Alopecia (8% to 66%)
etoposide phosphate notes that it may cause amenor-
Gastrointestinal: Nausea and vomiting (31% to 43%),
anorexia (10% to 13%), diarrhea (1% to 13%) rhea, infertility, or premature menopause; effective con-
Hematologic & oncologic: Leukopenia (60% to 91%; traception should be used during therapy and for at
grade 4: 3% to 17%; nadir: 7 to 14 days; recovery: by least 6 months after the last dose. In males, azoosper-
day 20), thrombocytopenia (22% to 41%; grades 3/4: mia, oligospermia, or permanent loss of fertility may
1% to 20%; nadir: 9 to 16 days; recovery: by day 20), occur. In addition, spermatozoa and testicular tissue
anemia (≤33%) may be damaged. Males with female partners of repro-
1% to 10%: ductive potential should use condoms during therapy
Cardiovascular: Hypotension (1% to 2%; due to rapid and for at least 4 months after the last dose.
infusion)
Central nervous system: Peripheral neuropathy (1% Etoposide Phosphate (e toe POE side FOS fate)
to 2%)
Gastrointestinal: Stomatitis (1% to 6%), abdominal Related Information
pain (≤2%) Etoposide on page 549
Hepatic: Hepatotoxicity (≤3%) Brand Names: US Etopophos
Hypersensitivity: Anaphylactoid reaction (intravenous:
1% to 2%; oral capsules: <1%; including broncho-
Podophyllotoxin Derivative; Antineoplastic Agent, Top-
spasm, chills, dyspnea, fever, tachycardia)
oisomerase II Inhibitor
<1%, postmarketing, and/or case reports: Amenorrhea,
apnea (hypersensitivity-associated), back pain, con- Use
stipation, cortical blindness (transient), cough, cyano- Small cell lung cancer: First-line treatment of small
sis, diaphoresis, drowsiness, dysphagia, erythema, cell lung cancer (in combination with cisplatin)
esophagitis, extravasation (induration/necrosis), facial Testicular cancer, refractory: Treatment of refractory
swelling, fatigue, fever, hyperpigmentation, hypersen- testicular tumors (in combination with other chemo-
sitivity reaction, interstitial pneumonitis, ischemic heart therapy agents)
disease, laryngospasm, maculopapular rash, malaise, Local Anesthetic/Vasoconstrictor Precautions
metabolic acidosis, mucositis, myocardial infarction, No information available to require special precautions
549
ETOPOSIDE PHOSPHATE
Effects on Dental Treatment Key adverse event(s) avoid pregnancy during treatment. Fetal growth restric-
related to dental treatment: Mucositis (especially at high tion and newborn myelosuppression have been
doses), stomatitis, and taste perversion. observed following maternal use of regimens containing
Effects on Bleeding Myelosuppression is dose etoposide during pregnancy (NTP 2013; Peccatori
related. When thrombocytopenia occurs, platelet nadirs 2013). The European Society for Medical Oncology
develop 10-15 days after drug administration. Bone has published guidelines for diagnosis, treatment, and
marrow recovery is usually complete by day 21, and follow-up of cancer during pregnancy. The guidelines
no cumulative toxicity has been reported. recommend referral to a facility with expertise in cancer
Adverse Reactions Also see adverse reactions for during pregnancy and encourage a multidisciplinary
etoposide; etoposide phosphate is converted to etopo- team (obstetrician, neonatologist, oncology team). In
side, adverse reactions experienced with etoposide general, if chemotherapy is indicated, it should be
would also be expected with etoposide phosphate. avoided during in the first trimester, there should be a
>10%: 3-week time period between the last chemotherapy
Central nervous system: Malaise (≤39%), dose and anticipated delivery, and chemotherapy
chills (≤24%) should not be administered beyond week 33 of gesta-
Dermatologic: Alopecia (33% to 44%) tion. Guidelines for the treatment of SCLC are not
Gastrointestinal: Nausea and vomiting (37%), ano- provided (Peccatori 2013).
rexia (16%), mucositis (11%)
Hematologic & oncologic: Leukopenia (91%; grade 4: In women of reproductive potential, etoposide phos-
17%; nadir: day 15 to 22; recovery: usually by day phate may cause amenorrhea, infertility, or premature
21), neutropenia (88%; grade 4: 37%; nadir: day 12 menopause; effective contraception should be used
to 19; recovery: usually by day 21), anemia (72%; during therapy and for at least 6 months after the last
grades 3/4: 19%), thrombocytopenia (23%; grade 4: dose. In males, azoospermia, oligospermia, or perma-
9%; nadir: day 10 to 15; recovery: usually by day 21) nent loss of fertility may occur. In addition, spermatozoa
Neuromuscular & skeletal: Weakness (≤39%) and testicular tissue may be damaged. Males with
Miscellaneous: Fever (≤24%) female partners of reproductive potential should use
1% to 10%: condoms during therapy and for 4 months after the last
Cardiovascular: Hypotension (1% to 5%), localized dose.
phlebitis (≤5%; including cellulitis at injection site,
local pain, local swelling, local tissue necrosis, tissue
necrosis at injection site), hypertension (3%), facial Etravirine (et ra VIR een)
flushing (2%) Related Information
Central nervous system: Dizziness (5%)
Gastrointestinal: Constipation (8%), abdominal pain Brand Names: US Intelence
(7%), diarrhea (6%), dysgeusia (6%) Brand Names: Canada Intelence
Hypersensitivity: Anaphylactoid reaction (3%; includ- Pharmacologic Category Antiretroviral, Reverse
ing bronchospasm, chills, diaphoresis, dyspnea, Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)
fever, pruritus, rigors, tachycardia) Use HIV-1 infection: Treatment of HIV-1 infection in
Local: Extravasation (≤5%; including cellulitis at injec- combination with other antiretroviral agents in treat-
tion site, local pain, local swelling, local tissue ment-experienced patients 2 years of age and older
necrosis, tissue necrosis at injection site) Local Anesthetic/Vasoconstrictor Precautions
<1%, postmarketing, and/or case reports: Acute leuke- No information available to require special precautions
mia (with/without preleukemia phase), apnea (hyper- Effects on Dental Treatment Key adverse event(s)
sensitivity-associated), back pain, cortical blindness related to dental treatment: Stomatitis has been
(transient), cough, cyanosis, diaphoresis, dysphagia, reported.
erythema, facial swelling, febrile neutropenia, hepato- Effects on Bleeding No information available to
toxicity, hyperpigmentation, infection, interstitial pneu- require special precautions related to hemostasis.
monitis, laryngospasm, maculopapular rash, optic
Adverse Reactions
neuritis, pruritic erythematous rash, pulmonary fibro-
>10%:
sis, radiation recall phenomenon, seizure, Stevens-
Johnson syndrome, swollen tongue, toxic epidermal Dermatologic: Skin rash (10% to 15%)
necrolysis, urticaria Endocrine & metabolic: Increased serum cholesterol
Mechanism of Action Etoposide phosphate is con- (grades 2/3: 8% to 20%), increased serum glucose
verted in vivo to the active moiety, etoposide, by (grades 2/3: 4% to 15%), increased LDL choles-
dephosphorylation. Etoposide inhibits mitotic activity; terol (13%)
inhibits cells from entering prophase; inhibits DNA syn- 1% to 10%:
thesis. Initially thought to be mitotic inhibitors similar to Cardiovascular: Angina pectoris (<2%), atrial fibrilla-
podophyllotoxin, but actually have no effect on micro- tion (<2%), facial edema (<2%), myocardial infarction
tubule assembly. However, later shown to induce DNA (<2%), syncope (<2%)
strand breakage and inhibition of topoisomerase II (an Central nervous system: Peripheral neuropathy (4%),
enzyme which breaks and repairs DNA); etoposide acts abnormal dreams (<2%), amnesia (<2%), anxiety
in late S or early G2 phases. (<2%), confusion (<2%), disorientation (<2%), dis-
Pharmacodynamics/Kinetics turbance in attention (<2%), drowsiness (<2%),
Half-life Elimination Terminal: 4 to 11 hours; Chil- hypersomnia (<2%), hypoesthesia (<2%), lethargy
dren: Normal renal/hepatic function: 6 to 8 hours (<2%), nervousness (<2%), nightmares (<2%), par-
Pregnancy Considerations Based on animal repro- esthesia (<2%), seizure (<2%), sleep disturbance
duction studies and the mechanism of action, etoposide (<2%), vertigo (<2%)
phosphate may cause fetal harm if administered during Dermatologic: Hyperhidrosis (<2%), night sweats
pregnancy. Women of reproductive potential should (<2%), prurigo (<2%), xeroderma (<2%)
550
EVEROLIMUS
Endocrine & metabolic: Increased serum triglycerides tolerance or poor virologic response of current regi-
(grades 2 to 4: 4% to 9%), increased amylase (grade men), and who are not yet pregnant but are trying to
4: 2%), diabetes mellitus (<2%), dyslipidemia (<2%), conceive. In addition, females who become pregnant
gynecomastia (<2%), lipohypertrophy (<2%) while taking etravirine may continue if viral suppression
Gastrointestinal: Diarrhea (children and adolescents: is effective and the regimen is well tolerated. The
≥2%), abdominal distention (<2%), anorexia (<2%), pharmacokinetics of etravirine are not significantly
constipation (<2%), flatulence (<2%), gastritis (<2%), altered in pregnancy and dosing adjustment is not
gastroesophageal reflux disease (<2%), hemateme- needed.
sis (<2%), pancreatitis (<2%), retching (<2%), sto-
matitis (<2%), xerostomia (<2%), increased serum In general, ART is recommended for all pregnant
lipase (grade 4: 1%) females with HIV to keep the viral load below the limit
Hematologic & oncologic: Hemolytic anemia (<2%), of detection and reduce the risk of perinatal trans-
decreased white blood cell count (grade 4: 1%) mission. Monitoring during pregnancy is more frequent
Hepatic: Increased serum alanine aminotransferase than in non-pregnant adults. ART should be continued
(grades 2 to 4: 1% to 6%), increased serum aspar- postpartum for all females living with HIV and can be
tate aminotransferase (grade 3: 3%), hepatic failure modified after delivery.
(<2%), hepatitis (<2%), hepatomegaly (<2%), liver Health care providers are encouraged to enroll preg-
steatosis (<2%) nant females exposed to antiretroviral medications as
Hypersensitivity: Hypersensitivity reaction (<2%) early in pregnancy as possible in the Antiretroviral
Immunologic: Immune reconstitution syndrome (<2%) Pregnancy Registry (1-800-258-4263 or http://www.-
Neuromuscular & skeletal: Tremor (<2%) APRegistry.com). Health care providers caring for
Ophthalmic: Blurred vision (<2%) HIV-infected females and their infants may contact the
Renal: Increased serum creatinine (grades 2/3: 2% to National Perinatal HIV Hotline (888-448-8765) for clin-
6%), acute renal failure (<2%) ical consultation (HHS [perinatal] 2018).
Respiratory: Bronchospasm (<2%), dyspnea on exer-
tion (<2%)
<1%, postmarketing, and/or case reports: Angioedema, Everolimus (e ver OH li mus)
DRESS syndrome, erythema multiforme, hemorrhagic
Related Information
stroke, lipodystrophy, rhabdomyolysis, Stevens-John-
son syndrome, toxic epidermal necrolysis Dentin Hypersensitivity, Acid Erosion, High Caries
Mechanism of Action As a non-nucleoside reverse
mia on page 1548
transcriptase inhibitor, etravirine has activity against
HIV-1 by binding to reverse transcriptase. It conse- Osteonecrosis of the Jaw on page 1486
quently blocks the RNA-dependent and DNA-depend- Brand Names: US Afinitor; Afinitor Disperz; Zortress
ent DNA polymerase activities, including HIV-1 Brand Names: Canada Afinitor; Afinitor Disperz
replication. It does not require intracellular phosphor- Pharmacologic Category Antineoplastic Agent,
ylation for antiviral activity. mTOR Kinase Inhibitor; Immunosuppressant Agent;
Pharmacodynamics/Kinetics mTOR Kinase Inhibitor
Half-life Elimination 41 hours (± 20 hours) Use
Time to Peak 2.5 to 4 hours Breast cancer, advanced (Afinitor only): Treatment
Pregnancy Considerations of advanced hormone receptor-positive, HER2-nega-
Etravirine has a variable (moderate to high) level of tive breast cancer in postmenopausal women (in
transfer across the human placenta. combination with exemestane and after letrozole or
anastrozole failure)
Only limited data has been reported to the antiretroviral Liver transplantation (Zortress only): Prophylaxis of
pregnancy registry and information is insufficient to allograft rejection in liver transplantation (in combina-
evaluate teratogenic effects in humans. Maternal anti- tion with corticosteroids and reduced doses of tacro-
retroviral therapy (ART) may increase the risk of pre- limus, everolimus should not be administered earlier
term delivery, although available information is than 30 days post-transplant)
conflicting possibly due to variability of maternal factors Neuroendocrine tumors (Afinitor only): Treatment of
(disease severity; gestational age at initiation of ther- locally advanced, metastatic or unresectable progres-
apy). An increased risk of stillbirth, low birth weight, and sive pancreatic neuroendocrine tumors (PNET); treat-
small for gestational age infants has been observed in ment of progressive, well-differentiated, nonfunctional
some but not all studies. Because there is clear benefit GI or lung neuroendocrine tumors in patients with
to appropriate treatment, maternal ART should not be unresectable, locally advanced or metastatic disease
withheld due to concerns for adverse neonatal out- Limitations of use: Not indicated for the treatment of
comes. Long-term follow-up is recommended for all functional carcinoid tumors.
infants exposed to antiretroviral medications; children Renal cell carcinoma, advanced (Afinitor only):
who develop significant organ system abnormalities of
Treatment of advanced renal cell cancer (RCC) after
unknown etiology (particularly of the CNS or heart)
sunitinib or sorafenib failure
should be evaluated for potential mitochondrial dysfunc-
Renal transplantation (Zortress only): Prophylaxis of
tion. Hypersensitivity reactions (including hepatic tox-
organ rejection in renal transplant patients at low to
icity and rash) are more common in women on NNRTI
moderate immunologic risk (in combination with basi-
therapy; it is not known if pregnancy increases this risk.
liximab induction and concurrent with corticosteroids
The Health and Human Services (HHS) Perinatal HIV and reduced doses of cyclosporine)
Guidelines do not recommend use in antiretroviral- Tuberous sclerosis complex-associated partial-
naive pregnant females; use is not recommended onset seizures (Afinitor Disperz only): Adjunctive
(except in special circumstances) in pregnant females treatment of partial-onset seizures associated with
who have had ART therapy in the past but are restart- tuberous sclerosis complex (TSC) in adult and pedia-
ing, who require a new ART regimen (due to poor tric patients ≥2 years of age
551
EVEROLIMUS
Tuberous sclerosis complex-associated renal hypotension, palpitations, phlebitis, pulmonary

angiomyolipoma (Afinitor only): Treatment of renal embolism, renal artery thrombosis, syncope, tachy-
angiomyolipoma with TSC not requiring immediate cardia, venous thromboembolism
surgery Central nervous system: Agitation, anxiety, chills,
Tuberous sclerosis complex-associated subepen- depression, dizziness, drowsiness, hallucination,
dymal giant cell astrocytoma (Afinitor or Afinitor hemiparesis, hypoesthesia, lethargy, malaise,
Disperz only): Treatment of subependymal giant cell migraine, myasthenia, neuralgia, pain, paresthesia
astrocytoma (SEGA) associated with TSC in adults Dermatologic: Acne vulgaris, acneiform eruption, alo-
and pediatric patients ≥1 year of age which requires pecia, cellulitis, diaphoresis, ecchymoses, folliculitis,
therapeutic intervention, but cannot be curatively hypertrichosis, night sweats, onychomycosis, pruri-
resected tus, skin rash, tinea pedis
Local Anesthetic/Vasoconstrictor Precautions Endocrine & metabolic: Acidosis, amenorrhea, cush-
No information available to require special precautions ingoid appearance, cyanocobalamin deficiency,
Effects on Dental Treatment Key adverse event(s) dehydration, fluid retention, gout, hirsutism, hyper-
related to dental treatment: High incidence of mouth calcemia, hyperparathyroidism, hypertriglyceride-
ulcers, mucositis, and stomatitis; xerostomia and taste mia, hyperuricemia, hypocalcemia, hypoglycemia,
alterations have been observed (normal salivary flow hyponatremia, hypothyroidism, iron deficiency, ovar-
resumes upon discontinuation) (see Dental Health Pro- ian cyst
fessional Considerations) Gastrointestinal: Stomatitis (kidney transplant: 8%),
Effects on Bleeding No information available to dyspepsia (kidney transplant: 4%), upper abdominal
require special precautions pain (kidney transplant: 3%), abdominal distention,
Adverse Reactions anorexia, biliary obstruction, cholangitis, cholestasis,
Transplantation: decreased appetite, dysphagia, epigastric distress,
Reactions occur in kidney and liver transplantation flatulence, gastritis, gastroenteritis, gastroesopha-
unless otherwise specified. geal reflux disease, gingival hyperplasia, hematem-
>10%: esis, hemorrhoids, hernia of abdominal cavity,
Cardiovascular: Peripheral edema (kidney transplant: inguinal hernia, intestinal obstruction, oral candidia-
45%; liver transplant: 18% to 20%), hypertension sis, oral herpes simplex infection, oral mucosa ulcer,
(17% to 30%) peritoneal effusion, peritonitis
Central nervous system: Headache (18% to 22%), Genitourinary: Erectile dysfunction (kidney transplant:
insomnia (kidney transplant: 17%; liver transplant: 5%), benign prostatic hyperplasia, bladder spasm,
6% to 7%), procedural pain (kidney transplant: nocturia, perinephric abscess, perinephric hema-
15%), fatigue (9% to 11%) toma, pollakiuria, proteinuria, pyuria, scrotal edema,
Endocrine & metabolic: Diabetes mellitus (new onset: urethritis, urinary retention, urinary urgency
liver transplant: 32%, kidney transplant: 9%), hyper- Hematologic & oncologic: Neoplasm (3% to 4%),
kalemia (renal transplant: 18%), hypercholesterole- leukocytosis, lymphadenopathy, lymphorrhea, neu-
mia (9% to 17%), hypomagnesemia (kidney tropenia, pancytopenia, thrombocythemia, thrombo-
transplant: 14%), hypophosphatemia (kidney trans- cytopenia
plant: 13%), hyperglycemia (kidney transplant: 12%), Hepatic: Abnormal hepatic function tests (liver trans-
hypokalemia (kidney transplant: 12%) plant: 7% to 8%), ascites (liver transplant: 4%),
Gastrointestinal: Constipation (kidney transplant: hepatitis (noninfectious), increased liver enzymes,
38%), nausea (kidney transplant: 29%; liver trans- increased serum alkaline phosphatase, increased
plant: 14% to 15%), diarrhea (19% to 24%), vomiting serum bilirubin
(kidney transplant: 15%), abdominal pain (13% Hypersensitivity: Angioedema (<1%)
to 15%) Infection: BK virus (kidney transplant: 1%), bactere-
Genitourinary: Urinary tract infection (kidney trans- mia, candidiasis, cytomegalovirus disease, herpes
plant: 22%), hematuria (kidney transplant: 12%), virus infection, influenza, sepsis, wound infection
Neuromuscular & skeletal: Tremor (8% to 10%),
dysuria (kidney transplant: 11%)
arthralgia, asthenia, joint swelling, muscle spasm,
Hematologic & oncologic: Anemia (kidney transplant:
musculoskeletal pain, myalgia, osteoarthritis, osteo-
26%), leukopenia (3% to 13%)
myelitis, osteonecrosis, osteoporosis, spondylitis
Infection: Infection (kidney transplant: 62%; liver trans-
Ophthalmic: Blurred vision, cataract, conjunctivitis
plant: 50%), viral infection (liver transplant: 17%;
Renal: Renal failure syndrome (5% to 10%; may be
kidney transplant: 10%), bacterial infection (liver
acute), hydronephrosis, increased blood urea nitro-
transplant: 16%), hepatitis C (liver transplant: 11%
gen, interstitial nephritis, polyuria, pyelonephritis,
to 14%)
renal insufficiency, renal tubular necrosis
Local: Incisional pain (kidney transplant: 16%)
Respiratory: Cough (kidney transplant: 7%), atelecta-
Neuromuscular & skeletal: Limb pain (kidney trans-
sis, bronchitis, dyspnea, epistaxis, lower respiratory
plant: 12%), back pain (kidney transplant: 11%)
tract infection, nasal congestion, nasopharyngitis,
Renal: Increased serum creatinine (kidney trans-
oropharyngeal pain, paranasal sinus congestion,
plant: 18%)
pleural effusion, pneumonia, pulmonary edema, rhi-
Respiratory: Upper respiratory tract infection (kidney
norrhea, sinusitis, wheezing
transplant: 16%)
Miscellaneous: Postoperative wound complication Antineoplastic:
(kidney transplant: 35%; liver transplant: 11%; Antineoplastic indications include advanced hormone
includes incisional hernia, lymphocele, seroma, receptor-positive, advanced nonfunctional NET of gas-
wound dehiscence), fever (13% to 19%) trointestinal or lung origin, HER2-negative breast can-
1% to 10%: cer, pancreatic neuroendocrine tumors, renal cell
Cardiovascular: Hypertensive crisis (1%), angina pec- carcinoma, and tuberous sclerosis complex associ-
toris, atrial fibrillation, cardiac failure, chest discom- ated renal angiomyolipoma, subependymal giant cell
fort, chest pain, deep vein thrombosis, edema, astrocytoma, or seizures
552
EVEROLIMUS
>10%: Gastrointestinal: Gastroenteritis (10%), hemorrhoids

Cardiovascular: Edema (≤39%), peripheral edema (5%), dysphagia (4%)
(≤39%), hypertension (4% to 13%) Genitourinary: Vaginal hemorrhage (8%), dysmenor-
Central nervous system: Fatigue (≤45%), malaise rhea (6%), uterine hemorrhage (6%), cystitis (3%),
(≤45%), headache (≤30%), migraine (≤30%), behav- proteinuria (2%)
ioral problems (21%; includes abnormal behavior, Hematologic & oncologic: Hemorrhage (3%)
agitation, anxiety, obsessive compulsive symptoms, Hepatic: Increased serum bilirubin (3%)
panic attack), insomnia (6% to 14%), dizziness (7% Hypersensitivity: Hypersensitivity reaction (≤3%;
to 12%) includes anaphylaxis, chest pain, dyspnea, flushing),
Dermatologic: Skin rash (6% to 59%), cellulitis (29%), angioedema (≤1%)
acne vulgaris (10% to 22%), nail disease (5% to Infection: Candidiasis (<1%), hepatitis C (<1%), sep-
22%), pruritus (13% to 21%), xeroderma (13%) sis (<1%)
Endocrine & metabolic: Hypercholesterolemia (71% to Neuromuscular & skeletal: Muscle spasm (10%), jaw
86%), hyperglycemia (14% to 75%), hypertriglycer- pain (3%)
idemia (27% to 73%), decreased serum bicarbonate Ophthalmic: Eyelid edema (4%), conjunctivitis (2%)
(56%), hypophosphatemia (9% to 49%), decreased Otic: Otitis media (6%)
serum calcium (37%), hypokalemia (27%), hypoal- Renal: Renal failure syndrome (3%)
buminemia (18%), amenorrhea (15% to 17%) Respiratory: Streptococcal pharyngitis (10%), pleural
Gastrointestinal: Stomatitis (9% to 78%), diarrhea effusion (7%), pneumonia (2% to 6%), bronchitis
(14% to 50%), abdominal pain (5% to 36%), (4%), pharyngolaryngeal pain (4%), rhinorrhea
decreased appetite (6% to 30%), vomiting (10% to (3%), sinusitis (3%)
29%), nausea (8% to 29%), weight loss (5% to 28%), Miscellaneous: Postoperative wound complication
anorexia (25%), dysgeusia (5% to 22%), mucositis (<1%; wound healing impairment)
(19%), constipation (10% to 14%), xerostomia (8%
<1%, postmarketing, and/or case reports: Arterial
to 11%)
thrombosis, aspergillosis, azoospermia, cholecystitis,
Genitourinary: Urinary tract infection (5% to 16%),
cholelithiasis, complex regional pain syndrome,
irregular menses (10% to 11%)
decreased plasma testosterone, hypersensitivity
Hematologic & oncologic: Anemia (27% to 81%;
angiitis, male infertility, nephrotoxicity, oligospermia,
grades 3/4: 5% to 15%), increase in fasting plasma
pancreatitis (including acute pancreatitis), pericardial
glucose (14% to 75%, grades 3/4: 17%), prolonged
effusion, polyoma virus infection, progressive multi-
partial thromboplastin time (72%; grades 3/4: 3%),
lymphocytopenia (20% to 66%, grades 3/4: 1% to focal leukoencephalopathy, reactivation of HBV, res-
18%), leukopenia (37% to 49%; grades 3/4: 2%), piratory distress, septic shock, thrombosis of vascular
neutropenia (25% to 46%, grades 3/4: ≤9%), throm- graft (kidney), thrombotic microangiopathy
bocytopenia (12% to 33%; grades 3/4: 1% to 3%) Mechanism of Action Everolimus is a macrolide
Hepatic: Increased serum alkaline phosphatase (32% immunosuppressant and a mechanistic target of rapa-
to 74%), increased serum aspartate aminotransfer- mycin (mTOR) inhibitor which has antiproliferative and
ase (13% to 69%), increased serum alanine amino- antiangiogenic properties, and also reduces lipoma
transaminase (17% to 51%) volume in patients with angiomyolipoma. Reduces pro-
Infection: Infection (37% to 58%) tein synthesis and cell proliferation by binding to the FK
Neuromuscular & skeletal: Asthenia (13% to 33%), binding protein-12 (FKBP-12), an intracellular protein,
arthralgia (13% to 20%), back pain (14% to 15%), to form a complex that inhibits activation of mTOR
limb pain (8% to 14%) (mechanistic target of rapamycin) serine-threonine kin-
Renal: Increased serum creatinine (19% to 50%) ase activity. Also reduces angiogenesis by inhibiting
Respiratory: Respiratory tract infection (31%), cough vascular endothelial growth factor (VEGF) and hypo-
(10% to 30%; includes productive cough), nasophar- xia-inducible factor (HIF-1) expression. Angiomyolipo-
yngitis (≤25%), rhinitis (≤25%), upper respiratory mas may occur due to unregulated mTOR activity in
tract infection (≤25%), dyspnea (20% to 24%; TSC-associated renal angiomyolipoma (Budde 2012);
includes dyspnea on exertion), epistaxis (5% to everolimus reduces lipoma volume (Bissler 2013).
22%), pneumonitis (≤19%; may include interstitial Pharmacodynamics/Kinetics
pulmonary disease, pulmonary alveolar hemorrhage, Half-life Elimination ~30 hours (Afinitor and Zor-
pulmonary alveolitis, pulmonary fibrosis, pulmonary tress); in pediatric renal transplant patients (3 to 16
infiltrates, pulmonary toxicity, restrictive pulmonary years), half-life similar to adult data (Van Damme-
disease), oropharyngeal pain (11%) Lombaerts 2002)
Miscellaneous: Fever (14% to 31%) Time to Peak 1 to 2 hours (Afinitor and Zortress)
1% to 10%: Pregnancy Considerations
Cardiovascular: Chest pain (5%), tachycardia (3%), Based on the mechanism of action and data from
cardiac failure (1%), deep vein thrombosis (<1%) animal reproduction studies, everolimus may cause
Central nervous system: Depression (5%), paresthe- fetal harm if administered during pregnancy. Information
sia (5%), chills (4%), aggressive behavior (≤2%) related to the use of everolimus in pregnancy is limited
Dermatologic: Alopecia (10%), palmar-plantar eryth- (Yamamura 2017).
rodysesthesia (5%), erythema (4%), onychoclasis
(4%), skin lesion (4%), acneiform eruption (3%) Verify pregnancy status in females of reproductive
Endocrine & metabolic: Diabetes mellitus (10%; new potential prior to initiating therapy. Females of repro-
onset: <1%), heavy menstrual bleeding (6% to 10%), ductive potential should be advised to avoid pregnancy
menstrual disease (6% to 10%), decreased serum and use highly effective birth control during treatment
fibrinogen (8%), increased luteinizing hormone (1% and for 8 weeks after the last everolimus dose. Male
to 4%), increased follicle-stimulating hormone (3%), patients with female partners of reproductive potential
ovarian cyst (≤3%), exacerbation of diabetes melli- should use effective contraception during treatment and
tus (2%) for 4 weeks after the last everolimus dose.
553
EVEROLIMUS
Everolimus may cause infertility. In females, menstrual Respiratory: Upper respiratory tract infection (9%),
irregularities, secondary amenorrhea, and increases in cough (1% to 5%), sinusitis (4%)
luteinizing hormone and follicle-stimulating hormone <1%, postmarketing, and/or case reports: Angioedema,
have occurred. Azoospermia and oligospermia have antibody development, flu-like symptoms, hypersensi-
been observed in males. Females of reproductive tivity reaction
potential should consider family planning options prior Mechanism of Action Evolocumab is a human mono-
to therapy. clonal antibody (IgG2 isotype) that binds to proprotein
convertase subtilisin kexin type 9 (PCSK9). PCSK9
The Transplant Pregnancy Registry International (TPR)
binds to the low-density lipoprotein receptors (LDLR)
is a registry that follows pregnancies that occur in
on hepatocyte surfaces to promote LDLR degradation
maternal transplant recipients or those fathered by male
within the liver. LDLR is the primary receptor that clears
transplant recipients. The TPR encourages reporting of circulating LDL; therefore, the decrease in LDLR levels
pregnancies following solid organ transplant by contact- by PCSK9 results in higher blood levels of LDL-choles-
ing them at 1-877-955-6877 or https://www.- terol (LDL-C). By inhibiting the binding of PCSK9 to
transplantpregnancyregistry.org. LDLR, evolocumab increases the number of LDLRs
Dental Health Professional Considerations Con- available to clear LDL from the blood, thereby lowering
sider a medical consultation prior to any invasive dental LDL-C levels.
procedure in patients who have received an organ Pharmacodynamics/Kinetics
transplant; delayed wound healing due to the immuno- Onset of Action Peak effect: Proprotein convertase
suppressive effects and an increased potential for post- subtilisin kexin type 9 (PCSK9) suppression: 4 hours
operative infection may be of concern. Half-life Elimination 11 to 17 days
Time to Peak SubQ: 3 to 4 days
Evolocumab (e voe LOK ue mab) Pregnancy Considerations Adverse events were not
observed in animal reproduction studies. IgG antibodies
Brand Names: US Repatha; Repatha Pushtronex are known to cross the placenta in increasing amounts
System; Repatha SureClick during the second and third trimesters; exposure of the
Brand Names: Canada Repatha fetus to evolocumab is expected.
Pharmacologic Category Antilipemic Agent, PCSK9
Inhibitor; Monoclonal Antibody
Use
Exemestane (ex e MES tane)
Homozygous familial hypercholesterolemia: Adjunct Brand Names: US Aromasin

to diet and other LDL-lowering therapies (eg, statins, Brand Names: Canada Aromasin; CO Exemestane
ezetimibe, LDL apheresis) for the treatment of patients Pharmacologic Category Antineoplastic Agent, Aro-
with homozygous familial hypercholesterolemia who matase Inhibitor
require additional lowering of LDL-C Use Breast cancer: Treatment of advanced breast
Hyperlipidemia, primary: Adjunct to diet, alone or in cancer in postmenopausal women whose disease has
combination with other lipid-lowering therapies (eg, progressed following tamoxifen therapy; adjuvant treat-
maximum tolerated dose of statins), for the treatment ment of postmenopausal women with estrogen recep-
of adults with primary hyperlipidemia, including heter- tor-positive early breast cancer following 2 to 3 years of
ozygous familial hyperlipidemia, to reduce LDL-C tamoxifen (for a total of 5 consecutive years of adjuvant
(Sabatine 2015) therapy).
Prevention of cardiovascular events in patients with Local Anesthetic/Vasoconstrictor Precautions
established cardiovascular disease: To reduce the No information available to require special precautions
risk of MI, stroke, and coronary revascularization in Effects on Dental Treatment No significant effects or
adults with established cardiovascular disease. Note: complications reported
Use in combination with an optimized regimen of lipid- Effects on Bleeding No information available to
lowering therapy (eg, high-intensity statin) (Saba- require special precautions
tine 2017).
Adverse Reactions
Local Anesthetic/Vasoconstrictor Precautions Frequency not always defined. *Incidence not specifi-
No information available to require special precautions cally defined, but reported in the range of 1% to 10%.
Effects on Dental Treatment Key adverse event(s) Cardiovascular: Hypertension (5% to 15%), edema (6%
related to dental treatment: Nasopharyngitis has been to 7%), ischemic heart disease (2%; angina pectoris,
reported myocardial infarction), chest pain*
Effects on Bleeding No information available to Central nervous system: Fatigue (8% to 22%), insomnia
require special precautions (11% to 14%), pain (13%), headache (7% to 13%),
Adverse Reactions depression (6% to 13%), dizziness (8% to 10%),
>10%: Respiratory: Nasopharyngitis (6% to 11%) anxiety (4% to 10%), paresthesia (3%), carpal tunnel
1% to 10%: syndrome (2%), confusion,* hypoesthesia*
Cardiovascular: Hypertension (3%) Dermatological: Hyperhidrosis (4% to 18%), alopecia
Central nervous system: Dizziness (4%), fatigue (2%) (15%), dermatitis (8%), pruritus,* skin rash*
Dermatologic: Skin rash (1%) Endocrine & metabolic: Hot flash (13% to 33%), weight
Endocrine & metabolic: Diabetes mellitus (9%) gain (8%), increased follicle-stimulating hormone,
Gastrointestinal: Gastroenteritis (3% to 6%), nau- increased luteinizing hormone, increased sex hor-
sea (2%) mone binding globulin (with daily doses of ≥2.5 mg;
Genitourinary: Urinary tract infection (5%) dose-dependent)
Hematologic & oncologic: Bruise (1%) Gastrointestinal: Nausea (9% to 18%), abdominal pain
Infection: Influenza (8% to 9%) (6% to 11%), diarrhea (4% to 10%), vomiting (7%),
Local: Injection site reaction (6%) anorexia (6%), constipation (5%), increased appetite
Neuromuscular & skeletal: Myalgia (4%) (3%), dyspepsia*
554
EXENATIDE
Genitourinary: Urinary tract infection (2% to 5%) Immunologic: Immunogenicity (20%, injection site
Hematologic & oncologic: Lymphedema* reaction)
Hepatic: Increased serum alkaline phosphatase (14% Local: Injection site reaction (17%), injection site nod-
to 15%), increased serum bilirubin (5% to 7%) ule (11%)
Infection: Infection* 1% to 10%:
Neuromuscular & skeletal: Arthralgia (15% to 29%), Central nervous system: Headache (4% to 8%), dizzi-
back pain (9%), limb pain (9%), myalgia (6%), osteo- ness (extended release: 3%; immediate release:
arthritis (6%), weakness (6%), osteoporosis (5%), ≥1% to 2%)
pathological fracture (4%), muscle cramps (2%) Dermatologic: Injection site pruritus (3%)
Ophthalmic: Visual disturbance (5%) Endocrine & metabolic: Hypoglycemia (4% to 5%),
Renal: Increased serum creatinine (6%) severe hypoglycemia (≤2%)
Respiratory: Dyspnea (10%), cough (6%), flu-like symp- Gastrointestinal: Constipation (2% to 9%), dyspepsia
toms (6%), bronchitis,* pharyngitis,* rhinitis,* sinusitis,* (extended release: 7%; immediate release: 3%),
upper respiratory tract infection* vomiting (immediate release: 4%, extended release:
Miscellaneous: Fever (5%) 3%), decreased appetite (immediate release: ≥1%
<1%, postmarketing, and/or case reports: Abnormal to <2%)
bone growth (osteochondrosis), acute generalized Immunologic: Antibody development (extended
exanthematous pustulosis, cardiac failure, cholestatic release: 6%; immediate release: 1%; associated with
hepatitis, endometrial hyperplasia, endometrial pol- glycemic response)
yps, gastric ulcer, hepatitis, hypersensitivity reaction, Local: Erythema at injection site (2% to 5%)
increased gamma-glutamyl transferase, increased Frequency not defined: Cardiovascular: Increased heart
serum transaminases, neuropathy, tenosynovitis (fin- rate (Robinson 2013)
gers), thromboembolism, urticaria <1%, postmarketing, and/or case reports (all formula-
Mechanism of Action Exemestane is an irreversible, tions): Abdominal distention, abdominal pain, abscess
steroidal aromatase inactivator. It is structurally related at injection site, acute pancreatitis, acute renal failure,
to androstenedione, and is converted to an intermediate alopecia, anaphylaxis, angioedema, cellulitis at injec-
that irreversibly blocks the active site of the aromatase tion site, drowsiness, dysgeusia, eructation, exacer-
enzyme, leading to inactivation ("suicide inhibition") and bation of renal failure, flatulence, hemorrhagic
thus preventing conversion of androgens to estrogens pancreatitis, hypersensitivity reaction, increased
in peripheral tissues. Significantly lowers circulating serum creatinine, kidney transplant dysfunction, mac-
estrogens in postmenopausal breast cancers where ular eruption, necrotizing pancreatitis, papular rash,
growth is estrogen-dependent. prolongation P-R Interval on ECG (Linnebjerg 2011),
Pharmacodynamics/Kinetics pruritus, renal function abnormality, renal insufficiency,
Half-life Elimination ~24 hours tissue necrosis at injection site, urticaria
Time to Peak Women with breast cancer: 1.2 hours Mechanism of Action Exenatide is an analog of the
hormone incretin (glucagon-like peptide 1 or GLP-1)
Pregnancy Considerations Exemestane is not indi-
which increases glucose-dependent insulin secretion,
cated for use in premenopausal women. Based on the
decreases inappropriate glucagon secretion, increases
mechanism of action and on animal data, exemestane
B-cell growth/replication, slows gastric emptying, and
is expected to cause fetal harm if administered to a
decreases food intake. Exenatide administration results
pregnant woman. Women of reproductive potential in decreases in hemoglobin A1c by approximately 0.5%
should use effective contraception during treatment to 1% (immediate release) or 1.5% to 1.9% (extended
and for 1 month after the final dose. Pregnancy testing release).
is recommended (for females of reproductive potential) Pharmacodynamics/Kinetics
within 7 days prior to therapy initiation. Half-life Elimination
Immediate release (daily) formulation: 2.4 hours
Exenatide (ex EN a tide) Extended release (weekly) formulation: ~2 weeks
Time to Peak SubQ:
Related Information Immediate release (daily) formulation: 2.1 hours
Endocrine Disorders and Pregnancy on page 1471 Extended release (weekly) formulation: Single dose:
Brand Names: US Bydureon; Bydureon BCise; Byetta Initial period of release of surface-bound exenatide is
10 MCG Pen; Byetta 5 MCG Pen followed by a gradual release from microspheres
Brand Names: Canada Bydureon; Byetta with peaks at week 2 and week 6 to 7 respectively;
Pharmacologic Category Antidiabetic Agent, Gluca- with once-weekly dosing steady state is achieved at
gon-Like Peptide-1 (GLP-1) Receptor Agonist 6 to 7 weeks (Bydureon) and 10 weeks (Bydureon
Use Diabetes mellitus, type 2: Treatment of type 2 BCise).
diabetes mellitus to improve glycemic control as an Pregnancy Considerations
adjunct to diet and exercise. Based on in vitro data, exenatide has a low potential to
Local Anesthetic/Vasoconstrictor Precautions cross the placenta (Hiles 2003).
No information available to require special precautions In women with diabetes, maternal hyperglycemia can
Effects on Dental Treatment No significant effects or be associated with congenital malformations as well as
complications reported adverse effects in the fetus, neonate, and the mother
Effects on Bleeding No information available to (ACOG 2005; ADA 2018c; Metzger 2007). To prevent
require special precautions adverse outcomes, prior to conception and throughout
Adverse Reactions Incidence rates are for the pregnancy maternal blood glucose and HbA1c should
extended release formulation unless otherwise noted. be kept as close to target goals as possible but without
>10%: causing significant hypoglycemia (ADA 2018c; Blumer
Gastrointestinal: Nausea (extended release: 8% to 2013). Agents other than exenatide are currently rec-
11%; immediate release: 8%), diarrhea (extended ommended to treat diabetes in pregnant women (ADA
release: 4% to 11%; immediate release: ≥1% to 2%) 2018c).
555
EZETIMIBE
an increased clearance of cholesterol from the blood;

Ezetimibe (ez ET i mibe) decreases total C, LDL-cholesterol (LDL-C), ApoB, and
triglycerides (TG) while increasing HDL-cholesterol
Related Information (HDL-C).
Cardiovascular Diseases on page 1442 Pharmacodynamics/Kinetics
Brand Names: US Zetia Onset of Action Within 1 week; Maximum effect: 2-4
Brand Names: Canada Ezetrol weeks
Pharmacologic Category Antilipemic Agent, 2-Azeti- Half-life Elimination 22 hours (ezetimibe and metab-
dinone olite)
Use Time to Peak Plasma: 4-12 hours (ezetimibe); 1-2
Homozygous familial hypercholesterolemia: In com- hours (active metabolite); Effects: ~2 weeks
bination with atorvastatin or simvastatin for the reduc- Pregnancy Risk Factor C
tion of elevated total cholesterol (total-C) and low- Pregnancy Considerations Adverse events were
density lipoprotein cholesterol (LDL-C) levels in observed in some animal reproduction studies. Use is
patients with homozygous familial hypercholesterole- contraindicated in pregnant women who require combi-
mia as an adjunct to other lipid-lowering treatments nation therapy with an HMG-CoA reductase inhibitor. If
(eg, LDL apheresis) or if such treatments are unavail- treatment for familial hypercholesterolemia is needed
able. during pregnancy, other agents are preferred (Wiegman
Homozygous sitosterolemia: As adjunctive therapy to 2015).
diet for the reduction of elevated sitosterol and cam-
pesterol levels in patients with homozygous familial
sitosterolemia. Ezetimibe and Simvastatin
Primary hyperlipidemia: (ez ET i mibe & SIM va stat in)
Combination therapy with HMG-CoA reductase inhib-
Related Information
itors: In combination with a 3-hydroxy-3-methylglu-
taryl-coenzyme A (HMG-CoA) reductase inhibitor Ezetimibe on page 556
(statin) as adjunctive therapy to diet for the reduction Simvastatin on page 1200
of elevated total-C, LDL-C, apolipoprotein B (apo B), Brand Names: US Vytorin
and non-high-density lipoprotein cholesterol (non- Pharmacologic Category Antilipemic Agent, 2-Azeti-
HDL-C) in patients with primary (heterozygous fam- dinone; Antilipemic Agent, HMG-CoA Reductase Inhib-
ilial and nonfamilial) hyperlipidemia. itor
Combination therapy with fenofibrate: In combination Use
with fenofibrate as adjunctive therapy to diet for the Homozygous familial hypercholesterolemia: As an
reduction of elevated total-C, LDL-C, apo B, and adjunct to diet for the reduction of elevated total
non-HDL-C in adult patients with mixed hyperlipi- cholesterol (total-C) and low-density lipoprotein cho-
demia. lesterol (LDL-C) in patients with homozygous familial
Monotherapy: As adjunctive therapy to diet for the hypercholesterolemia, as an adjunct to other lipid-low-
reduction of elevated total-C, LDL-C, apo B, and ering treatments (eg, LDL apheresis), or if such treat-
non-HDL-C in patients with primary (heterozygous ments are unavailable
familial and nonfamilial) hyperlipidemia. Primary hyperlipidemia: As an adjunct to diet for the
Local Anesthetic/Vasoconstrictor Precautions reduction of elevated total-C, LDL-C, apolipoprotein B
No information available to require special precautions (apo B), triglycerides, and non-high-density lipoprotein
Effects on Dental Treatment No significant effects or cholesterol (HDL-C), and to increase HDL-C in
complications reported patients with primary (heterozygous familial and non-
Effects on Bleeding No information available to familial) hyperlipidemia or mixed hyperlipidemia
require special precautions Guideline recommendations:
Adverse Reactions Simvastatin: Primary and secondary prevention of
1% to 10%: atherosclerotic cardiovascular disease (ASCVD) to
Central nervous system: Fatigue (2%) reduce the risk of ASCVD in select adult patients
Gastrointestinal: Diarrhea (4%) (ACC/AHA [Stone 2013]; ADA 2017a; NLA [Jacob-
Hepatic: Increased serum transaminases (with HMG- son 2015]; USPSTF 2016). Refer to respective
CoA reductase inhibitors; ≥3 x ULN: 1%) guideline for specific recommendations.
Infection: Influenza (2%)
Neuromuscular & skeletal: Arthralgia (3%), limb Limitations of use: No incremental benefit of ezetimibe/
pain (3%) simvastatin on cardiovascular morbidity and mortality
Respiratory: Upper respiratory tract infection (4%), over and above that demonstrated for simvastatin has
sinusitis (3%) been established. Ezetimibe/simvastatin has not been
<1%, postmarketing, and/or case reports: Abdominal studied in Fredrickson type I, III, IV, and V dyslipi-
pain, anaphylaxis, angioedema, autoimmune hepatitis demias.
(Stolk 2006), cholecystitis, cholelithiasis, cholestatic Local Anesthetic/Vasoconstrictor Precautions
hepatitis (Stolk 2006), depression, dizziness, eryth- No information available to require special precautions
ema multiforme, headache, hepatitis, hypersensitivity Effects on Dental Treatment Key adverse event(s)
reaction, increased creatine phosphokinase, myalgia, related to dental treatment: Assess unusual presenta-
myopathy, nausea, pancreatitis, paresthesia, rhabdo- tions of muscle weakness or myopathy resulting from
myolysis, skin rash, thrombocytopenia, urticaria lipid therapy such as patient having a difficult time
Mechanism of Action Inhibits absorption of choles- brushing teeth or weakness with chewing. Refer patient
terol at the brush border of the small intestine via the back to their physician for evaluation and adjustment of
sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). lipid therapy.
This leads to a decreased delivery of cholesterol to Effects on Bleeding No information available to
the liver, reduction of hepatic cholesterol stores and require special precautions
556
FAMOTIDINE
Adverse Reactions Incidences refer to combination, Hepatic: Increased serum ALT (3%), increased serum
Vytorin. Also see individual agents. AST (2%), increased serum bilirubin (2%)
1% to 10%: <1%, postmarketing, and/or case reports: Abnormal
Central nervous system: Headache (6%) hepatic function tests, anaphylactic shock, anaphy-
Gastrointestinal: Diarrhea (3%) laxis, anemia, angioedema (eyelid edema, facial
Hepatic: Increased serum ALT (4%) edema, periorbital edema, pharyngeal edema), cho-
Infection: Influenza (2%) lestatic jaundice, confusion, delirium, disorientation,
Neuromuscular & skeletal: Myalgia (4%), limb pain dizziness, drowsiness, erythema multiforme, halluci-
(2%), myopathy nation, hypersensitivity angiitis, palpitations, seizure,
Respiratory: Upper respiratory infection (4%) Stevens-Johnson syndrome, thrombocytopenia, toxic
Mechanism of Action epidermal necrolysis, urticaria
Ezetimibe: Inhibits absorption of cholesterol at the Mechanism of Action Famciclovir undergoes rapid
brush border of the small intestine, leading to a
biotransformation to the active compound, penciclovir
decreased delivery of cholesterol to the liver. Ezeti-
(prodrug), which is phosphorylated by viral thymidine
mibe inhibits the enzyme Niemann-Pick C1-Like1
kinase in HSV-1, HSV-2, and VZV-infected cells to a
(NPC1L1), a sterol transporter.
Simvastatin: A methylated derivative of lovastatin that monophosphate form; this is then converted to penci-
acts by competitively inhibiting 3-hydroxy-3-methylglu- clovir triphosphate and competes with deoxyguanosine
taryl-coenzyme A (HMG-CoA) reductase, the enzyme triphosphate to inhibit HSV-2 polymerase, therefore,
that catalyzes the rate-limiting step in cholesterol herpes viral DNA synthesis/replication is selectively
biosynthesis. In addition to the ability of HMG-CoA inhibited.
reductase inhibitors to decrease levels of high-sensi- Pharmacodynamics/Kinetics
tivity C-reactive protein (hsCRP), they also possess Half-life Elimination
pleiotropic properties including improved endothelial Penciclovir: 2 to 4 hours; Prolonged in renal impair-
function, reduced inflammation at the site of the cor- ment:
onary plaque, inhibition of platelet aggregation, and CrCl 40 to 59 mL/minute: ~3.4 hours
anticoagulant effects (de Denus 2002; Ray 2005). CrCl 20 to 39 mL/minute: ~6.2 hours
Pregnancy Risk Factor X CrCl <20 mL/minute: ~13.4 hours
Pregnancy Considerations Use is contraindicated in Intracellular penciclovir triphosphate: HSV 1: 10 hours;
pregnant women or women who may become pregnant. HSV 2: 20 hours; VZV: 7 hours
See individual agents. Time to Peak Penciclovir: ~1 hour
Famciclovir (fam SYE kloe veer) Based on available data, use during pregnancy appears
to be well tolerated; however, other agents are pre-
Related Information ferred when treatment is needed (CDC [Workowski
Systemic Viral Diseases on page 1496 2015]; Werner 2017).
Viral Infections on page 1540
Health care providers are encouraged to enroll women
Brand Names: US Famvir [DSC]
exposed to famciclovir during pregnancy in the Famvir
Brand Names: Canada Apo-Famciclovir; Ava-Famci-
clovir; CO Famciclovir; Famvir; PMS-Famciclovir; San- Pregnancy reporting system (888-669-6682).
doz-Famciclovir
Pharmacologic Category Antiviral Agent Famotidine (fa MOE ti deen)
Use Treatment of acute herpes zoster (shingles) in
immunocompetent patients; treatment and suppression Related Information
of recurrent episodes of genital herpes in immunocom- Gastrointestinal Disorders on page 1465
petent patients; treatment of herpes labialis (cold sores) Brand Names: US Acid Controller Max St [OTC]; Acid
in immunocompetent patients; treatment of recurrent Controller Original Str [OTC]; Acid Reducer Maximum
orolabial/genital (mucocutaneous) herpes simplex in Strength [OTC]; Acid Reducer [OTC]; Heartburn Relief
HIV-infected adult patients Max St [OTC]; Heartburn Relief [OTC]; Pepcid; Pepcid
Local Anesthetic/Vasoconstrictor Precautions AC Maximum Strength [OTC]
No information available to require special precautions Brand Names: Canada Acid Control; Apo-Famotidine;
Effects on Dental Treatment No significant effects or Famotidine Omega; Maximum Strength Pepcid AC;
complications reported Mylan-Famotidine; Pepcid AC; Pepcid Complete; Pep-
Effects on Bleeding No information available to tic guard; Teva-Famotidine; Ulcidine
require special precautions Pharmacologic Category Histamine H2 Antagonist
Adverse Reactions Frequencies vary with dose and Use
duration.
Oral:
>10%:
Gastroesophageal reflux disease: Treatment of
Gastrointestinal: Nausea (11% to 13%) gastroesophageal reflux disease (GERD) and
1% to 10%: esophagitis due to GERD.
Central nervous system: Fatigue (≤5%), migraine Heartburn (OTC only): Relief of heartburn, acid indi-
(≤3%), paresthesia (≤3%) gestion, and sour stomach.
Dermatologic: Pruritus (2% to 4%), skin rash (3%) Peptic ulcer disease: Treatment of active duodenal
Gastrointestinal: Diarrhea (2% to 8%), flatulence or gastric ulcers. Note: Although a labeled indication,
(≤5%), vomiting (≤5%) proton pump inhibitors (PPIs) are considered the
Genitourinary: Dysmenorrhea (≤8%) standard of care for treatment of peptic ulcer disease
Hematologic & oncologic: Neutropenia (3%), leukope- (PUD) rather than H 2 -receptor antagonists (eg,
nia (1%) famotidine) (Lanas 2017; Vakil 2019).
557
FAMOTIDINE
Injection:
Patients not able to take oral medication: As an Febuxostat (feb UX oh stat)
alternative to the oral dosage form for short-term use
in patients who are unable to take oral medication. Brand Names: US Uloric
Local Anesthetic/Vasoconstrictor Precautions Brand Names: Canada Uloric
No information available to require special precautions Pharmacologic Category Antigout Agent; Xanthine
Effects on Dental Treatment No significant effects or Oxidase Inhibitor
Effects on Bleeding No information available to Hyperuricemia: Chronic management of hyperurice-
require special precautions mia in patients with gout who have an inadequate
Adverse Reactions All reported ADRs are for the oral response to a maximally titrated dose of allopurinol,
formulations unless otherwise noted. who are intolerant to allopurinol, or for whom treat-
>10%: Central nervous system: Agitation (infants: ment with allopurinol is not advisable
≤14%; adults: <1%) Limitations of use: Not recommended for treatment of
1% to 10%: asymptomatic hyperuricemia.
Central nervous system: Headache (5%), dizzi- Local Anesthetic/Vasoconstrictor Precautions
ness (1%) No information available to require special precautions
Gastrointestinal: Diarrhea (2%), constipation (1%), Effects on Dental Treatment Key adverse event(s)
necrotizing enterocolitis (very low birth weight neo- related to dental treatment: Xerostomia (normal salivary
nates; Guillet 2006) flow resumes upon discontinuation) and taste alteration
Frequency not defined: Local: Irritation at injection has been reported in <1% of patients.
site (IV) Effects on Bleeding No information available to
<1%, postmarketing, and/or case reports: Abdominal require special precautions
distress, acne vulgaris, agranulocytosis, alopecia, Adverse Reactions
anaphylaxis, angioedema, anorexia, anxiety, arthral- 1% to 10%:
gia, asthenia, atrioventricular block, bronchospasm, Dermatologic: Skin rash (1% to 2%)
cardiac arrhythmia, cholestatic jaundice, confusion, Gastrointestinal: Nausea (1%)
conjunctival injection, decreased libido, depression, Hepatic: Liver function abnormalities (5% to 7%)
drowsiness, facial edema, fatigue, fever, flushing, Neuromuscular & skeletal: Arthralgia (1%)
hallucination, hepatitis, hypersensitivity reaction, <1%, postmarketing, and/or case reports: Abnormal
impotence, increased liver enzymes, insomnia, inter- electroencephalogram, abnormal gait, aggressive
stitial pneumonitis, leukopenia, muscle cramps, mus- behavior, agitation, agranulocytosis, alopecia, ana-
culoskeletal pain, nausea, palpitations, pancytopenia, phylaxis, anemia, angina pectoris, angioedema, ano-
paresthesia, periorbital edema, prolonged Q-T interval rexia, anxiety, arthralgia, atrial fibrillation, atrial flutter,
on ECG, pruritus, psychiatric disturbance, rhabdo- blurred vision, bruise, cardiac failure, cerebral infarc-
myolysis, seizure, skin rash, Stevens-Johnson syn- tion, cerebrovascular accident, cholecystitis, choleli-
drome, taste disorder, thrombocytopenia, tinnitus, thiasis, constipation, deafness, decreased
toxic epidermal necrolysis, urticaria, vomiting, xero- hematocrit, decreased libido, decreased serum bicar-
derma, xerostomia bonate, decreased urine output, dehydration, depres-
Mechanism of Action Competitive inhibition of hista- sion, dermatitis, diabetes mellitus, DRESS syndrome,
dysgeusia, dyspepsia, dyspnea, ECG abnormality,
mine at H2 receptors of the gastric parietal cells, which
eczema, edema, eosinophilia, epistaxis, erectile dys-
inhibits gastric acid secretion
Pharmacodynamics/Kinetics function, erythema multiforme, flu-like symptoms,
flushing, gastritis, gastroesophageal reflux disease,
Onset of Action Antisecretory effect: Oral: Within 1
gingival pain, Guillain-Barré syndrome, gynecomastia,
hour; Peak effect: Antisecretory effect: Oral: Within 1
hair discoloration, heart murmur, hematemesis, hem-
to 3 hours (dose-dependent); IV: Within 30 minutes
atochezia, hematuria, hemiparesis, hepatic failure,
Duration of Action Antisecretory effect: IV, Oral: 10 hepatitis, hepatomegaly, herpes zoster, hirsutism, hot
to 12 hours
flash, hyperacidity, hypercholesterolemia, hyperglyce-
Half-life Elimination IV: mia, hyperhidrosis, hyperkalemia, hyperlipidemia,
Infants: ≤3 months: 8.1 ± 3.5 hours to 10.5 ± 5.4 hours; hypernatremia, hypersensitivity reaction, hyperten-
>3 to 12 months: 4.5 ± 1.1 hours sion, hypertriglyceridemia, hypokalemia, hypotension,
Children <11 years: 3.38 ± 2.6 hours immune thrombocytopenia, increased amylase,
Children ≥11 years and Adolescents ≤15 years: 2.3 ± increased blood urea nitrogen, increased creatine
0.4 hours phosphokinase, increased lactate dehydrogenase,
Adults: 2.5 to 3.5 hours; prolonged with renal impair- increased MCV, increased serum alkaline phospha-
ment; Oliguria: >20 hours; Anuria: 24 hours tase, increased serum creatinine, increased thyroid
Time to Peak Serum: Oral: ~1 to 3 hours stimulating hormone level, increased urine output,
Pregnancy Considerations interstitial nephritis, jaundice, joint swelling, lethargy,
Famotidine crosses the placenta (Wang 2013). leukocytosis, leukopenia, liver steatosis, lymphocyto-
Due to pregnancy-induced physiologic changes, renal penia, migraine, muscle spasm, muscle twitching,
clearance of famotidine may be increased (Wang 2011). myalgia, myocardial infarction, nephrolithiasis, neutro-
penia, oral mucosa ulcer, pain, palpitations, pancrea-
Histamine H2 antagonists have been evaluated for the titis, pancytopenia, panic attack, paresthesia, peptic
treatment of gastroesophageal reflux disease (GERD) ulcer, personality changes, petechia, pharyngeal
during pregnancy. Agents other than famotidine may be edema, pollakiuria, prolonged partial thromboplastin
preferred for initial therapy (Richter 2005; van der time, prolonged prothrombin time, prostate specific
Woude 2014). Histamine H2 antagonists may be used antigen increase, proteinuria, psychotic symptoms,
for aspiration prophylaxis prior to cesarean delivery renal failure, respiratory tract infection, rhabdomyoly-
(ASA 2016). sis, sinus bradycardia, skin discoloration, skin
558
FELBAMATE
photosensitivity, splenomegaly, Stevens-Johnson syn- attempted suicide (≤1%), dystonia (≤1%), euphoria
drome, tachycardia, thrombocytopenia, tinnitus, toxic (≤1%), hallucination (≤1%), migraine (≤1%)
epidermal necrolysis, transient ischemic attacks, Dermatologic: Skin rash (children: 10%; adults: 3% to
tremor, urinary incontinence, urinary tract infection, 4%), acne vulgaris (3%), pruritus (≥1%), bullous rash
urticaria (including dermographism), vertigo, vomiting, (≤1%), urticaria (≤1%)
weakness, weight gain, weight loss Endocrine and metabolic: Menstrual disease (3%),
Mechanism of Action Selectively inhibits xanthine hypophosphatemia (≤3%), hypokalemia (≤1%),
oxidase, the enzyme responsible for the conversion of hyponatremia (≤1%), increased lactate dehydrogen-
hypoxanthine to xanthine to uric acid thereby decreas- ase (≤1%)
ing uric acid. At therapeutic concentration does not Gastrointestinal: Hiccups (children: 10%), weight loss
inhibit other enzymes involved in purine and pyrimidine (children: 7%; adults: 3%), dysgeusia (6%), abdomi-
synthesis. nal pain (5%), diarrhea (5%), xerostomia (3%),
Pharmacodynamics/Kinetics weight gain (≥1%), esophagitis (≤1%), increased
Half-life Elimination ~5 to 8 hours appetite (≤1%)
Time to Peak Plasma: 1 to 1.5 hours Genitourinary: Urinary tract infection (3%)
Pregnancy Considerations Adverse events were Hematologic & oncologic: Leukopenia (children: 7%;
observed in some animal reproduction studies. adults: ≤1%), granulocytopenia (≤1%), leukocytosis
(≤1%), lymphadenopathy (≤1%), thrombocytope-
nia (≤1%)
Felbamate (FEL ba mate) Hepatic: Increased liver enzymes (1% to 5%),
increased serum alkaline phosphatase (≤1%)
Brand Names: US Felbatol
Neuromuscular & skeletal: Tremor (6%), myalgia
Pharmacologic Category Anticonvulsant, Miscella- (3%), weakness (≥1%)
neous Ophthalmic: Miosis (children: 7%), diplopia (3% to
Use 6%), visual disturbance (5%)
Partial seizures (monotherapy or adjunctive): Mono- Otic: Otitis media (children: 10%; adults: 3%)
therapy or adjunctive therapy in the treatment of Respiratory: Pharyngitis (children: 10%; adults: 3%),
partial seizures (with and without generalization) in cough (children: 7%), rhinitis (7%), sinusitis (4%), flu-
adults and adolescents 14 years and older like symptoms (≥1%)
Lennox-Gastaut syndrome: Adjunctive therapy in the <1%, postmarketing, and/or case reports: Acute renal
treatment of partial and generalized seizures associ- failure, agranulocytosis, alopecia, anaphylactoid reac-
ated with Lennox-Gastaut syndrome in children tion, anemia, apathy, aphthous stomatitis, aplastic
Limitations of use: Not indicated for use as first-line anemia, atrial arrhythmia, atrial fibrillation, blood coag-
treatment ulation disorder, blood platelet disorder, body odor,
Local Anesthetic/Vasoconstrictor Precautions bradycardia, brain disease, buccal mucous membrane
No information available to require special precautions swelling, cardiac failure, cerebral edema, cerebrovas-
Effects on Dental Treatment Key adverse event(s) cular disease, choreoathetosis, coma, confusion,
related to dental treatment: Xerostomia (normal salivary delusions, diaphoresis, disseminated intravascular
flow resumes upon discontinuation) and abnormal coagulation (DIC), dysarthria, dyskinesia, dysphagia,
taste. dyspnea, dysuria, embolism, enteritis, eosinophilia,
Effects on Bleeding Associated with marked increase epistaxis, exacerbation of asthma, extrapyramidal
in aplastic anemia and may present with signs of reaction, flatulence, flushing, gastric ulcer, gastritis,
infection, bleeding, or anemia; therefore, incidents of gastroesophageal reflux disease, gastrointestinal
abnormal bleeding should be reported to prescribing hemorrhage, gingival hemorrhage, glossitis, hema-
physician. Incidence of thrombocytopenia is ≤1%. temesis, hematuria, hemianopia, hemolytic anemia,
Adverse Reactions hepatic failure, hepatitis, hepatorenal syndrome,
>10%: hyperammonemia, hyperglycemia, hypernatremia,
Central nervous system: Drowsiness (children: 48%; hypersensitivity reaction, hypertension, hypocalcemia,
adults: 19%), headache (adults: 7% to 37%; children: hypoglycemia, hypomagnesemia, hypotension, hypo-
7%), dizziness (18%), insomnia (9% to 18%), fatigue xia, IgA vasculitis, increased creatine phosphokinase,
(7% to 17%), nervousness (children: 16%; intestinal obstruction, jaundice, lack of concentration,
adults: 7%) leukemia, lichen planus, livedo reticularis, manic reac-
Gastrointestinal: Anorexia (children: 55%; adults: tion, nephrosis, neuritis (mononeuritis), nystagmus,
19%), vomiting (children: 39%; adults: 9% to 17%), pancreatitis, pancytopenia, paralysis, paranoia,
nausea (adults: 34%; children: 7%), dyspepsia (9% peripheral ischemia (potentially leading to necrosis),
to 12%), constipation (7% to 11%) pleural effusion, pneumonitis, psychosis, pulmonary
Hematologic & oncologic: Purpura (children: 13%) hemorrhage, rectal hemorrhage, renal insufficiency,
Respiratory: Upper respiratory infection (children: respiratory depression, rhabdomyolysis, SIADH (syn-
45%; adults: 5% to 9%) drome of inappropriate antidiuretic hormone secre-
Miscellaneous: Fever (children: 23%; adults: 3%) tion), skin photosensitivity, status epilepticus,
1% to 10%: Stevens-Johnson syndrome, suicidal ideation, suicidal
Cardiovascular: Chest pain (3%), facial edema (3%), tendencies, supraventricular tachycardia, thrombo-
palpitations (≥1%), tachycardia (≥1%) phlebitis, torsades de pointes, toxic epidermal necrol-
Central nervous system: Abnormal gait (children: ysis, urinary retention, urticaria, vaginal hemorrhage
10%; adults: 5%), abnormality in thinking (children: Mechanism of Action Mechanism of action is
7%), ataxia (children: 7%; adults: 4%), emotional unknown but has properties in common with other
lability (children: 7%), pain (children: 7%), anxiety marketed anticonvulsants; has weak inhibitory effects
(5%), depression (5%), paresthesia (4%), stupor on GABA-receptor binding, benzodiazepine receptor
(3%), aggressive behavior (≥1%), agitation (≥1%), binding, and is devoid of activity at the MK-801 receptor
malaise (≥1%), psychological disorder (≥1%), binding site of the NMDA receptor-ionophore complex.
559
FELBAMATE
Pharmacodynamics/Kinetics vasodilation; increases myocardial oxygen delivery in

Half-life Elimination 20 to 23 hours (average); pro- patients with vasospastic angina
longed by 9 to 15 hours in patients with renal impair- Pharmacodynamics/Kinetics
ment Onset of Action Antihypertensive: 2 to 5 hours
Time to Peak Serum: 2 to 6 hours (Patsalos 2008) Duration of Action Antihypertensive effect: 24 hours
Pregnancy Risk Factor C Half-life Elimination Immediate release: 11 to 16
Pregnancy Considerations Adverse events have not hours
been observed in animal reproduction studies. Post- Time to Peak 2.5 to 5 hours
marketing case reports in humans include fetal death, Pregnancy Risk Factor C
genital malformation, anencephaly, encephalocele, and
placental disorder.
observed in animal reproduction studies. Untreated
Patients exposed to felbamate during pregnancy are chronic maternal hypertension is associated with
encouraged to enroll themselves into the North Amer- adverse events in the fetus, infant, and mother. If treat-
ican Antiepileptic Drug (AED) Pregnancy Registry by ment for hypertension during pregnancy is needed,
calling 1-888-233-2334. Additional information is avail- other agents are preferred (ACOG, 2013). The Cana-
able at www.aedpregnancyregistry.org. dian labeling contraindicates use in women of child-
Prescribing and Access Restrictions A patient bearing potential and during pregnancy.
"informed consent" form should be completed and
signed by the patient and physician. Copies are avail-
ab le fro m MEDA Pha rma ceu tic als by c all ing Fenofibrate and Derivatives
800-526-3840. (fen oh FYE brate & dah RIV ah tives)
Related Information
Felodipine (fe LOE di peen) Cardiovascular Diseases on page 1442
Brand Names: US Antara; Fenoglide; Fibricor [DSC];
Related Information Lipofen; Lofibra [DSC]; Tricor; Triglide; Trilipix
Calcium Channel Blockers and Gingival Hyperplasia on Brand Names: Canada Lipidil EZ; Lipidil Supra
page 1601
Pharmacologic Category Antilipemic Agent, Fibric
Acid
Brand Names: Canada Plendil; Sandoz-Felodipine
Use
Pharmacologic Category Antihypertensive; Calcium Hypercholesterolemia or mixed dyslipidemia:
Channel Blocker; Calcium Channel Blocker, Dihydro-
Adjunctive therapy to diet for the reduction of low-
pyridine
density lipoprotein cholesterol (LDL-C), total choles-
Use Hypertension: Management of hypertension
terol (total-C), triglycerides, and apolipoprotein B (apo
B), and to increase high-density lipoprotein cholesterol
(HDL-C) in adults with primary hypercholesterolemia
or mixed dyslipidemia (Fredrickson types IIa and IIb).
related to dental treatment: Gingival hyperplasia (fewer
reports than other CCBs, resolves upon discontinua- Use lipid-altering agents in addition to a diet restricted
tion, consultation with physician is suggested). in saturated fat and cholesterol when response to diet
Effects on Bleeding No information available to and nonpharmacological interventions alone has been
require special precautions inadequate.
Adverse Reactions Note: While FDA-approved for hypercholesterolemia,
>10%: fenofibrate is not a first- or second-line choice; other
Cardiovascular: Peripheral edema (2% to 17%) agents may be more suitable (ACC/AHA [Stone
Central nervous system: Headache (11% to 15%) 2013]). In addition, use is not recommended to lower
1% to 10%: Cardiovascular: Flushing (4% to 7%), LDL-C or raise HDL-C in the absence of hyper-
tachycardia (≤3%) triglyceridemia.
<1%, postmarketing, and/or case reports: Abdominal Hypertriglyceridemia: Adjunctive therapy to diet for
pain, acid regurgitation, anemia, angina pectoris, treatment of adult patients with severe hypertriglycer-
angioedema, anxiety disorder, arm pain, arthralgia, idemia (Fredrickson types IV and V hyperlipidemia).
back pain, bronchitis, bruise, cardiac arrhythmia, car- Local Anesthetic/Vasoconstrictor Precautions
diac failure, cerebrovascular accident, chest pain, No information available to require special precautions
constipation, decreased libido, depression, diarrhea, Effects on Dental Treatment Key adverse event(s)
dizziness, drowsiness, dyspnea, dysuria, epistaxis, related to dental treatment: Dry mouth
erythema, extrasystoles, facial edema, flatulence, flu- Effects on Bleeding Thrombocytopenia has been
like symptoms, flushing, foot pain, gingival hyperpla-
reported through postmarketing surveillance.
sia, gynecomastia, hip pain, hypersensitivity angiitis,
hypotension, impotence, influenza, insomnia, irritabil-
Adverse Reactions
ity, knee pain, leg pain, muscle cramps, myalgia, >10%: Hepatic: Increased serum transaminases (≥3 x
myocardial infarction, nausea, nervousness, palpita- ULN: 5% to 13%)
tions, paresthesia, pharyngitis, polyuria, respiratory 1% to 10%:
tract infection, sinusitis, syncope, urinary frequency, Cardiovascular: Pulmonary embolism (≤5%), throm-
urinary urgency, urticaria, visual disturbance, vomiting, bophlebitis (≤5%)
xerostomia Central nervous system: Dizziness (≥3%), pain (≥3%)
Mechanism of Action Inhibits calcium ions from enter- Dermatologic: Skin rash (1%), urticaria (1%)
ing the "slow channels" or select voltage-sensitive Gastrointestinal: Abdominal pain (5%), diarrhea
areas of vascular smooth muscle and myocardium (≥3%), dyspepsia (≥3%), constipation (2%)
during depolarization, producing a relaxation of coro- Hepatic: Abnormal hepatic function tests (8%),
nary vascular smooth muscle and coronary increased serum alanine aminotransferase (2%)
560
FENOPROFEN
Neuromuscular & skeletal: Arthralgia (≥3%), limb pain ≥5%:

(≥3%), myalgia (≥3%), increased creatine phospho- Cardiovascular: Flushing, hypotension
kinase in blood specimen (3%) Central nervous system: Headache
Respiratory: Nasopharyngitis (≥3%), sinusitis (≥3%), Gastrointestinal: Nausea
upper respiratory tract infection (≥3%), rhinitis (2%) <5%:
<1%, postmarketing, and/or case reports: Acute renal Cardiovascular: Angina pectoris, bradycardia, cardiac
failure, agranulocytosis, anaphylaxis, anemia, angioe- failure, chest pain, ECG abnormality (ST-T abnormal-
dema, asthenia, cholestatic hepatitis, chronic active ities), extrasystoles, inversion T wave on ECG, myo-
hepatitis, decreased HDL cholesterol (severe), ca rdia l inf arcti on, o rthos tati c hy pot ens ion ,
decreased hematocrit, decreased hemoglobin, palpitations, tachycardia
decreased white blood cell count, drug reaction with Central nervous system: Anxiety, dizziness, insomnia
eosinophilia and systemic symptoms, headache, hep- Dermatologic: Diaphoresis
atic cirrhosis, hepatitis, hepatocellular hepatitis, hyper- Endocrine & metabolic: Hyperglycemia, hypokalemia,
sensitivity reaction, increased serum aspartate increased lactate dehydrogenase
aminotransferase, increased serum creatinine, muscle Gastrointestinal: Abdominal distention, abdominal
spasm, myopathy, pancreatitis, renal failure syn- pain, constipation, diarrhea, vomiting
drome, rhabdomyolysis, severe dermatological reac- Genitourinary: Oliguria, urinary tract infection
tion (severe cutaneous adverse reactions [SCAR]), Hematologic & oncologic: Hemorrhage, leukocytosis
skin photosensitivity, Stevens-Johnson syndrome, Hepatic: Increased serum transaminases
thrombocytopenia, toxic epidermal necrolysis Local: Injection site reaction
Mechanism of Action Fenofibric acid, an agonist for Neuromuscular & skeletal: Back pain, muscle cramps
the nuclear transcription factor peroxisome proliferator- (limbs)
activated receptor-alpha (PPAR-alpha), downregulates Ophthalmic: Increased intraocular pressure
apoprotein C-III (an inhibitor of lipoprotein lipase) and Renal: Increased blood urea nitrogen, increased
upregulates the synthesis of apolipoprotein A-I, fatty serum creatinine
acid transport protein, and lipoprotein lipase resulting Respiratory: Dyspnea, nasal congestion
in an increase in VLDL catabolism, fatty acid oxidation, Miscellaneous: Fever
and elimination of triglyceride-rich particles; as a result Mechanism of Action A selective postsynaptic dop-
of a decrease in VLDL levels, total plasma triglycerides amine agonist (D1-receptors) which exerts hypotensive
are reduced by 30% to 60%; modest increase in HDL effects by decreasing peripheral vasculature resistance
occurs in some hypertriglyceridemic patients. with increased renal blood flow, diuresis, and natriure-
Pharmacodynamics/Kinetics sis; 6 times as potent as dopamine in producing renal
Half-life Elimination Half-life elimination: Fenofibric vasodilatation; has minimal adrenergic effects
acid: Mean: 20 hours (range: 10 to 35 hours); half-life Pharmacodynamics/Kinetics
prolonged in patients with renal impairment Onset of Action IV: Children: 5 minutes; Adults: 10
Time to Peak 2 to 8 hours minutes; Note: Majority of effect of a given infusion
Pregnancy Considerations Triglyceride and lipid rate is attained within 15 minutes.
concentrations increase during pregnancy as required Duration of Action IV: 1 hour
for normal fetal development. When increases are Half-life Elimination IV: Children: 3 to 5 minutes;
greater than expected, supervised dietary intervention Adults: ~5 minutes
should be initiated. In women who develop very severe Pregnancy Risk Factor B
hypertriglyceridemia and are at risk for pancreatitis, use Pregnancy Considerations Fetal harm was not
of fenofibrate beginning in the second trimester is one observed in animal studies; however, safety and effi-
intervention that may be considered. Agents other than cacy have not been established for use during preg-
fenofibrate should be used for hypercholesterolemia nancy. Use during pregnancy only if clearly needed.
(Avis 2009; Berglund 2012; Jacobson 2015; Wong
2015). Fenoprofen (fen oh PROE fen)
Fenoldopam (fe NOL doe pam) Related Information

Brand Names: US Corlopam on page 1484
Pharmacologic Category Antihypertensive; Dopa- Temporomandibular Dysfunction (TMD), Chronic Pain,
mine Agonist and Fibromyalgia on page 1559
Use Severe hypertension: Short-term treatment of Brand Names: US Fenortho; Nalfon; ProFeno [DSC]
severe hypertension (up to 48 hours in adults while in Generic Availability (US) Yes
hospital), including patients with malignant hyperten- Pharmacologic Category Analgesic, Nonopioid; Non-
sion with deteriorating end-organ function; short-term steroidal Anti-inflammatory Drug (NSAID), Oral
(up to 4 hours while in hospital) blood pressure reduc- Use
tion in pediatric patients while in hospital Osteoarthritis: Relief of the signs and symptoms of
Local Anesthetic/Vasoconstrictor Precautions osteoarthritis.
No information available to require special precautions Pain: Relief of mild to moderate pain in adults.
Effects on Dental Treatment Key adverse event(s) Rheumatoid arthritis (RA): Relief of the signs and
related to dental treatment: Xerostomia and changes in symptoms of RA.
salivation (normal salivary flow resumes upon discon- Local Anesthetic/Vasoconstrictor Precautions
tinuation). No information available to require special precautions
Effects on Bleeding No information available to Effects on Dental Treatment The dentist should be
require special precautions aware of the potential of abnormal coagulation. Caution
Adverse Reactions should also be exercised in the use of NSAIDs in
Frequency not defined. patients already on anticoagulant therapy with drugs
561
FENOPROFEN
such as warfarin (Coumadin®). See Effects on Bleed- lymphocyte activity, inhibiting neutrophil aggregation/
ing. activation, and decreasing proinflammatory cytokine
Effects on Bleeding Nonselective NSAIDs such as levels.
fenoprofen inhibit platelet aggregation and prolong Contraindications Hypersensitivity to fenoprofen (eg,
bleeding time in some patients. Unlike aspirin, the anaphylactic reactions, serious skin reactions) or any
NSAID effect on platelet function is quantitatively less, component of the formulation; history of asthma, urti-
of shorter duration, and reversible. caria, or allergic-type reaction to aspirin or other
Adverse Reactions NSAIDs; in the setting of coronary artery bypass graft
1% to 10%: (CABG) surgery; severe renal impairment (ProFeno
Cardiovascular: Peripheral edema (5%), palpita- only).
tions (3%) Warnings/Precautions [US Boxed Warning]:
Central nervous system: Drowsiness (9%), headache NSAIDs cause an increased risk of serious (and
(9%), dizziness (7%), nervousness (6%), fatigue potentially fatal) adverse cardiovascular thrombotic
(2%), confusion (1%) events, including MI and stroke. Risk may occur
Dermatologic: Diaphoresis (5%), pruritus (4%), skin early during treatment and may increase with dura-
rash (4%) tion of use. Relative risk appears to be similar in those
Gastrointestinal: Dyspepsia (10%), nausea (8%), con- with and without known cardiovascular disease or risk
stipation (7%), vomiting (3%), abdominal pain (2%) factors for cardiovascular disease; however, absolute
Neu romusc ula r & skeletal: Weakness (5%), incidence of cardiovascular events (which may occur
tremor (2%) early during treatment) was higher in patients with
Ophthalmic: Blurred vision (2%) known cardiovascular disease or risk factors. New
Otic: Tinnitus (5%), auditory impairment (2%) onset hypertension or exacerbation of hypertension
Respiratory: Dyspnea (3%), nasopharyngitis (1%) may occur (NSAIDs may also impair response to ACE
<1%, postmarketing, and/or case reports: Agranulocy- inhibitors, thiazide diuretics, or loop diuretics); may
tosis, alopecia, anaphylaxis, anemia, angioedema contribute to cardiovascular events; monitor blood pres-
(angioneurotic edema), anorexia, anuria, aphthous sure; use with caution in patients with hypertension.
stomatitis, aplastic anemia, atrial fibrillation, azotemia, May cause sodium and fluid retention, use with caution
bloody stools, bruise, cholestatic hepatitis, cystitis, in patients with edema. Avoid use in patients with heart
depression, diplopia, disorientation, dysgeusia, dysu- failure (ACCF/AHA [Yancy 2013]). Avoid use in patients
ria, ECG changes, exfoliative dermatitis, fever, flat- with recent MI unless benefits outweigh risk of cardio-
ulence, gastritis, gastrointestinal hemorrhage, vascular thrombotic events. Use the lowest effective
gastrointestinal perforation, gastrointestinal ulcer, dose for the shortest duration of time, consistent with
glossopyrosis, hematuria, hemolytic anemia, hemor- individual patient goals, to reduce risk of cardiovascular
rhage, hepatotoxicity (idiosyncratic; Chalasani, 2014), events; alternate therapies should be considered for
hypertension, increased lactate dehydrogenase, patients at high risk. [US Boxed Warning]: Use is
increased serum alkaline phosphatase, increased contraindicated in the setting of coronary artery
serum AST, insomnia, interstitial nephritis, jaundice, bypass graft (CABG) surgery. Risk of MI and stroke
lymphadenopathy, malaise, mastalgia, nephrosis, oli- may be increased with use following CABG surgery.
guria, optic neuritis, pancreatitis, pancytopenia, peptic
ulcer, pulmonary edema, purpura, renal failure, renal [US Boxed Warning]: NSAIDs cause an increased
papillary necrosis, seizure, Stevens-Johnson syn- risk of serious GI inflammation, ulceration, bleed-
drome, supraventricular tachycardia, tachycardia, ing, and perforation (may be fatal); elderly patients
thrombocytopenia, toxic epidermal necrolysis, trigemi- and patients with history of peptic ulcer disease
nal neuralgia, urticaria, xerostomia and/or GI bleeding are at greater risk for serious
Dosing GI events. These events may occur at any time
Adult & Geriatric Note: Use the lowest effective dose during therapy and without warning. Avoid use in
for the shortest possible duration. patients with active GI bleeding. In patients with a
Osteoarthritis, rheumatoid arthritis: Oral: 400 to history of acute lower GI bleeding, avoid use of non-
600 mg 3 to 4 times daily; adjust dose based on aspirin NSAIDs, especially if due to angioectasia or
patient response; maximum dose: 3,200 mg/day diverticulosis (Strate 2016). Use caution with a history
Pain (mild to moderate): Oral: 200 mg every 4 to 6 of GI ulcers, concurrent therapy known to increase the
hours as needed. risk of GI bleeding (eg, aspirin, anticoagulants and/or
Renal Impairment: Adult corticosteroids, selective serotonin reuptake inhibitors),
There are no dosage adjustments provided in the advanced hepatic disease, coagulopathy, smoking, use
manufacturer’s labeling; use with caution. Not rec- of alcohol, or in elderly or debilitated patients. Use the
ommended in patients with advanced renal disease. lowest effective dose for the shortest duration of time,
ProFeno is contraindicated in patients with severe consistent with individual patient goals, to reduce risk of
renal impairment. GI adverse events; alternate therapies should be con-
Dialysis: Not removed by hemodialysis. sidered for patients at high risk. When used concom-
Hepatic Impairment: Adult There are no dosage itantly with aspirin, a substantial increase in the risk of
adjustments provided in the manufacturer’s labeling; GI complications (eg, ulcer) occurs; concomitant gastro-
use with caution. protective therapy (eg, proton pump inhibitors) is rec-
Mechanism of Action Reversibly inhibits cyclooxyge- ommended (Bhatt 2008).
Platelet adhesion and aggregation may be decreased;
decreased formation of prostaglandin precursors; has
may prolong bleeding time; patients with coagulation
antipyretic, analgesic, and anti-inflammatory properties
disorders or who are receiving anticoagulants should be
Other proposed mechanisms not fully elucidated (and monitored closely. Anemia may occur; patients on long-
possibly contributing to the anti-inflammatory effect to term NSAID therapy should be monitored for anemia.
varying degrees), include inhibiting chemotaxis, altering Rarely, NSAID use has been associated with potentially
562
FENOPROFEN
severe blood dyscrasias (eg, agranulocytosis, thrombo- Pelubiprofen; Phenylbutazone; Talniflumate; Tenoxi-
cytopenia, aplastic anemia). cam; Urokinase; Zaltoprofen
Use the lowest effective dose for the shortest duration
Fenoprofen may increase the levels/effects of: 5-Ami-
of time, consistent with individual patient goals, to
nosalicylic Acid Derivatives; Agents with Antiplatelet
reduce risk of cardiovascular or GI adverse events.
Properties; Aliskiren; Aminoglycosides; Aminolevulinic
Alternate therapies should be considered for patients
Acid (Systemic); Aminolevulinic Acid (Topical); Anti-
at high risk.
coagulants; Apixaban; Bisphosphonate Derivatives;
NSAIDs may cause serious skin adverse events includ- Cephalothin; Collagenase (Systemic); CycloSPOR-
ing exfoliative dermatitis, Stevens-Johnson syndrome INE (Systemic); Dabigatran Etexilate; Deferasirox;
(SJS), and toxic epidermal necrolysis (TEN); may occur Deoxycholic Acid; Desmopressin; Dexibuprofen;
without warning; discontinue use at first sign of skin Digoxin; Drospirenone; Edoxaban; Eplerenone; Halo-
rash (or any other hypersensitivity). Anaphylactoid reac- peridol; Ibritumomab Tiuxetan; Lithium; Methotrexate;
tions may occur, even without prior exposure; patients Nonsteroidal Anti-Inflammatory Agents (COX-2 Selec-
with "aspirin triad" (bronchial asthma, aspirin intoler- tive); Obinutuzumab; Omacetaxine; Porfimer; Potas-
ance, rhinitis) may be at increased risk. Contraindicated sium-Sparing Diuretics; PRALAtrexate; Quinolones;
in patients who experience bronchospasm, asthma, Rivaroxaban; Salicylates; Tacrolimus (Systemic);
rhinitis, or urticaria with NSAID or aspirin therapy; Tenofovir Products; Thrombolytic Agents; Tolperisone;
severe bronchospasm may occur. Use caution in other Urokinase; Vancomycin; Verteporfin; Vitamin K Antag-
forms of asthma. onists
Avoid use in patients with advanced renal disease; The levels/effects of Fenoprofen may be increased by:
discontinue use with persistent or worsening abnormal Acemetacin; Alcohol (Ethyl); Angiotensin II Receptor
renal function tests. ProFeno is contraindicated in Blockers; Angiotensin-Converting Enzyme Inhibitors;
patients with severe renal impairment. NSAID use Corticosteroids (Systemic); CycloSPORINE (Sys-
may compromise existing renal function; dose-depend- temic); Dasatinib; Dexketoprofen; Diclofenac (Sys-
ent decreases in prostaglandin synthesis may result temic); Fat Emulsion (Fish Oil Based); Felbinac;
from NSAID use, reducing renal blood flow which may Floctafenine; Glucosamine; Herbs (Anticoagulant/
cause renal decompensation (usually reversible). Antiplatelet Properties); Ibrutinib; Inotersen; Ketorolac
Patients with impaired renal function, dehydration, (Nasal); Ketorolac (Systemic); Limaprost; Loop Diu-
hypovolemia, heart failure, hepatic impairment, those retics; Morniflumate; Multivitamins/Fluoride (with
taking diuretics, and ACE inhibitors, and the elderly are ADE); Multivitamins/Minerals (with ADEK, Folate,
at greater risk of renal toxicity. Rehydrate patient before Iron); Multivitamins/Minerals (with AE, No Iron); Nafta-
starting therapy; monitor renal function closely. Long- zone; Omega-3 Fatty Acids; Pelubiprofen; Pentosan
term NSAID use may result in renal papillary necrosis Polysulfate Sodium; Pentoxifylline; Phenylbutazone;
and other renal injury. Probenecid; Prostacyclin Analogues; Selective Sero-
tonin Reuptake Inhibitors; Serotonin/Norepinephrine
Use with caution in patients with hepatic impairment; Reuptake Inhibitors; Sodium Phosphates; Talniflu-
patients with advanced hepatic disease are at an mate; Tenoxicam; Thiazide and Thiazide-Like Diu-
increased risk of GI bleeding with NSAIDs. Transami- r e t i c s ; T i p r a n a v i r ; To l p e r i s o n e ; T r i c y c l i c
nase elevations have been reported with use; closely Antidepressants (Tertiary Amine); Vitamin E (Sys-
monitor patients with any abnormal LFT. Rare (some- temic); Zaltoprofen
times fatal) severe hepatic reactions (eg, fulminant Decreased Effect
hepatitis, hepatic necrosis, hepatic failure) have Fenoprofen may decrease the levels/effects of: Alis-
occurred with NSAID use; discontinue immediately if kiren; Angiotensin II Receptor Blockers; Angiotensin-
signs or symptoms of hepatic disease develop or if Converting Enzyme Inhibitors; Beta-Blockers; Eplere-
systemic manifestations occur. none; HydrALAZINE; Loop Diuretics; Macimorelin;
Mifamurtide; Potassium-Sparing Diuretics; Prosta-
NSAIDs may cause drowsiness, dizziness, blurred
glandins (Ophthalmic); Salicylates; Selective Seroto-
vision and other neurologic effects which may impair
nin Reuptake Inhibitors; Sincalide; Thiazide and
physical or mental abilities; patients must be cautioned
Thiazide-Like Diuretics
about performing tasks which require mental alertness
(eg, operating machinery or driving). If visual disturban- The levels/effects of Fenoprofen may be decreased
ces occur, preform ophthalmologic exam. by: Bile Acid Sequestrants; Salicylates
Food Interactions Fenoprofen peak serum levels may
Periodically monitor auditory function in patients with
be decreased if taken with food; total amount absorbed
hearing impairment during prolonged therapy. Poten-
is not affected. Management: Administer with food to
tially significant interactions may exist, requiring dose or
minimize stomach upset.
frequency adjustment, additional monitoring, and/or
selection of alternative therapy
Dietary Considerations May be taken with food or
milk.
Withhold for at least 4 to 6 half-lives prior to surgical or Pharmacodynamics/Kinetics
dental procedures. Onset of Action A few days; full benefit: up to 2 to 3
Drug Interactions weeks
Metabolism/Transport Effects None known. Half-life Elimination ~3 hours
Avoid Concomitant Use Time to Peak Serum: ~2 hours
Avoid concomitant use of Fenoprofen with any of the Pregnancy Considerations Birth defects have been
following: Acemetacin; Aminolevulinic Acid (Sys- observed following in utero NSAID exposure in some
temic); Dexibuprofen; Dexketoprofen; Floctafenine; studies; however, data is conflicting (Bloor 2013). Non-
Ketorolac (Nasal); Ketorolac (Systemic); Macimorelin; teratogenic effects, including prenatal constriction of the
Mifamurtide; Morniflumate; Nonsteroidal Anti-Inflam- ductus arteriosus, persistent pulmonary hypertension of
matory Agents (COX-2 Selective); Omacetaxine; the newborn, oligohydramnios, necrotizing enterocolitis,
563
FENOPROFEN
renal dysfunction or failure, and intracranial hemor- otherwise inadequate to provide sufficient manage-
rhage have been observed in the fetus/neonate follow- ment of pain. Only for use in patients who are alert
ing in utero NSAID exposure. In addition, nonclosure of enough and have adequate cognitive ability to under-
the ductus arteriosus postnatally may occur and be stand the directions for use. Not for home use.
resistant to medical management (Bermas 2014; Bloor Transdermal device is for use only in patients in
2013). Because NSAIDs may cause premature closure the hospital. Discontinue treatment with the device
of the ductus arteriosus, product labeling for fenoprofen before patients leave the hospital. The device is for
specifically states use should be avoided starting at 30- use after patients have been titrated to an acceptable
weeks gestation. Use of NSAIDs can be considered for level of analgesia using alternate opioid analgesics.
the treatment of mild rheumatoid arthritis flares in Transdermal patch (eg, Duragesic): Chronic pain:
pregnant women; however, use should be minimized Management of pain in opioid-tolerant patients, severe
or avoided early and late in pregnancy (Bermas 2014; enough to require daily, around-the-clock, long-term
Saavedra Salinas 2015). opioid treatment and for which alternative treatment
options are inadequate.
The chronic use of NSAIDs in women of reproductive
Limitations of use: Reserve for use in patients for
age may be associated with infertility that is reversible
whom alternative treatment options (eg, nonopioid
upon discontinuation of the medication. Consider dis-
analgesics, immediate-release opioids) are ineffec-
continuing use in women having difficulty conceiving or
tive, not tolerated, or would be otherwise inadequate
those undergoing investigation of fertility. The use of
to provide sufficient management of pain. Not indi-
NSAIDs close to conception may be associated with an
cated as an as-needed analgesic.
increased risk of miscarriage (Bermas 2014;
Transmucosal lozenge (eg, Actiq), buccal tablet
Bloor 2013).
(Fentora), buccal film (Onsolis), intranasal (Laz-
Breastfeeding Considerations Fenoprofen is anda), sublingual tablet (Abstral), sublingual spray
present in breast milk.
(Subsys): Cancer pain: Management of break-
In general, NSAIDs may be used in postpartum women through cancer pain in opioid-tolerant patients ≥18
who wish to breastfeed; however, agents other than years (Abstral, Fentora, Lazanda, Onsolis, Subsys)
fenoprofen are preferred (Montgomery 2012) and use and ≥16 years (Actiq) who are already receiving and
should be avoided in women breastfeeding infants with who are tolerant to around-the-clock opioid therapy for
platelet dysfunction or thrombocytopenia (Bloor 2013; their underlying persistent cancer pain.
Sammaritano 2014). According to the manufacturer, the Limitations of use: Not for use in opioid non-tolerant
decision to continue or discontinue breastfeeding dur- patients. Not for use in the management of acute or
ing therapy should take into account the risk of infant postoperative pain, including headache/migraine,
exposure, the benefits of breastfeeding to the infant, dental pain, or in the emergency department. As a
and benefits of treatment to the mother. part of the TIRF REMS Access program, these
Dosage Forms: US products may be dispensed only to outpatients
Capsule, Oral: enrolled in the program. For inpatient administration
Fenortho: 200 mg (eg, hospitals, hospices, and long-term care facilities
Nalfon: 400 mg that prescribe for inpatient use), patient and pre-
Generic: 200 mg, 400 mg scriber enrollment is not required.
Tablet, Oral: Note: "Opioid-tolerant" patients are defined as patients
Nalfon: 600 mg who are taking at least:
Generic: 600 mg Oral morphine 60 mg/day, or
Transdermal fentanyl 25 mcg/hour, or
FentaNYL (FEN ta nil) Oral oxycodone 30 mg/day, or
Oral hydromorphone 8 mg/day, or
Related Information Oral oxymorphone 25 mg/day, or
Management of the Chemically Dependent Patient on Oral hydrocodone 60 mg/day, or
page 1511 Equianalgesic dose of another opioid for at least
Brand Names: US Abstral; Actiq; Duragesic; Fentora; 1 week
Ionsys; Lazanda; Onsolis [DSC]; Sublimaze; Subsys Local Anesthetic/Vasoconstrictor Precautions
Brand Names: Canada Abstral; Duragesic; Fentora No information available to require special precautions
Generic Availability (US) Yes: Injection, lozenge, Effects on Dental Treatment Key adverse event(s)
patch related to dental treatment: Xerostomia, changes in
Pharmacologic Category Analgesic, Opioid; Anilido- salivation (normal salivary flow resumes upon discon-
piperidine Opioid; General Anesthetic tinuation); Patients may experience orthostatic hypo-
Dental Use Adjunct in preoperative intravenous con- tension as they stand up after treatment; especially if
scious sedation in patients undergoing dental surgery lying in dental chair for extended periods of time. Use
Use caution with sudden changes in position during and
Injection: Surgery: Adjunct to general or regional after dental treatment. Actiq may contribute to dental
anesthesia; preoperative medication; analgesic during caries due to sugar and acid content of oral lozenge;
anesthesia and in the immediate postoperative period. advise patients to maintain good oral hygiene and have
Transdermal device (eg, Ionsys): Postoperative regular dental examinations. See Dental Health Profes-
pain, acute: Short-term management of acute post- sional Considerations.
operative pain severe enough to require an opioid Effects on Bleeding No information available to
analgesic in the hospital and for which alternative require special precautions
treatments are inadequate. Adverse Reactions
Limitations of use: Reserve for use in patients for >10%:
whom alternative treatment options (eg, nonopioid Central nervous system: Confusion, dizziness, drowsi-
analgesics) are ineffective, not tolerated, or would be ness, fatigue, headache, sedated state
564
FENTANYL
Endocrine & metabolic: Dehydration Respiratory: Apnea, asthma, atelectasis, bronchitis,

Gastrointestinal: Constipation, nausea, vomiting cough, dyspnea on exertion, epistaxis, flu-like symp-
Local: Application site erythema (transdermal device) toms, hemoptysis, hyperventilation, hypoventilation,
Neuromuscular & skeletal: Asthenia hypoxia, laryngitis, nasal congestion (nasal spray),
Respiratory: Dyspnea nasal discomfort (nasal spray), nasopharyngitis,
1% to 10%: pharyngitis, pharyngolaryngeal pain, pneumonia,
Cardiovascular: Atrial fibrillation, bigeminy, cardiac post nasal drip (nasal spray), rhinitis, rhinorrhea
arrhythmia, chest pain, deep vein thrombosis, (nasal spray), sinusitis, upper respiratory tract infec-
edema, hypertension, hypotension, myocardial tion, wheezing
infarction, orthostatic hypotension, palpitations, Miscellaneous: Fever
peripheral edema, pulmonary embolism (nasal <1%, postmarketing, and/or case reports: Allergic der-
spray), sinus tachycardia, syncope, tachycardia, vas- matitis, anaphylactoid shock, anaphylaxis, angina
odilatation pectoris, bradycardia, bronchoconstriction, candidia-
Central nervous system: Abnormal dreams, abnormal sis, chest wall rigidity, clonus, contact dermatitis,
gait, abnormality in thinking, agitation, altered sense crusted skin, cyanosis, decreased libido, dental caries,
of smell, amnesia, anxiety, ataxia, chills, depression, dermatitis, drug dependence (physical and psycholog-
disorientation, dysphoria, euphoria, hallucination, ical; with prolonged use), eczema, emotional lability,
hypertonia, hypoesthesia, hypothermia, insomnia, eructation, esophageal stenosis, exfoliative dermatitis,
irritability, lack of concentration, lethargy, malaise, falling, fecal impaction, flank pain, flushing, genito-
mental status changes, migraine, nervousness, neu- urinary tract spasm, gingival hemorrhage, gingival
ropathy, paranoia, paresthesia, restlessness, speech recession, hematuria, hiccups, hostility, hyperesthe-
disturbance, stupor, vertigo, withdrawal syndrome sia, hypoglycemia, hypogonadism (Brennan 2013;
Dermatologic: Alopecia, cellulitis, decubitus ulcer, dia- Debono 2011), impaired consciousness, increased
phoresis, erythema, exfoliation of skin (application bronchial secretions, joint swelling, local hemorrhage,
site, transdermal device), hyperhidrosis, night local hypersensitivity reaction, localized infection, local
sweats, pallor, papule (application site, transdermal skin hyperpigmentation (lasted 2 to 3 weeks), local
device), pruritus, pustules (application site, trans- tissue necrosis, loss of consciousness, miosis, muscle
dermal device), skin rash, vesicobullous rash (appli- rigidity (transient; observed in infants whose mothers
cation site, transdermal device) were treated with IV fentanyl), muscle spasm, muscle
Endocrine & metabolic: Hot flash, hypercalcemia, twitching, myasthenia, nocturia, oliguria, pancytope-
hyperglycemia, hypoalbuminemia, hypocalcemia, nia, pleural effusion, polyuria, respiratory depression,
hypokalemia, hypomagnesemia, hyponatremia, respiratory distress, seizure, sexual disorder, skin
weight loss erosion, Stevens-Johnson syndrome, swelling, swol-
Gastrointestinal: Abdominal distention, abdominal len tongue, tonic-clonic epilepsy, tooth loss, upper
pain, anorexia, decreased appetite, diarrhea, dys- abdominal pain, urticaria, voice disorder
geusia, dyspepsia, dysphagia (buccal tablet/film/sub- Dental Usual Dosage Surgery: Adults:
lingual spray), flatulence, gastritis, gastroenteritis, Premedication: IM, slow IV: 25 to 100 mcg/dose 30 to
gastroesophageal reflux disease, gastrointestinal 60 minutes prior to surgery
hemorrhage, gastrointestinal ulcer (gingival, lip, Adjunct to regional anesthesia: Slow IV: 25 to 100
mouth; transmucosal use/nasal spray), gingival pain mcg/dose over 1 to 2 minutes. Note: An IV should
(buccal tablet), gingivitis (lozenge), glossitis (loz- be in place with regional anesthesia so the IM route
enge), hematemesis, intestinal obstruction, perio- is rarely used but still maintained as an option in the
dontal abscess (lozenge/buccal tablet), rectal pain, package labeling.
stomatitis (lozenge/buccal tablet/sublingual tablet/ Dosing
sublingual spray), tongue disease (sublingual tablet), Adult Note: Ranges listed may not represent the
xerostomia maximum doses that may be required in some
Genitourinary: Urinary retention (3%), difficulty in mic- patients. Doses and dosage intervals should be
turition, dysuria, erectile dysfunction, mastalgia, uri- titrated to pain relief/prevention. Monitor vital signs
nary incontinence, urinary tract infection, urinary routinely. Single IM doses have duration of 1 to 2
urgency, vaginal hemorrhage, vaginitis hours, single IV doses last 0.5 to 1 hour.
Hematologic & oncologic: Anemia (3%), bruise, leu- Surgery:
kopenia, lymphadenopathy, neutropenia, thrombocy- Premedication: IM, slow IV: 50 to 100 mcg adminis-
topenia tered 30 to 60 minutes prior to surgery or slow IV:
Hepatic: Ascites, increased serum alkaline phospha- 25 to 50 mcg given shortly before induction (Bar-
tase, increased serum AST, jaundice ash 2009)
Hypersensitivity: Hypersensitivity reaction Adjunct to general anesthesia: Slow IV:
Infection: Abscess Low dose: 1 to 2 mcg/kg depending on the indica-
Local: Application site burning (transdermal device), tion (Miller 2010); additional maintenance doses
application site discharge (transdermal device), are generally not needed.
application site edema (transdermal device), appli- Moderate dose (fentanyl plus a sedative/hypnotic):
cation site irritation, application site itching (trans- Initial: 2 to 4 mcg/kg; Maintenance (bolus or
dermal device), application site pain, application infusion): 25 to 50 mcg every 15 to 30 minutes
site rash (transdermal device), application site or 0.5 to 2 mcg/kg/hour (Miller 2010). Discontinu-
vesicles (transdermal device) ing fentanyl infusion 30 to 60 minutes prior to the
Neuromuscular & skeletal: Arthralgia, back pain, lower end of surgery will usually allow adequate venti-
limb cramp, limb pain, myalgia, tremor lation upon emergence from anesthesia.
Ophthalmic: Blepharoptosis, blurred vision, diplopia, High dose (opioid anesthesia): 4 to 20 mcg/kg
dry eye syndrome, strabismus, swelling of eye, vis- bolus then 2 to 10 mcg/kg/hour (Miller 2010);
ual disturbance Note: High-dose fentanyl (ie, 20 to 50 mcg/kg) is
Renal: Renal failure syndrome rarely used, but is still described in the
565
FENTANYL
manufacturer's label. The concept of fast-tracking Lockout interval: 4 to 10 minutes

and early extubation following cardiac surgery has Usual basal rate: ≤50 mcg/hour. Note: Continuous
essentially replaced high-dose fentanyl anes- basal infusions are not recommended for initial
thesia. programming and should rarely be used; con-
Adjunct to regional anesthesia: 50 to 100 mcg IM or sider limiting infusion rate to 10 mcg/hour if used
slow IV over 1 to 2 minutes. Note: An IV should be (Grass 2005).
in place with regional anesthesia so the IM route is Intrathecal (off-label use; American Pain Society
rarely used but still maintained as an option in the 2008): Must be preservative-free. Doses must
manufacturer's labeling. be adjusted for age, injection site, and patient's
Postoperative recovery: IM: 50 to 100 mcg every 1 to medical condition and degree of opioid tolerance.
2 hours as needed. Single dose: 5 to 25 mcg; may provide adequate
Postoperative pain: Epidural (Canadian labeling; not relief for up to 6 hours
in US labeling): Initial: 100 mcg (diluted in 8 mL of Continuous infusion: Not recommended in acute
preservative free NS to final concentration of 10 pain management due to risk of excessive accu-
mcg/mL); may repeat with additional 100 mcg mulation. For chronic cancer pain, infusion of
boluses on demand or alternatively may administer very small doses may be practical (American
by continuous infusion at a rate of 1 mcg/kg/hour. Pain Society, 2008).
Pain management: Epidural (off-label use; American Pain Society
Postoperative pain, acute: Transdermal device 2008): Must be preservative-free. Doses must
(Ionsys): Apply one device to chest or upper outer be adjusted for age, injection site, and patient's
arm only. Only the patient may activate the device medical condition and degree of opioid tolerance
(40 mcg dose of fentanyl per activation; maximum 6 Single dose: 25 to 100 mcg; may provide
doses per hour). Only one device may be applied at adequate relief for up to 8 hours
a time for up to 24 hours or 80 doses, whichever Continuous infusion: 25 to 100 mcg/hour (fentanyl
comes first. May be used for a maximum of 72 alone). When combined with a local anesthetic
hours, with each subsequent device applied to a (eg, bupivacaine or ropivacaine), fentanyl
different skin site. If inadequate analgesia is requirement are less (Manion 2011).
achieved with one device, either provide additional Breakthrough cancer pain: Transmucosal: For
supplemental analgesic medication or replace with patients who are tolerant to and currently receiving
an alternate analgesic medication. Refer to manu- opioid therapy for persistent cancer pain; dosing
facturer's labeling for activation instructions. should be individually titrated to provide adequate
Note: For hospital use only by patients under analgesia with minimal side effects. Dose titration
medical supervision and direction and only after should be done if patient requires more than 1
patients have been titrated to an acceptable level dose/breakthrough pain episode for several consec-
of analgesia using another opioid analgesic. utive episodes. Patients experiencing >4 break-
Severe pain: through pain episodes per day should have the
Intermittent dosing: IM, IV (off-label): 25 to 35 mcg dose of their long-term opioid re-evaluated. Patients
(based on ~70 kg patient) or 0.35 to 0.5 mcg/kg must remain on around-the-clock opioids dur-
every 30 to 60 minutes as needed (SCCM [Barr ing use.
2013]). Note: After the first dose, if severe pain Lozenge (Actiq): Note: Do not convert patients from
persists and adverse effects are minimal at the any other fentanyl product to Actiq on a mcg-per-
time of expected peak effect (eg, ~5 minutes after mcg basis. Patients previously using another fen-
IV administration), may repeat dose (APS 2008). tanyl product should be initiated at a dose of 200
Since the duration of activity with IV administration mcg; individually titrate to provide adequate anal-
is 30 to 60 minutes, more frequent administration gesia while minimizing adverse effects.
may be necessary when administered by this Initial dose: 200 mcg (consumed over 15 minutes)
route. SubQ administration is a reasonable alter- for all patients; if after 30 minutes from the start of
native to IV or IM (Jabalameli 2016). the lozenge (ie, 15 minutes following the comple-
Continuous infusion: tion of the lozenge), the pain is unrelieved, a
IV (off label): Critically ill patients: 50 to 700 mcg/ second 200 mcg dose may be given over 15
hour (based on ~70 kg patient) or 0.7 to 10 mcg/ minutes. A maximum of 1 additional dose can be
kg/hour (SCCM [Barr 2013]). Note: When pain given per pain episode; must wait at least 4
is not controlled, may administer an additional hours before treating another episode. To limit
small bolus dose (eg, 25 to 50 mcg) prior to the number of units in the home during titration,
increasing the infusion rate (Loper 1990; Peng only prescribe an initial titration supply of six 200
1999; Salomaki 1991). mcg lozenges.
SubQ (off label): Based on limited data, however, Dose titration: From the initial dose, closely follow
this route of administration is a reasonable alter- patients and modify the dose until patient reaches
native to IV for continuous infusion; doses in the a dose providing adequate analgesia using a
range of 25 to 200 mcg/hour have been reported single dosage unit per breakthrough cancer pain
in the management of cancer pain. Choose episode. If signs/symptoms of excessive opioid
starting dose and titrate based on level of pain effects (eg, respiratory depression) occur, imme-
and previous opioid tolerance using appropriate diately remove the dosage unit from the patient's
opioid analgesic equivalents (Mercadante 1997; mouth, dispose of properly, and reduce subse-
Paix 1995; Watanabe 1998). quent doses. If adequate relief is not achieved
Patient-controlled analgesia (PCA) (off-label use; 15 minutes after completion of the first dose (ie,
American Pain Society 2008; Miller 2010): 30 minutes after the start of the lozenge), only 1
Opioid-naive: IV: additional lozenge of the same strength may be
Usual concentration: 10 mcg/mL given for that episode; must wait at least 4 hours
Demand dose: Usual: 10 to 20 mcg before treating another episode.
566
FENTANYL
Maintenance dose: Once titrated to an effective another fentanyl product should be initiated at a
dose, patients should generally use a single dos- dose of 100 mcg; individually titrate to provide
age unit per breakthrough pain episode. During adequate analgesia while minimizing adverse
any pain episode, if adequate relief is not effects. For patients previously using the transmu-
achieved 15 minutes after completion of the first cosal lozenge (Actiq), the initial dose should be
dose (ie, 30 minutes after the start of the lozenge), selected using the conversions listed; see Conver-
only 1 additional lozenge of the same strength sion from lozenge (Actiq) to buccal tablet (Fentora).
may be given over 15 minutes for that episode; Initial dose: 100 mcg for all patients unless patient
must wait at least 4 hours before treating already using Actiq; see Conversion from lozenge
another episode. Consumption should be limited (Actiq) to buccal tablet (Fentora); if after 30
to ≤4 units per day (once an effective break- minutes pain is unrelieved, the US labeling sug-
through dose is found). If adequate analgesia is gests that a second 100 mcg dose may be admin-
not provided after treating several episodes of istered (maximum of 2 doses per breakthrough
breakthrough pain using the same dose, increase pain episode). The Canadian labeling recom-
dose to next highest lozenge strength (initially mends only a single dose per breakthrough pain
dispense no more than 6 units of the new episode; patients experiencing breakthrough pain
strength). Re-evaluate the around-the-clock after administration may take an alternative anal-
opioid therapy in patients experiencing >4 break- gesic as rescue medication after 30 minutes.
through pain episodes per day. If signs/symptoms Must wait at least 4 hours before treating
of excessive opioid effects (eg, respiratory another episode with Fentora buccal tablet.
depression) occur, immediately remove the dos-
Dose titration: If titration required, 100 mcg dose
age unit from the patient's mouth, dispose of
may be increased to 200 mcg using two 100 mcg
properly, and reduce subsequent doses.
tablets (one on each side of mouth) with the next
Buccal film (Onsolis): Note: Do not convert patients breakthrough pain episode. If 200 mcg dose is not
from any other fentanyl product to Onsolis on a
successful, patient can use four 100 mcg tablets
mcg-per-mcg basis. Patients previously using
(two on each side of mouth) with the next break-
another fentanyl product should be initiated at a
dose of 200 mcg; individually titrate to provide through pain episode. If titration requires >400
adequate analgesia while minimizing adverse mcg per dose, titrate using 200 mcg tablets; do
effects. not use more than 4 tablets simultaneously (max-
Initial dose: 200 mcg for all patients; if after 30 imum single dose: 800 mcg). During any pain
minutes pain is unrelieved, the patient may use episode, if adequate relief is not achieved after
an alternative rescue medication as directed by 30 minutes following buccal tablet application, a
their health care provider. Do not redose with second dose of same strength per breakthrough
Onsolis within an episode; buccal film should only pain episode may be used. The Canadian labeling
be used once per breakthrough cancer pain epi- recommends only a single dose per breakthrough
sode. Must wait at least 2 hours before treating pain episode; patients experiencing breakthrough
another episode with buccal film.
pain after administration may take an alternative
Dose titration: If titration required, increase dose in analgesic as rescue medication after 30 minutes.
200 mcg increments once per episode using Must wait at least 4 hours before treating
multiples of the 200 mcg film (for doses up to another episode with Fentora buccal tablet.
800 mcg); do not redose within a single episode Maintenance dose: Following titration, the effective
of breakthrough pain and separate single doses
maintenance dose using 1 tablet of the appropri-
by ≥2 hours. During titration, do not exceed 4
ate strength should be administered once per
simultaneous applications of the 200 mcg films
episode; if after 30 minutes pain is unrelieved,
(800 mcg) (when using multiple films, do not place
may administer a second dose of the same
on top of each other; film may be placed on both
strength; The Canadian labeling recommends
sides of mouth); if >800 mcg required, treat next
only a single dose per breakthrough pain episode;
episode with one 1,200 mcg film (maximum dose:
1,200 mcg). Once maintenance dose is deter- patients experiencing breakthrough pain after
mined, all other unused films should be disposed administration may take an alternative analgesic
of and that strength (using a single film) should be as rescue medication after 30 minutes. Must wait
used. During any pain episode, if adequate relief ≥4 hours before treating another episode with
is not achieved after 30 minutes following buccal Fentora buccal tablet. Limit to 4 applications per
film application, a rescue medication (as deter- day. Re-evaluate the around-the-clock opioid ther-
mined by health care provider) may be used. apy in patients experiencing >4 breakthrough pain
Maintenance dose: Determined dose applied as a episodes per day. Once an effective maintenance
single film once per episode and separated by ≥2 dose has been established, the buccal tablet may
hours (dose range: 200 to 1,200 mcg); limit to 4 be administered sublingually (alternate route). To
applications per day. Consider increasing the
prevent confusion, patient should only have one
around-the-clock opioid therapy in patients expe-
strength available at a time. Once maintenance
riencing >4 breakthrough pain episodes per day.
dose is determined, all other unused tablets
Buccal tablet (Fentora): Note: Do not convert
should be disposed of and that strength (using a
patients from any other fentanyl product to Fentora
on a mcg-per-mcg basis. Patients previously using single tablet) should be used. Using more than
four buccal tablets at a time has not been studied.
567
FENTANYL
Conversion from lozenge (Actiq) to buccal tablet Sublingual spray (Subsys): Note: Do not convert
(Fentora): patients from any other fentanyl product to Subsys
Lozenge dose 200 to 400 mcg: Initial buccal tablet on a mcg-per-mcg basis. Patients previously using
dose is 100 mcg; may titrate using multiples of
another fentanyl product should be initiated at a
100 mcg
Lozenge dose 600 to 800 mcg: Initial buccal tablet dose of 100 mcg; individually titrate to provide
dose is 200 mcg; may titrate using multiples of adequate analgesia while minimizing adverse
200 mcg effects. For patients previously using the transmu-
Lozenge dose 1,200 to 1,600 mcg: Initial buccal cosal lozenge (Actiq), the initial dose should be
tablet dose is 400 mcg (using two 200 mcg selected using the conversions listed; see Conver-
tablets); may titrate using multiples of 200 mcg
sion from lozenge (Actiq) to sublingual spray
Intranasal (Lazanda): Note: Do not convert patients
(Subsys).
from any other fentanyl product to Lazanda on a
mcg-per-mcg basis. Patients previously using Initial dose: 100 mcg for all patients unless patient
another fentanyl product should be initiated at a already using Actiq; see Conversion from lozenge
dose of 100 mcg; individually titrate to provide (Actiq) to sublingual spray (Subsys). If pain is
adequate analgesia while minimizing adverse unrelieved, 1 additional 100 mcg dose may be
effects. given 30 minutes after administration of the first
Initial dose: 100 mcg (one 100 mcg spray in one
dose. A maximum of 2 doses can be given per
nostril) for all patients; if after 30 minutes pain is
unrelieved, an alternative rescue medication may breakthrough pain episode. Must wait at least 4
be used as directed by their health care provider. hours before treating another episode with
Must wait at least 2 hours before treating sublingual spray.
another episode with fentanyl intranasal. How- Dose titration: If titration required, titrate to a dose
ever, for the next pain episode, increase to a that provides adequate analgesia (with tolerable
higher dose using the recommended dose titration
side effects) using the following titration steps: If
steps.
Dose titration: If titration required, increase to a no relief with 100 mcg dose, increase to 200 mcg
higher dose for the next pain episode using these dose (using one 200 mcg unit); if no relief with 200
titration steps (Note: Must wait at least 2 hours mcg dose, increase to 400 mcg dose (using one
before treating another episode with fentanyl 400 mcg unit); if no relief with 400 mcg dose,
intranasal): If no relief with 100 mcg dose, increase to 600 mcg dose (using one 600 mcg
increase to 200 mcg dose per episode (one 100
unit); if no relief with 600 mcg dose, increase to
mcg spray in each nostril); if no relief with 200 mcg
800 mcg dose (using one 800 mcg unit); if no relief
dose, increase to 300 mcg dose per episode
(alternating one 100 mcg spray in right nostril, with 800 mcg dose, increase to 1200 mcg dose
one 100 mcg spray in left nostril, and one 100 (using two 600 mcg units); if no relief with 1200
mcg spray in the right nostril); if no relief with 300 mcg dose, increase to 1600 mcg dose (using two
mcg dose, increase to 400 mcg per episode (one 800 mcg units). During dose titration, if break-
400 mcg spray in one nostril or alternating two 100 through pain unrelieved 30 minutes after Subsys
mcg sprays in each nostril); if no relief with 400
administration, 1 additional dose using the same
mcg dose, increase to 600 mcg dose per episode
(one 300 mcg spray in each nostril); if no relief strength may be administered (maximum: 2 doses
with 600 mcg dose, increase to 800 mcg dose per per breakthrough pain episode); patient must
episode (one 400 mcg spray in each nostril). wait 4 hours before treating another break-
Note: Single doses >800 mcg have not been through pain episode with sublingual spray.
evaluated. There are no data supporting the use Maintenance dose: Once maintenance dose for
of a combination of dose strengths. Avoid use of a
breakthrough pain episode has been determined,
combination of dose strengths to treat an episode,
as this may cause confusion and dosing errors. use that dose for subsequent episodes. If occa-
Maintenance dose: Once maintenance dose for sional episodes of unrelieved breakthrough pain
breakthrough pain episode has been determined, occur following 30 minutes of Subsys administra-
use that dose for subsequent episodes. For pain tion, 1 additional dose using the same strength
that is not relieved after 30 minutes of Lazanda may be administered (maximum: 2 doses per
administration or if a separate breakthrough pain
breakthrough pain episode); patient must wait
episode occurs within the 2 hour window before
4 hours before treating another breakthrough
the next Lazanda dose is permitted, a rescue
medication may be used. Limit Lazanda use to pain episode with Subsys. Once maintenance
≤4 episodes of breakthrough pain per day. If dose is determined, limit Subsys use to ≤4 epi-
patient is experiencing >4 breakthrough pain episodes of breakthrough pain per day. If response to
sodes per day, consider increasing the around- maintenance dose changes (increase in adverse
the-clock, long-acting opioid therapy; if long-acting reactions or alterations in pain relief), dose read-
opioid therapy dose is altered, re-evaluate and
justment may be necessary. If patient is experi-
retitrate Lazanda dose as needed. If response to
maintenance dose changes (increase in adverse encing >4 breakthrough pain episodes per day, re-
reactions or alterations in pain relief), dose read- evaluate the around-the-clock, long-acting opioid
justment may be necessary. therapy.
568
FENTANYL
Conversion from lozenge (Actiq) to sublingual spray Consider re-evaluating the around-the-clock long-
(Subsys): acting opioid therapy in patients experiencing
Lozenge dose 200 to 400 mcg: Initial sublingual >4 breakthrough pain episodes per day; if long-
spray dose is 100 mcg; may titrate using multi- acting opioid therapy dose altered, re-evaluate
ples of 100 mcg and retitrate Abstral dose as needed.
Lozenge dose 600 to 800 mcg: Initial sublingual Conversion from lozenge (Actiq) to sublingual tablet
spray dose is 200 mcg; may titrate using multi- (Abstral):
ples of 200 mcg Lozenge dose 200 mcg: Initial sublingual tablet
Lozenge dose 1,200 to 1,600 mcg: Initial sublin- dose is 100 mcg; may titrate using multiples of
gual spray dose is 400 mcg; may titrate using 100 mcg
multiples of 400 mcg Lozenge dose 400 to 1,200 mcg: Initial sublingual
Sublingual tablet (Abstral): Note: Do not convert tablet dose is 200 mcg; may titrate using multi-
patients from any other fentanyl product to Abstral ples of 200 mcg
on a mcg-per-mcg basis. Patients previously using Lozenge dose 1,600 mcg: Initial sublingual tablet
another fentanyl product should be initiated at a dose is 400 mcg; may titrate using multiples of
dose of 100 mcg (except Actiq); individually titrate 400 mcg
to provide adequate analgesia while minimizing Discontinuation of therapy: Gradually titrate dose
adverse effects. downward to prevent withdrawal signs/symptoms.
Initial dose: In patients who continue to take chronic opioid
US labeling: 100 mcg for all patients; if pain is therapy for persistent pain but no longer require
unrelieved, a second 100 mcg dose may be treatment for breakthrough pain, fentanyl for
given 30 minutes after administration of the first breakthrough pain can usually be discontinued
dose. A maximum of 2 doses can be given per immediately.
breakthrough pain episode. Must wait at least 2
hours before treating another episode with Chronic pain management (opioid-tolerant
sublingual tablet. patients only): Transdermal patch: Discontinue or
Canadian labeling: 100 mcg for all patients; if pain taper all other around-the-clock or extended release
is unrelieved 30 minutes after administration of opioids when initiating therapy with fentanyl trans-
Abstral, an alternative rescue medication (other dermal patch.
than Abstral) may be given. Administer only 1 Initial: To convert patients from oral or parenteral
dose of Abstral per breakthrough pain episode. opioids to fentanyl transdermal patch, a 24-hour
Must wait at least 2 hours before treating analgesic requirement should be calculated (based
another episode with sublingual tablet. on prior opioid use). Using the tables below, the
Dose titration: If titration required, increase in 100 appropriate initial dose can be determined. The
mcg increments (up to 400 mcg) over consecutive initial fentanyl dosage may be approximated from
breakthrough episodes. If titration requires >400 the 24-hour morphine dosage equivalent and
mcg per dose, increase in increments of 200 mcg, titrated to minimize adverse effects and provide
starting with 600 mcg dose and titrating up to 800 analgesia. Substantial interpatient variability exists
mcg. During titration, patients may use multiples in relative potency. Therefore, it is safer to under-
of 100 mcg and/or 200 mcg tablets for any single estimate a patient's daily fentanyl requirement and
dose; do not exceed 4 tablets at one time; safety provide breakthrough pain relief with rescue medi-
and efficacy of doses >800 mcg have not been cation (eg, immediate release opioid) than to over-
evaluated. During dose titration, if breakthrough estimate requirements. With the initial application,
pain unrelieved 30 minutes after sublingual tablet the absorption of transdermal fentanyl requires
administration, the US labeling suggests that 1 several hours to reach plateau; therefore trans-
additional dose using the same strength may be dermal fentanyl is inappropriate for management
administered (maximum: 2 doses per break- of acute pain. Change patch every 72 hours.
through pain episode); the Canadian labeling rec- Conversion from continuous infusion of fentanyl: In
ommends use of an alternative rescue medication patients who have adequate pain relief with a
and limits use of Abstral to 1 dose per break- fentanyl infusion, fentanyl may be converted to
through pain episode. Patient must wait 2 hours transdermal dosing at a rate equivalent to the intra-
before treating another breakthrough pain epi- venous rate. A two-step taper of the infusion to be
sode with sublingual tablet. completed over 12 hours has been recommended
Maintenance dose: Once maintenance dose for (Kornick, 2001) after the patch is applied. The
breakthrough pain episode has been determined, infusion is decreased to 50% of the original rate
use only 1 tablet in the appropriate strength per six hours after the application of the first patch, and
episode; if pain is unrelieved with maintenance subsequently discontinued twelve hours after appli-
dose: cation.
US labeling: A second dose may be given after 30 Titration: Short-acting agents may be required until
minutes; maximum of 2 doses/episode of break- analgesic efficacy is established and/or as supple-
through pain; separate treatment of subsequent ments for "breakthrough" pain. The amount of
episodes by ≥2 hours; limit treatment to ≤4 supplemental doses should be closely monitored.
breakthrough episodes per day. Appropriate dosage increases may be based on
Canadian labeling: Administer alternative rescue daily supplemental dosage using the ratio of
medication after 30 minutes; maximum of 1 45 mg/24 hours of oral morphine to a 12 mcg/hour
Abstral dose/episode of breakthrough pain; sep- increase in fentanyl dosage (US labeling) or using
arate treatment of subsequent episodes by ≥2 the ratio of 45 to 59 mg/24 hours of oral morphine
hours; limit treatment to ≤4 breakthrough epi- to a 12 mcg/hour increase in fentanyl dosage
sodes per day. (Canadian labeling).
569
FENTANYL
Frequency of adjustment: The dosage should not be

titrated more frequently than every 3 days after the
initial dose or every 6 days thereafter. Titrate dose US Labeling: Dose Conversion Guidelines1,2
based on the daily dose of supplemental opioids
Current Daily Dosage
required by the patient on the second or third day of Analgesic (mg/day)
the initial application. Note: Upon discontinuation,
Morphine
≥17 hours are required for a 50% decrease in (IM/IV)
10 to 22 23 to 37 38 to 52 53 to 67
fentanyl levels.
Oxycodone 30 to 67 67.5 to 112.5 to 157.5 to
Frequency of application: The majority of patients (oral) 112 157 202
may be controlled on every 72-hour administration; 150 to
Codeine (oral) 447 - - -
however, a small number of adults require every
48-hour administration. Hydromorphone
8 to 17
17.1 to 28.1 to
39.1 to 51
(oral) 28 39
Discontinuation of therapy: When discontinuing
transdermal fentanyl and not converting to another Hydromorphone 1.5 to 3.4 3.5 to 5.6 5.7 to 7.9 8 to 10
(IV)
opioid, use a gradual downward titration, such as
decreasing the dose by 50% every 6 days. If patient 166 to 279 to 391 to
Meperidine (IM) 75 to 165
278 390 503
displays withdrawal symptoms, increase dose to
Methadone 105 to
previous level and then reduce dose more slowly (oral)
20 to 44 45 to 74 75 to 104
134
by increasing interval between dose reductions,
decreasing amount of daily dose reduction, or both.
Fentanyl
Dose conversion guidelines for transdermal fen- transdermal 25 mcg/h 50 mcg/h 100 mcg/h
75 mcg/h
tanyl (see tables). recommended
dose (mcg/h)
Note: US and Canadian dose conversion guidelines 1
The table should NOT be used to convert from transdermal fentanyl
differ; consult appropriate table. The conversion (Duragesic) to other opioid analgesics. Rather, following removal of the
factors in these tables are only to be used for the patch, titrate the dose of the new opioid until adequate analgesia is
conversion from current opioid therapy to Durage- achieved.
2
Recommendations are based on US product labeling for Duragesic.
sic. Conversion factors in this table cannot be used
to convert from Duragesic to another opioid (doing Transdermal patch (Duragesic): Canadian labeling:
so may lead to fatal overdose due to overestimation Adults:
of the new opioid). These are not tables of equi-
analgesic doses.
Canadian Labeling: Dose Conversion
Guidelines (Adults): Recommended
US Labeling: Dose Conversion Initial Duragesic Dose Based Upon
Guidelines: Recommended Initial Daily Oral Morphine Dose1,2
Duragesic Dose Based Upon Daily
Oral Morphine Dose1,2 Oral 24-Hour Morphine
Duragesic Dose
(Current Dose in
mg/day) (Initial Dose in mcg/h)
3,4
Oral 24-Hour Morphine Duragesic Dose
(mg/day) (mcg/h) 45 to 59 12
60 to 134 25 60 to 134 25
135 to 224 50 135 to 179 37
225 to 314 75 180 to 224 50
315 to 404 100 225 to 269 62
405 to 494 125 270 to 314 75
495 to 584 150 315 to 359 87
585 to 674 175 360 to 404 100
675 to 764 200 405 to 494 125
765 to 854 225 495 to 584 150
855 to 944 250 585 to 674 175
945 to 1,034 275 675 to 764 200
1,035 to 1,124 300 765 to 854 225
1
The table should NOT be used to convert from 855 to 944 250
transdermal fentanyl (Duragesic) to other opioid
analgesics. Rather, following removal of the patch, titrate 945 to 1,034 275
the dose of the new opioid until adequate analgesia is 1,035 to 1,124 300
achieved.
2 1
Recommendations are based on US product labeling for The table should NOT be used to convert from
Duragesic. transdermal fentanyl (Duragesic) to other opioid
3 analgesics. Rather, following removal of the patch,
Pediatric patients initiating therapy on a 25 mcg/hour titrate the dose of the new opioid until adequate
Duragesic system should be opioid-tolerant and receiving analgesia is achieved.
at least 60 mg oral morphine equivalents per day. 2
4 Recommendations are based on Canadian product
A fentanyl 37.5 mcg/hour transdermal system is also labeling for Duragesic.
available and may be considered during conversion from
prior opioids or dose titration. Note: The 12 mcg/hour dose included in this table is to be
used for incremental dose adjustment and is generally
not recommended for initial dosing, except for patients
in whom lower starting doses are deemed clinically
appropriate.
570
FENTANYL
Manufacturer's labeling:
Injection: There are no dosage adjustments provided
Canadian Labeling: Dosing Conversion in the manufacturer's labeling; use with caution.
Guidelines (Adults)1,2 Transdermal (device): There are no dosage adjust-
ments provided in the manufacturer's labeling (has
Current Daily Dosage not been studied); fentanyl pharmacokinetics may
Analgesic (mg/day)
be altered in renal disease.
20 45 61 76
Morphine3 to to to to n/a4 n/a4 n/a4
Transdermal (patch): Degree of impairment (ie, CrCl)
(IM/IV) not defined in manufacturer's labeling.
44 60 75 90
30 67 91 113 135 158 180 Mild-to-moderate impairment: Initial: Reduce dose
Oxycodone by 50%.
to to to to to to to
(oral)
66 90 112 134 157 179 202 Severe impairment: Use not recommended.
Transmucosal (buccal film/tablet, sublingual spray/
150 448 598 748 898 1,048 1,198 tablet, lozenge) and intranasal: There are no dos-
Codeine to to to to to to to
(oral) age adjustments provided in the manufacturer's
447 597 747 897 1,047 1,197 1,347
labeling; use with caution. Although fentanyl phar-
8 17 23 29 34 40 46 macokinetics may be altered in renal disease,
Hydromorphone to to to to to to to fentanyl can be used successfully in the manage-
(oral) 16 22 28 33 39 45 51
ment of breakthrough cancer pain. Doses should
Hydromorphone 4 8.5 11.5 14.5 16.6 19.6 22.6 be titrated to reach clinical effect with careful mon-
to to to to to to to
(IV) 8.4 11.4 14.4 16.5 19.5 22.5 25.5 itoring of patients with severe renal disease.
Hepatic Impairment: Adult
Fentanyl
transdermal 25 37 50 62 75 87 100 in the manufacturer’s labeling; use with caution.
recommended mcg/h mcg/h mcg/h mcg/h mcg/h mcg/h mcg/h Transdermal (device): There are no dosage adjust-
dose (mcg/h) ments provided in the manufacturer’s labeling (has
1
not been studied); fentanyl pharmacokinetics may be
The table should NOT be used to convert from transdermal fentanyl altered in hepatic disease.
(Duragesic) to other opioid analgesics. Rather, following removal of the
patch, titrate the dose of the new opioid until adequate analgesia is Transdermal (patch):
achieved. Mild-to-moderate impairment: Initial: Reduce dose
2
Recommendations are based on Canadian product labeling for by 50%.
Duragesic.
3
Morphine dose conversion based upon IM to oral dose ratio of 1:3. Severe impairment: Use not recommended.
4
Insufficient data available to provide specific dosing recommendations. Transmucosal (buccal film/tablet, sublingual spray/
Use caution; adjust dose conservatively. tablet, lozenge) and intranasal: There are no dosage
Geriatric Elderly have been found to be twice as use with caution. Although fentanyl pharmacoki-
sensitive as younger patients to the effects of fentanyl. netics may be altered in hepatic disease, fentanyl
A wide range of doses may be used. When choosing a can be used successfully in the management of
breakthrough cancer pain. Doses should be titrated
dose, take into consideration the following patient
to reach clinical effect with careful monitoring of
factors: age, weight, physical status, underlying dis-
patients with severe hepatic disease.
ease states, other drugs used, type of anesthesia
Pediatric Note: Doses should be titrated to appropri-
used, and the surgical procedure to be performed. ate effects; wide range of doses exist, dependent
Transmucosal lozenge (eg, Actiq): In clinical trials, upon desired degree of analgesia/anesthesia, clinical
patients who were >65 years of age were titrated to environment, patient's status, and presence of opioid
a mean dose that was 200 mcg less than that of tolerance.
younger patients. Infants, Children and Adolescents <18 years of
age:
Renal Impairment: Adult Note: Although limited Acute, short-term uses:
pharmacokinetic data exists in patients with renal Acute pain: Opioid-naïve:
insufficiency, <7% to 10% of fentanyl is excreted as Infants: Limited data available: IV: Initial: 1 to 2
unchanged drug and its metabolites are inactive. mcg/kg/dose; may repeat at 2 to 4 hour intervals;
Fentanyl may be used in patients with renal impair- in opioid-tolerant or younger infants, titration to
ment with careful monitoring for accumulation and higher doses may be required (up to 4 mcg/kg/
adverse effects. In critically ill patients with renal dose) (Hegenbarth 2008; Nelson 1996;
impairment, fentanyl or hydromorphone are preferred WHO 2012)
(Dean 2004; Jacobi 2002; Koncicki 2017; Van Nim- Children: Limited data available in <2 years of age:
men 2010). IV: Initial: 1 to 2 mcg/kg/dose; may repeat at 30- to
Injection: CrCl <50 mL/minute: May need to decrease 60-minute intervals; in opioid-tolerant children,
dose to avoid accumulation, especially with continu- titration to higher doses may be required. Note:
ous infusions; titrate to clinical effect with careful Usual adolescent starting dose is 25 to 50 mcg
(Hegenbarth 2008; Nelson 1996; WHO 2012).
monitoring for adverse effects (Jacobi 2002).
Adolescents <18 years: Note: After the first dose, if
Transdermal (patch): severe pain persists and adverse effects are min-
CrCl 10 to 50 mL/minute: Initial: 75% of normal dose imal at the time of expected peak effect, may
(Koncicki 2017) repeat dose (APS 2008)
CrCl <10 mL/minute: Initial: 50% of normal dose <50 kg: Initial: IV: 0.5 to 1 mcg/kg/dose may
(Koncicki 2017) repeat every 1 to 2 hours although some patients
Intermittent hemodialysis: Initial: 50% of normal dose may require more frequent dosing (eg, 30-
(Koncicki 2017) minute intervals) (APS 2008; Berde 2002)
571
FENTANYL
≥50 kg: Initial: IV: 25 to 50 mcg every 1 to 2 hours Adolescents <18 years:
although some patients may require more fre- ≤50 kg: Initial IV bolus: 0.5 to 2 mcg/kg followed by
quent dosing (eg, 30-minute intervals) (APS continuous IV infusion at initial rate: 0.5 to 2 mcg/
2008; Berde 2002) kg/hour based on expert recommendations for
Analgesia for minor procedures/sedation: children and pediatric patients ≤50 kg (APS
Parenteral: 2008; Berde 2002; WHO 2012)
Infants and Children: Limited data available in <2 >50 kg: Initial IV bolus: 25 to 100 mcg/dose
years of age: IM, IV: 1 to 2 mcg/kg/dose; admin- followed by continuous IV infusion at initial rate:
ister 3 minutes before the procedure; maximum 25 to 200 mcg/hour based on expert recommen-
dose: 50 mcg/dose; may repeat 1/2 original dose dations for pediatric patients and experience in
adult patients (APS 2008; Berde 2002; Liu 2003;
every 3 to 5 minutes if necessary; titrate to effect
Peng 1999)
(Cramton 2012; Krauss 2006; Zeltzer 1990)
Endotracheal intubation, emergent: Limited data
Adolescents <18 years: IV: 0.5 to 1 mcg/kg/dose;
available: Infants and Children: IV: 1 to 5 mcg/kg/
may repeat after 30 to 60 minutes; or 25 to 50 dose (Hegenbarth 2008)
mcg, repeat full dose in 5 minutes if needed, may Preoperative sedation: Adolescents <18 years: IM,
repeat 4 to 5 times with 25 mcg at 5-minute IV: 50 to 100 mcg administered 30 to 60 minutes
intervals if needed. Note: Higher doses are used prior to surgery or slow IV: 25 to 50 mcg given
for major procedures. shortly before induction (Barash 2009)
Intranasal (using parenteral preparation): Limited Patient-controlled analgesia (PCA): Limited data
data available: Infants and Children weighing available: Children ≥5 years and Adolescents <18
≥10 kg: Intranasal: 1.5 mcg/kg once (maximum: years; opioid-naïve: Note: PCA has been used in
100 mcg/dose); reported range: 1 to 2 mcg/kg; children as young as 5 years; however, clinicians
some studies that used an initial dose of 1.5 mcg/ need to assess children 5 to 8 years of age to
kg allowed for additional incremental doses of 0.3 determine if they are able to use the PCA device
to 0.5 mcg/kg to be administered every 5 minutes, correctly. All patients should receive an initial load-
not to exceed a total dose of 3 mcg/kg depending ing dose of an analgesic (to attain adequate control
on pain type and severity (Borland 2002; Borland of pain) before starting PCA for maintenance.
2005; Borland 2007; Chung 2010; Cole 2009; Adjust doses, lockouts, and limits based on
Crellin 2010; Herd 2009; Manjushree 2002; Saun- required loading dose, age, state of health, and
ders 2010) presence of opioid tolerance. Use lower end of
Anesthesia, general; adjunct: dosing range for opioid-naïve. Assess patient and
Children 2 to 12 years: IM, IV: 2 to 3 mcg/kg/dose; pain control at regular intervals and adjust settings
if needed (APS 2008): IV:
Note: An IV should be in place with general
Patient weight ≤50 kg:
anesthesia so the IM route is rarely used but still
Usual concentration: Determined by weight; some
maintained as an option in the manufacturer's
centers use the following:
labeling. Children <12 kg: 10 mcg/mL
Adolescents <18 years: IV: Children 12 to 30 kg: 25 mcg/mL
Low dose: 0.5 to 2 mcg/kg/dose depending on the Children >30 kg: 50 mcg/mL
indication Demand dose: Usual initial: 0.5 to 1 mcg/kg/dose;
Moderate dose: Initial: 2 to 20 mcg/kg/dose; Main- usual range: 0.5 to 1 mcg/kg/dose
tenance (bolus or infusion): 1 to 2 mcg/kg/hour. Lockout: Usual initial: 5 doses/hour
Discontinuing fentanyl infusion 30 to 60 minutes Lockout interval: Range: 6 to 8 minutes
prior to the end of surgery will usually allow Usual basal rate: 0 to 0.5 mcg/kg/hour
adequate ventilation upon emergence from Patient weight >50 kg:
anesthesia. For "fast-tracking" and early extuba- Usual concentration: 50 mcg/mL
tion following major surgery, total fentanyl doses Demand dose: Usual initial: 20 mcg; usual range:
are limited to 10 to 15 mcg/kg. 10 to 50 mcg
High dose: 20 to 50 mcg/kg/dose; Note: High- Lockout interval: Usual initial: 6 minutes; usual
dose fentanyl as an adjunct to general anesthe- range: 5 to 8 minutes
sia is rarely used, but is still described in the Usual basal rate: ≤50 mcg/hour
manufacturer's label. Chronic uses or opioid-tolerant patients (eg, can-
Anesthesia, general without additional anes- cer pain):
thetic agents: Adolescents <18 years: IV: 50 to Chronic pain, moderate to severe (opioid-toler-
100 mcg/kg/dose with O2 and skeletal muscle ant): Transdermal patch: Duragesic: Children ≥2
years and Adolescents <18 years who are opioid-
relaxant
tolerant receiving at least 60 mg oral morphine
Anesthesia, regional; adjunct: Adolescents <18
equivalents per day: Note: Discontinue or taper
years: IM, IV: 50 to 100 mcg; Note: An IV should
all other around-the-clock or extended release
be in place with regional anesthesia so the IM route opioids when initiating therapy with fentanyl trans-
is rarely used but still maintained as an option in the dermal patch:
manufacturer's labeling. Initial: 25 mcg/hour system or higher based on
Continuous analgesia/sedation: previous opioid dosing. To convert patients from
Infants and Children: Limited data available in <2 oral or parenteral opioids to transdermal patch, a
years of age: Initial IV bolus: 1 to 2 mcg/kg 24-hour analgesic requirement should be calcu-
followed by continuous IV infusion at initial rate: lated (based on prior opioid use). Using the follow-
1 mcg/kg/hour; titrate to effect; usual range: 1 to 3 ing tables, the appropriate initial dose can be
mcg/kg/hour; some patients may require higher determined. The initial fentanyl dosage may be
rates (5 mcg/kg/hour) (WHO 2012) approximated from the 24-hour morphine dosage
572
FENTANYL
equivalent and titrated to minimize adverse effects

and provide analgesia. Substantial interpatient
variability exists in relative potency. Therefore, it US Labeling: Dose Conversion
is safer to underestimate a patient's daily fentanyl Guidelines: Recommended Initial
requirement and provide breakthrough pain relief Duragesic Dose Based Upon Daily
with rescue medication (eg, immediate release Oral Morphine Dosea
opioid) than to overestimate requirements. With Oral 24-Hour Morphine Duragesic Doseb,c
the initial application, the absorption of transder- (mg/day) (mcg/hour)
mal fentanyl requires several hours to reach pla- 60 to 134 25
t e a u ; t h e r e f o r e , t r a n s d e r m a l f e n t a n y l is 135 to 224 50
inappropriate for management of acute pain. 225 to 314 75
Change patch every 72 hours. 315 to 404 100
Conversion from continuous infusion of fentanyl: In 405 to 494 125
patients who have adequate pain relief with a 495 to 584 150
fentanyl infusion, fentanyl may be converted to 585 to 674 175
transdermal dosing at a rate equivalent to the 675 to 764 200
intravenous rate. Based on experience in adults, 765 to 854 225
a two-step taper of the infusion to be completed 855 to 944 250
over 12 hours may be considered (Kornick 2001) 945 to 1,034 275
after the patch is applied. The infusion is 1,035 to 1,124 300
decreased to 50% of the original rate 6 hours after a
The table should NOT be used to convert from
the application of the first patch, and subsequently transdermal fentanyl (Duragesic) to other opioid
analgesics. Rather, following removal of the patch, titrate
discontinued twelve hours after application. the dose of the new opioid until adequate analgesia is
achieved.
Titration: Short-acting agents may be required until b
Pediatric patients initiating therapy on a 25 mcg/hour
analgesic efficacy is established and/or as supple- Duragesic system should be opioid-tolerant and receiving
at least 60 mg oral morphine equivalents per day.
ments for "breakthrough" pain. The amount of c
A fentanyl 37.5 mcg/hour transdermal system is also
supplemental doses should be closely monitored. available and may be considered during conversion from
prior opioids or dose titration.
Appropriate dosage increases may be based on
daily supplemental dosage using the ratio of
45 mg/24 hours of oral morphine to a 12.5 mcg/
hour increase in fentanyl dosage
US Labeling: Dose Conversion Guidelinesa
Frequency of adjustment: The dosage should not
be titrated more frequently than every 3 days after Current Daily Dosage
Analgesic (mg/day)
the initial dose or every 6 days thereafter. Titrate
Morphine (IM/IV) 10 to 22 23 to 37 38 to 52 53 to 67
dose based on the daily dose of supplemental
Oxycodone (oral) 30 to 67 67.5 to 112.5 to 157.5 to
opioids required by the patient on the second or 112 157 202
third day of the initial application. Note: Upon 150 to
Codeine (oral) 447 - - -
discontinuation, ~17 hours are required for a
50% decrease in fentanyl levels. Hydromorphone 17.1 to 28.1 to
8 to 17 39.1 to 51
(oral) 28 39
Frequency of application: The majority of patients
Hydromorphone 1.5 to 3.5 to 5.7 to 8 to 10
may be controlled on every 72-hour administra- (IV) 3.4 5.6 7.9
tion; however, a small number of adult patients 75 to 166 to 279 to 391 to
Meperidine (IM)
have required every 48-hour administration. 165 278 390 503
Discontinuation: When discontinuing transdermal 75 to 105 to
Methadone (oral) 20 to 44 45 to 74
104 134
fentanyl and not converting to another opioid,
use a gradual downward titration, such as
Duragesic
decreasing the dose by 50% every 6 days, to (fentanyl 25 mcg/ 50 mcg/ 75 mcg/ 100 mcg/
reduce the possibility of withdrawal symptoms. transdermal)
hour hour hour hour
recommended
Dose conversion guidelines for transdermal fen- dose (mcg/hour)
tanyl from other opioids (see tables). a
The table should NOT be used to convert from transdermal fentanyl
Note: The conversion factors in these tables are (Duragesic) to other opioid analgesics. Rather, following removal of the
patch, titrate the dose of the new opioid until adequate analgesia is
only to be used for the conversion from current achieved.
opioid therapy to Duragesic patch. Conversion Cancer pain; breakthrough: Transmucosal loz-
factors in this table cannot be used to convert enge: Actiq: Adolescents ≥16 years: Note: For
from Duragesic to another opioid (doing so may patients who are tolerant to and currently receiving
lead to fatal overdose due to overestimation of opioid therapy for persistent cancer pain; dosing
should be individually titrated to provide adequate
the new opioid). US and Canadian dose con-
analgesia with minimal side effects. Patients must
version guidelines differ; consult table for US remain on around-the-clock opioids during
recommendations. The Canadian product is not use.
approved in pediatric patients. These are not Initial dose: 200 mcg (consumed over 15 minutes)
tables of equianalgesic doses. for all patients; if after 30 minutes from the start of
573
FENTANYL
the lozenge (ie, 15 minutes following the comple- Adjunct to general anesthesia: Slow IV:
tion of the lozenge), the pain is unrelieved, a Low dose: 1 to 2 mcg/kg depending on the
second 200 mcg dose may be given over 15 indication (Miller 2010); additional maintenance
minutes. A maximum of 1 additional dose can be doses are generally not needed
given per pain episode; must wait at least 4 Moderate dose (fentanyl plus a sedative/hyp-
hours before treating another episode. To limit notic): Initial: 2 to 4 mcg/kg; Maintenance (bolus
the number of units in the home during titration, or infusion): 25 to 50 mcg every 15 to 30 minutes
only prescribe an initial titration supply of six 200 or 0.5 to 2 mcg/kg/hour. Discontinuing fentanyl
mcg lozenges. Note: Do not convert patients from infusion 30 to 60 minutes prior to the end of
any other fentanyl product to Actiq on a mcg-per- surgery will usually allow adequate ventilation
upon emergence from anesthesia.
mcg basis. Patients previously using another fen-
High dose (opioid anesthesia): 4 to 20 mcg/kg
tanyl product should be initiated at a dose of 200
bolus then 2 to 10 mcg/kg/hour (Miller 2010);
mcg; individually titrate to provide adequate anal-
Note: High-dose fentanyl (ie, 20 to 50 mcg/kg) is
gesia while minimizing adverse effects. rarely used, but is still described in the manu-
Dose titration: Dose titration should be done if facturer's label. The concept of fast-tracking and
patient requires more than 1 dose/breakthrough early extubation following cardiac surgery has
pain episode for several consecutive episodes. essentially replaced high-dose fentanyl anes-
From the initial dose, closely follow patients and thesia.
modify the dose until patient reaches a dose Adjunct to regional anesthesia: 50 to 100 mcg IM or
providing adequate analgesia using a single dos- slow IV over 1 to 2 minutes. Note: An IV should be
age unit per breakthrough cancer pain episode. If in place with regional anesthesia so the IM route is
signs/symptoms of excessive opioid effects (eg, rarely used but still maintained as an option in the
respiratory depression) occur, immediately manufacturer's labeling.
remove the dosage unit from the patient's mouth, Postoperative recovery: IM, slow IV: 50 to 100 mcg
dispose of properly, and reduce subsequent every 1 to 2 hours as needed
doses. If adequate relief is not achieved 15 Pain management:
minutes after completion of the first dose (ie, 30 Postoperative pain, acute: Transdermal device
minutes after the start of the lozenge), only 1 (Ionsys): Apply one device to chest or upper outer
additional lozenge of the same strength may be arm only. Only the patient may activate the device
given for that episode; must wait at least 4 hours (40 mcg dose of fentanyl per activation; maximum:
before treating another episode. 6 doses per hour). Only one device may be
Maintenance dose: Once titrated to an effective applied at a time for up to 24 hours or 80 doses,
whichever comes first. May be used for a max-
dose, patients should generally use a single dos-
imum of 72 hours, with each subsequent device
age unit per breakthrough pain episode. During
applied to a different skin site. If inadequate
any pain episode, if adequate relief is not
analgesia is achieved with one device, either
achieved 15 minutes after completion of the first provide additional supplemental analgesic medi-
dose (ie, 30 minutes after the start of the lozenge), cation or replace with an alternate analgesic med-
only 1 additional lozenge of the same strength ication. Refer to manufacturer's labeling for
may be given over 15 minutes for that episode; activation instructions.
must wait at least 4 hours before treating Note: For hospital use only by patients under
another episode. Consumption should be limited medical supervision and direction and only after
to ≤4 units per day (once an effective break- patients have been titrated to an acceptable
through dose is found). If adequate analgesia is level of analgesia using another opioid anal-
not provided after treating several episodes of gesic.
breakthrough pain using the same dose, increase Severe pain:
dose to next highest lozenge strength (initially Intermittent dosing: IM, IV: Slow IV: 25 to 35 mcg
dispense no more than 6 units of the new (based on ~70 kg patient) or 0.35 to 0.5 mcg/kg
strength). Consider increasing the around-the- every 30 to 60 minutes as needed (SCCM [Barr
clock opioid therapy in patients experiencing >4 2013]). Note: After the first dose, if severe pain
breakthrough pain episodes per day and have persists and adverse effects are minimal at the
their long-term opioid re-evaluated. If signs/symp- time of expected peak effect (eg, ~5 minutes
toms of excessive opioid effects (eg, respiratory after IV administration), may repeat dose (APS
depression) occur, immediately remove the dos- 2008). In addition, since the duration of activity
age unit from the patient's mouth, dispose of with IV administration is 30 to 60 minutes, more
frequent administration may be necessary when
properly, and reduce subsequent doses.
administered by this route.
Adolescents ≥ 18 years:
Patient-controlled analgesia (PCA) (APS 2008;
Note: Ranges listed may not represent the maximum
Miller 2010): Opioid-naive: IV:
doses that may be required in some patients. Doses Usual concentration: 10 mcg/mL
and dosage intervals should be titrated to pain relief/ Demand dose: Usual: 10 to 20 mcg
prevention. Monitor vital signs routinely. Single IM Lockout interval: 4 to 10 minutes
doses have duration of 1 to 2 hours; single IV doses Usual basal rate: ≤50 mcg/hour. Note: Continu-
last 0.5 to 1 hour. ous basal infusions are not recommended for
Surgery: initial programming and should rarely be used;
Premedication: IM, slow IV: 50 to 100 mcg admin- consider limiting infusion rate to 10 mcg/hour if
istered 30 to 60 minutes prior to surgery or slow used (Grass 2005).
IV: 25 to 50 mcg given shortly before induction Cancer pain; breakthrough: Transmucosal: Opioid-
(Barash 2009) tolerant patients: For patients who are tolerant to
574
FENTANYL
and currently receiving opioid therapy for persistent at a dose of 200 mcg; individually titrate to provide
cancer pain; dosing should be individually titrated to adequate analgesia while minimizing adverse
provide adequate analgesia with minimal side effects.
effects. Dose titration should be done if patient Initial dose: 200 mcg for all patients; if after 30
requires more than 1 dose/breakthrough pain epi- minutes pain is unrelieved, the patient may use
sode for several consecutive episodes. Patients an alternative rescue medication as directed by
experiencing >4 breakthrough pain episodes/day their health care provider. Do not redose with
should have the dose of their long-term opioid re- Onsolis within an episode; buccal film should
evaluated. Patients must remain on around-the- only be used once per breakthrough cancer pain
clock opioids during use. episode. Must wait at least 2 hours before
Lozenge (eg, Actiq): Note: Do not convert patients treating another episode with buccal film.
from any other fentanyl product to Actiq on a mcg- Dose titration: If titration required, increase dose
per-mcg basis. Patients previously using another in 200 mcg increments once per episode using
fentanyl product should be initiated at a dose of multiples of the 200 mcg film (for doses up to 800
200 mcg; individually titrate to provide adequate mcg); do not redose within a single episode of
analgesia while minimizing adverse effects. breakthrough pain and separate single doses by
Initial dose: 200 mcg (consumed over 15 minutes) ≥2 hours. During titration, do not exceed 4
for all patients; if after 30 minutes from the start simultaneous applications of the 200 mcg films
of the lozenge (ie, 15 minutes following the (800 mcg) (when using multiple films, do not
completion of the lozenge), the pain is unre- place on top of each other; film may be placed
lieved, a second 200 mcg dose may be given on both sides of mouth); if >800 mcg required,
over 15 minutes. A maximum of 1 additional treat next episode with one 1,200 mcg film
dose can be given per pain episode; must wait (maximum dose: 1,200 mcg). Once maintenance
at least 4 hours before treating another epi- dose is determined, all other unused films should
sode. To limit the number of units in the home be disposed of and that strength (using a single
during titration, only prescribe an initial titration film) should be used. During any pain episode, if
supply of six 200 mcg lozenges. adequate relief is not achieved after 30 minutes
Dose titration: From the initial dose, closely follow following buccal film application, a rescue med-
patients and modify the dose until patient ication (as determined by health care provider)
reaches a dose providing adequate analgesia may be used.
using a single dosage unit per breakthrough
Maintenance dose: Determined dose applied as a
cancer pain episode. If signs/symptoms of
single film once per episode and separated by
excessive opioid effects (eg, respiratory depres-
≥2 hours (dose range: 200 to 1,200 mcg); limit to
sion) occur, immediately remove the dosage unit
4 applications per day. Consider increasing the
from the patient's mouth, dispose of properly,
around-the-clock opioid therapy in patients expe-
and reduce subsequent doses. If adequate relief
riencing >4 breakthrough pain episodes per day.
is not achieved 15 minutes after completion of
Buccal tablets (Fentora): Note: Do not convert
the first dose (ie, 30 minutes after the start of the
patients from any other fentanyl product to Fen-
lozenge), only 1 additional lozenge of the same
tora on a mcg-per-mcg basis. Patients previously
strength may be given for that episode; must
wait at least 4 hours before treating another using another fentanyl product should be initiated
episode. at a dose of 100 mcg; individually titrate to provide
Maintenance dose: Once titrated to an effective adequate analgesia while minimizing adverse
dose, patients should generally use a single effects. For patients previously using the trans-
dosage unit per breakthrough pain episode. Dur- mucosal lozenge (Actiq), the initial dose should be
ing any pain episode, if adequate relief is not selected using the conversions listed; see Con-
achieved 15 minutes after completion of the first version from lozenge (Actiq) to buccal tablet
dose (ie, 30 minutes after the start of the loz- (Fentora).
enge), only 1 additional lozenge of the same Initial dose: 100 mcg for all patients unless patient
strength may be given over 15 minutes for that already using Actiq; see Conversion from loz-
episode; must wait at least 4 hours before enge (Actiq) to buccal tablet (Fentora); if after 30
treating another episode. Consumption should minutes pain is unrelieved, a second 100 mcg
be limited to ≤4 units per day (once an effective dose may be administered (maximum of 2 doses
breakthrough dose is found). If adequate anal- per breakthrough pain episode). Must wait at
gesia is not provided after treating several epi- least 4 hours before treating another episode
sodes of breakthrough pain using the same with Fentora buccal tablet.
dose, increase dose to next highest lozenge Dose titration: If titration required, 100 mcg dose
strength (initially dispense no more than 6 units may be increased to 200 mcg using two 100 mcg
of the new strength). Consider increasing the tablets (one on each side of mouth) with the next
around-the-clock opioid therapy in patients expe- breakthrough pain episode. If 200 mcg dose is
riencing >4 breakthrough pain episodes per day. not successful, patient can use four 100 mcg
If signs/symptoms of excessive opioid effects tablets (two on each side of mouth) with the next
(eg, respiratory depression) occur, immediately breakthrough pain episode. If titration requires
remove the dosage unit from the patient's mouth, >400 mcg per dose, titrate using 200 mcg tab-
dispose of properly, and reduce subsequent lets; do not use more than 4 tablets simultane-
doses. ously (maximum single dose: 800 mcg). During
Buccal film (eg, Onsolis): Note: Do not convert any pain episode, if adequate relief is not
patients from any other fentanyl product to Ons- achieved after 30 minutes following buccal tablet
olis on a mcg-per-mcg basis. Patients previously application, a second dose of same strength per
using another fentanyl product should be initiated breakthrough pain episode may be used. Must
575
FENTANYL
wait at least 4 hours before treating another Avoid use of a combination of dose strengths
episode with Fentora buccal tablet. to treat an episode.
Maintenance dose: Following titration, the effec- Maintenance dose: Once maintenance dose for
tive maintenance dose using 1 tablet of the breakthrough pain episode has been deter-
appropriate strength should be administered mined, use that dose for subsequent episodes.
once per episode; if after 30 minutes pain is For pain that is not relieved after 30 minutes of
unrelieved, may administer a second dose of Lazanda administration or if a separate break-
the same strength. Must wait ≥4 hours before through pain episode occurs within the 2 hour
treating another episode with Fentora buccal window before the next Lazanda dose is permit-
tablet. Limit to 4 applications per day. Consider ted, a rescue medication may be used. Limit
increasing the around-the-clock opioid therapy in Lazanda use to ≤4 episodes of breakthrough
patients experiencing >4 breakthrough pain epi- pain per day. If patient is experiencing >4 break-
sodes per day. Once an effective maintenance through pain episodes/day, consider increasing
dose has been established, the buccal tablet the around-the-clock, long-acting opioid therapy;
may be administered sublingually (alternate if long-acting opioid therapy dose is altered, re-
route). To prevent confusion, patient should only evaluate and retitrate Lazanda dose as needed.
have one strength available at a time. Once If response to maintenance dose changes
maintenance dose is determined, all other (increase in adverse reactions or alterations in
unused tablets should be disposed of and that pain relief), dose readjustment may be nec-
strength (using a single tablet) should be used. essary.
Using more than four buccal tablets at a time has Sublingual spray (Subsys): Note: Do not convert
not been studied. patients from any other fentanyl product to Subsys
Conversion from lozenge (Actiq) to buccal tablet on a mcg-per-mcg basis. Patients previously
(Fentora): using another fentanyl product should be initiated
Lozenge dose 200 to 400 mcg: Initial buccal at a dose of 100 mcg; individually titrate to provide
tablet dose is 100 mcg; may titrate using multi- adequate analgesia while minimizing adverse
ples of 100 mcg effects. For patients previously using the trans-
Lozenge dose 600 to 800 mcg: Initial buccal mucosal lozenge (Actiq), the initial dose should be
tablet dose is 200 mcg; may titrate using multi- selected using the conversions listed; see Con-
ples of 200 mcg version from lozenge (Actiq) to sublingual spray
Lozenge dose 1,200 to 1,600 mcg: Initial buccal (Subsys).
tablet dose is 400 mcg (using two 200 mcg Initial dose: 100 mcg for all patients unless patient
tablets); may titrate using multiples of 200 mcg already using Actiq; see Conversion from loz-
Nasal spray (Lazanda): Note: Do not convert enge (Actiq) to sublingual spray (Subsys) If pain
patients from any other fentanyl product to Laz- is unrelieved, one additional 100 mcg dose may
anda on a mcg-per-mcg basis. Patients previously be given 30 minutes after administration of the
using another fentanyl product should be initiated first dose. A maximum of two doses can be given
at a dose of 100 mcg; individually titrate to provide per breakthrough pain episode. Must wait at
adequate analgesia while minimizing adverse least 4 hours before treating another episode
effects. with sublingual spray.
Initial dose: 100 mcg (one 100 mcg spray in one Dose titration: If titration required, titrate to a dose
nostril) for all patients; if after 30 minutes pain is that provides adequate analgesia (with tolerable
unrelieved, an alternative rescue medication side effects) using the following titration steps: If
may be used as directed by their health care no relief with 100 mcg dose, increase to 200 mcg
provider. Must wait at least 2 hours before dose per episode (one 200 mcg unit); if no relief
treating another episode with Lazanda nasal with 200 mcg dose, increase to 400 mcg per
spray. However, for the next pain episode, episode (one 400 mcg unit); if no relief with 400
increase to a higher dose using the recom- mcg dose, increase to 600 mcg dose per epi-
mended dose titration steps. sode (one 600 mcg unit); if no relief with 600 mcg
Dose titration: If titration required, increase to a dose, increase to 800 mcg dose per episode
higher dose using the recommended titration (one 800 mcg unit); if no relief with 800 mcg
steps. (Note: Must wait at least 2 hours before dose, increase to 1,200 mcg dose per episode
treating another episode with nasal spray.) (two 600 mcg units); if no relief with 1,200 mcg
Dose titration steps: If no relief with 100 mcg dose, increase to 1,600 mcg per episode (two
dose, increase to 200 mcg dose per episode 800 mcg units). During dose titration, if break-
(one 100 mcg spray in each nostril); if no relief through pain unrelieved 30 minutes after Subsys
with 200 mcg dose, increase to 300 mcg dose administration, 1 additional dose using the same
per episode (alternating one 100 mcg spray in strength may be administered (maximum: 2
right nostril, one 100 mcg spray in left nostril, and doses per breakthrough pain episode); patient
one 100 mcg spray in the right nostril); if no relief must wait 4 hours before treating another
with 300 mcg dose, increase to 400 mcg per breakthrough pain episode with sublingual
episode (one 400 mcg spray in one nostril or two spray.
100 mcg sprays in each nostril); if no relief with Maintenance dose: Once maintenance dose for
400 mcg dose, increase to 600 mcg dose per breakthrough pain episode has been deter-
episode (one 300 mcg spray in each nostril); if mined, use that dose for subsequent episodes.
no relief with 600 mcg dose, increase to 800 mcg If occasional episodes of unrelieved break-
dose per episode (one 400 mcg spray in each through pain occur following 30 minutes of
nostril). Note: Single doses >800 mcg have not Subsys administration, one additional dose
been evaluated. There are no data supporting using the same strength may be administered
the use of a combination of dose strengths. (maximum: Two doses per breakthrough pain
576
FENTANYL
episode); patient must wait 4 hours before treat- Conversion from lozenge (Actiq) to sublingual
ing another breakthrough pain episode with tablet (Abstral):
Subsys. Once maintenance dose is determined, Lozenge dose 200 mcg: Initial sublingual tablet
limit Subsys use to ≤4 episodes of breakthrough dose is 100 mcg; may titrate using multiples of
pain per day. If response to maintenance dose 100 mcg
changes (increase in adverse reactions or alter- Lozenge dose 400 to 1,200 mcg: Initial sublin-
ations in pain relief), dose readjustment may be gual tablet dose is 200 mcg; may titrate using
necessary. If patient is experiencing >4 break- multiples of 200 mcg
through pain episodes/day, consider increasing Lozenge dose 1,600 mcg: Initial sublingual tablet
the around-the-clock, long-acting opioid therapy. dose is 400 mcg; may titrate using multiples of
400 mcg
Conversion from lozenge (Actiq) to sublingual
Chronic pain management (opioid-tolerant
spray (Subsys):
patients only): Transdermal patch: Discontinue
Lozenge dose 200 to 400 mcg: Initial sublingual
or taper all other around-the-clock or extended
spray dose is 100 mcg; may titrate using multi- release opioids when initiating therapy with fentanyl
ples of 100 mcg transdermal patch.
Lozenge dose 600 to 800 mcg: Initial sublingual Initial: To convert patients from oral or parenteral
spray dose is 200 mcg; may titrate using multi- opioids to transdermal patch, a 24-hour analgesic
ples of 200 mcg requirement should be calculated (based on prior
Lozenge dose 1,200 to 1,600 mcg: Initial sub- opioid use). Using the following tables, the appro-
lingual spray dose is 400 mcg; may titrate using priate initial dose can be determined. The initial
multiples of 400 mcg fentanyl dosage may be approximated from the
Sublingual tablet (Abstral): Note: Do not convert 24-hour morphine dosage equivalent and titrated
patients from any other fentanyl product to Abstral to minimize adverse effects and provide analge-
on a mcg-per-mcg basis. Patients previously sia. Substantial interpatient variability exists in
using another fentanyl product should be initiated relative potency. Therefore, it is safer to under-
at a dose of 100 mcg (except Actiq); individually estimate a patient's daily fentanyl requirement and
titrate to provide adequate analgesia while mini- provide breakthrough pain relief with rescue med-
mizing adverse effects. ication (eg, immediate release opioid) than to
Initial dose: 100 mcg for all patients unless patient overestimate requirements. With the initial appli-
already using Actiq; see Conversion from loz- cation, the absorption of transdermal fentanyl
enge (Actiq) to sublingual tablet (Abstral); if pain requires several hours to reach plateau; therefore,
is unrelieved, a second dose may be given 30 transdermal fentanyl is inappropriate for manage-
ment of acute pain. Change patch every 72 hours.
minutes after administration of the first dose. A
Conversion from continuous infusion of fentanyl: In
maximum of two doses can be given per break-
patients who have adequate pain relief with a
through pain episode. Must wait at least 2
fentanyl infusion, fentanyl may be converted to
hours before treating another episode. transdermal dosing at a rate equivalent to the
Dose titration: If titration required, increase in 100 intravenous rate. A two-step taper of the infusion
mcg increments (up to 400 mcg) over consec- to be completed over 12 hours has been recom-
utive breakthrough episodes. If titration requires mended (Kornick 2001) after the patch is applied.
>400 mcg/dose, increase in increments of 200 The infusion is decreased to 50% of the original
mcg, starting with 600 mcg dose and titrating up rate six hours after the application of the first
to 800 mcg. During titration, patients may use patch, and subsequently discontinued 12 hours
multiples of 100 mcg and/or 200 mcg tablets for after application.
any single dose; do not exceed 4 tablets at one Titration: Short-acting agents may be required until
time; safety and efficacy of doses >800 mcg analgesic efficacy is established and/or as supple-
have not been evaluated. During dose titration, ments for "breakthrough" pain. The amount of
if breakthrough pain unrelieved 30 minutes after supplemental doses should be closely monitored.
sublingual tablet administration, one additional Appropriate dosage increases may be based on
dose using the same strength may be adminis- daily supplemental dosage using the ratio of
tered (maximum: 2 doses per breakthrough pain 45 mg/24 hours of oral morphine to a 12.5 mcg/
episode). Patient must wait 2 hours before hour increase in fentanyl dosage.
treating another breakthrough pain episode Frequency of adjustment: The dosage should not
with sublingual tablet. be titrated more frequently than every 3 days after
Maintenance dose: Once maintenance dose for the initial dose or every 6 days thereafter. Titrate
dose based on the daily dose of supplemental
breakthrough pain episode has been deter-
opioids required by the patient on the second or
mined, use only one tablet in the appropriate
third day of the initial application. Note: Upon
strength per episode. If pain is unrelieved with
discontinuation, ~17 hours are required for a
maintenance dose, a second dose may be given 50% decrease in fentanyl levels.
after 30 minutes; maximum of 2 doses/episode Frequency of application: The majority of patients
of breakthrough pain; separate treatment of sub- may be controlled on every 72-hour administra-
sequent episodes by ≥2 hours; limit treatment to tion; however, a small number of adult patients
≤4 breakthrough episodes/day. Consider require every 48-hour administration.
increasing the around-the-clock, long-acting Discontinuation: When discontinuing transdermal
opioid therapy in patients experiencing >4 break- fentanyl and not converting to another opioid,
through pain episodes/day; if long-acting opioid use a gradual downward titration, such as
therapy dose altered, re-evaluate and retitrate decreasing the dose by 50% every 6 days, to
Abstral dose as needed. reduce the possibility of withdrawal symptoms.
577
FENTANYL
Dose conversion guidelines for transdermal fen- Renal Impairment: Pediatric

tanyl (see tables). Note: The conversion factors Injection: There are no dosage adjustments provided
in these tables are only to be used for the con- in the manufacturer’s labeling; however, the follow-
version from current opioid therapy to Duragesic ing guidelines have been used by some clinicians
(US labeling). Conversion factors in this table (Aronoff 2007):
cannot be used to convert from Duragesic to Infants, Children, and Adolescents: The following
another opioid (doing so may lead to fatal over- assumes dosages of 0.5 to 2 mcg/kg/dose or 1 to
dose due to overestimation of the new opioid). 5 mcg/kg/hour in normal renal function: IV:
These are not tables of equianalgesic doses. GFR >50 mL/minute/1.73 m 2 : No adjustment
required
US Labeling: Dose Conversion GFR 10 to 50 mL/minute/1.73 m2: Administer 75%
Guidelines: Recommended Initial of usual dose
Duragesic Dose Based Upon Daily GFR <10 mL/minute/1.73 m2: Administer 50% of
Oral Morphine Dosea usual dose
Intermittent hemodialysis: Administer 50% of
Oral 24-Hour Morphine Duragesic Doseb usual dose
(mg/day) (mcg/hour) Peritoneal dialysis (PD): Administer 50% of
60 to 134 25 usual dose
135 to 224 50 Continuous renal replacement therapy (CRRT):
225 to 314 75 Administer 75% of usual dose
Transdermal (device): Adolescents ≥18 years: There
315 to 404 100
are no dosage adjustments provided in the manu-
405 to 494 125 facturer’s labeling (has not been studied); fentanyl
495 to 584 150 pharmacokinetics may be altered in renal disease.
585 to 674 175 Transdermal (patch): Pediatric patients ≥2 years:
675 to 764 200 Degree of impairment (ie, CrCl) not defined in
765 to 854 225 manufacturer’s labeling.
Mild to moderate impairment: Initial: Reduce dose
855 to 944 250
by 50%
945 to 1,034 275 Severe impairment: Use not recommended
1,035 to 1,124 300 Transmucosal (buccal film/tablet, sublingual spray/
a
The table should NOT be used to convert from tablet, lozenge) and nasal spray: Adolescents ≥18
transdermal fentanyl (Duragesic) to other opioid years: Although fentanyl pharmacokinetics may be
analgesics. Rather, following removal of the patch, titrate
the dose of the new opioid until adequate analgesia is altered in renal disease, fentanyl can be used
achieved. successfully in the management of breakthrough
b
A fentanyl 37.5 mcg/hour transdermal system is also cancer pain. Use with caution; reduce initial dose
available and may be considered during conversion from
prior opioids or dose titration. and titrate to reach clinical effect with careful mon-
itoring of patients, especially those with severe
renal disease.
Hepatic Impairment: Pediatric
US Labeling: Dose Conversion Guidelinesa in the manufacturer’s labeling.
Current Daily Dosage Transdermal (device): Adolescents ≥18 years: There
Analgesic (mg/day) are no dosage adjustments provided in the manu-
Morphine (IM/IV) 10 to 22 23 to 37 38 to 52 53 to 67 facturer’s labeling (has not been studied); fentanyl
67.5 to 112.5 to 157.5 to pharmacokinetics may be altered in hepatic
Oxycodone (oral) 30 to 67 disease.
112 157 202
150 to Transdermal (patch): Pediatric patients ≥2 years:
Codeine (oral) - - - Mild to moderate impairment: Initial: Reduce dose
447
Hydromorphone 17.1 to 28.1 to by 50%
8 to 17 39.1 to 51
(oral) 28 39 Severe impairment: Use not recommended
Hydromorphone 1.5 to 3.5 to 5.7 to Transmucosal (buccal film/tablet, sublingual spray/
8 to 10
(IV) 3.4 5.6 7.9 tablet, lozenge) and nasal spray: Adolescents ≥18
75 to 166 to 279 to 391 to years: Although fentanyl pharmacokinetics may be
Meperidine (IM)
165 278 390 503 altered in hepatic disease, fentanyl can be used
Methadone (oral) 20 to 44 45 to 74 75 to 105 to successfully in the management of breakthrough
104 134 cancer pain. Use with caution; reduce initial dose
and titrate to reach clinical effect with careful mon-
Duragesic itoring of patients, especially those with severe
(fentanyl hepatic disease.
transdermal) 25 mcg/ 50 mcg/ 75 mcg/ 100 mcg/
hour hour hour hour Mechanism of Action Binds with stereospecific recep-
recommended
dose (mcg/hour) tors at many sites within the CNS, increases pain
a
The table should NOT be used to convert from transdermal fentanyl threshold, alters pain reception, inhibits ascending pain
(Duragesic) to other opioid analgesics. Rather, following removal of the pathways
patch, titrate the dose of the new opioid until adequate analgesia is
achieved. Contraindications
Hypersensitivity (eg, anaphylaxis, hypersensitivity) to
fentanyl or any component of the formulation.
Additional contraindications for transdermal device
(Ionsys): Significant respiratory depression; acute or
severe bronchial asthma in an unmonitored setting or
578
FENTANYL
in the absence of resuscitative equipment; gastro- bronchial asthma, chronic obstructive airway, status
intestinal obstruction, including paralytic ileus (known asthmaticus; acute respiratory depression; hyper-
or suspected); hypersensitivity to cetylpyridinium capnia; cor pulmonale; acute alcoholism, delirium
chloride (eg, Cepacol). tremens, and convulsive disorders; severe CNS
Additional contraindications for transdermal patch depression, increased cerebrospinal or intracranial
(Duragesic): Significant respiratory depression; acute pressure and head injury; concurrent use or use
or severe bronchial asthma in an unmonitored setting within 14 days of an MAO inhibitor
or in the absence of resuscitative equipment; gastro-
Documentation of allergenic cross-reactivity for opioids
intestinal obstruction, including paralytic ileus (known
is limited. However, because of similarities in chemical
or suspected); patients requiring short-term therapy,
structure and/or pharmacologic actions, the possibility
management of acute or intermittent pain, postoper-
of cross-sensitivity cannot be ruled out with certainty.
ative or mild pain; patients who are not opioid tolerant.
Additional contraindications for transmucosal buccal Warnings/Precautions An opioid-containing analge-
tablets (Fentora), buccal films (Onsolis), lozenges sic regimen should be tailored to each patient's needs
(Actiq), sublingual tablets (Abstral), sublingual spray and based upon the type of pain being treated (acute
(Subsys), intranasal (Lazanda): Significant respiratory versus chronic), the route of administration, degree of
depression (Actiq, Fentora only); acute or severe tolerance for opioids (naive versus chronic user), age,
bronchial asthma in an unmonitored setting or in the weight, and medical condition. The optimal analgesic
absence of resuscitative equipment; gastrointestinal dose varies widely among patients. Doses should be
obstruction, including paralytic ileus (known or sus- titrated to pain relief/prevention. May cause CNS
pected); acute or postoperative pain (including head- depression, which may impair physical or mental abil-
ache, migraine, or dental pain); patients who are not ities; patients must be cautioned about performing tasks
opioid tolerant; acute pain management in the emer- which require mental alertness (eg, operating machi-
gency room. nery or driving). [US Boxed Warning]: Concomitant
use of opioids with benzodiazepines or other CNS
Canadian labeling: Additional contraindication (not in depressants, including alcohol, may result in pro-
US labeling): found sedation, respiratory depression, coma, and
Injection: Septicemia; severe hemorrhage or shock; death. Reserve concomitant prescribing of oxyco-
local infection at proposed injection site; disturban- done/acetaminophen and benzodiazepines or other
ces in blood morphology and/or anticoagulant ther- CNS depressants for use in patients for whom
apy or other concomitant drug therapy or medical alternative treatment options are inadequate. Limit
conditions which could contraindicate the technique dosage and durations to the minimum required and
of epidural administration follow patients for signs and symptoms of respira-
Sublingual tablets (Abstral): Severe bronchial asthma, tory depression and sedation. [US Boxed Warning]:
chronic obstructive airway, or status asthmaticus; The concomitant use of fentanyl with all cyto-
acute respiratory depression; hypercapnia; cor pul- chrome P450 3A4 inhibitors may result in an
monale; known or suspected mechanical GI obstruc- increase in fentanyl plasma concentrations, which
tion (eg, bowel obstruction or strictures) or any could increase or prolong adverse reactions and
diseases/conditions that affect bowel transit (eg, may cause potentially fatal respiratory depression.
ileus of any type); suspected surgical abdomen (eg, In addition, discontinuation of a concomitantly
acute appendicitis or pancreatitis); mild pain that can used cytochrome P450 3A4 inducer may result in
be managed with other pain medications; acute pain an increase in fentanyl plasma concentration. Mon-
management other than breakthrough or postoper- itor patients receiving fentanyl and any CYP3A4
ative pain (including headache or migraine, dental inhibitor or inducer. Potentially significant drug/drug
pain or emergency room use); acute alcoholism, interactions may exist, requiring dose or frequency
delirium tremens, and convulsive disorders; severe adjustment, additional monitoring, and/or selection of
CNS depression, increased cerebrospinal or intra- alternative therapy. Rapid IV infusion may result in
cranial pressure and head injury; concurrent use or skeletal muscle and chest wall rigidity leading to respi-
use within 14 days of a monoamine oxidase (MAO) ratory distress and/or apnea, bronchoconstriction, lar-
inhibitor; breastfeeding women; during labor and yngospasm; inject slowly over 1 to 2 minutes. [US
delivery; opioid-nontolerant patients (including Boxed Warning]: Use exposes patients and other
patients on intermittent or as needed opioid dosing). users to the risks of opioid addiction, abuse, and
Transdermal patch: Hypersensitivity to other opioids; misuse, which can lead to overdose and death.
suspected surgical abdomen (eg, acute appendicitis, Assess each patient's risk prior to prescribing fen-
pancreatitis); known or suspected mechanical GI tanyl and monitor all patients regularly for the
obstruction (eg, bowel obstruction, strictures) or development of these behaviors and conditions.
any diseases/conditions that affect bowel transit Use with caution in patients with a history of drug abuse
(eg, ileus of any type); acute alcoholism, delirium or acute alcoholism; potential for drug dependency
tremens, and convulsive disorders; severe CNS exists. Consider offering naloxone prescriptions in
depression, increased cerebrospinal or intracranial patients with factors associated with an increased risk
pressure and head injury; concurrent use of MAO for overdose, such as history of overdose or substance
inhibitors or within 14 days of therapy; perioperative use disorder, higher opioid dosages (≥50 morphine
pain; women who are nursing, pregnant, or during milligram equivalents/day orally), and concomitant ben-
labor and delivery zodiazepine use (Dowell [CDC 2016]). [US Boxed
Transmucosal buccal tablets (Fentora): Hypersensitiv- Warning]: Accidental ingestion of even one dose,
ity to other opioids; acute pain management in the especially by children, can result in a fatal overdose
emergency room; known or suspected mechanical of fentanyl. Fentanyl must be kept out of reach of
GI obstruction (eg, bowel obstruction or strictures) or children. Use opioids with caution in chronic pain in
any diseases/conditions that affect bowel transit (eg, patients with mental health conditions (eg, depression,
ileus of any type); suspected surgical abdomen (eg, anxiety disorders, post-traumatic stress disorder) due to
acute appendicitis or pancreatitis); acute or severe increased risk for opioid use disorder and overdose;
579
FENTANYL
more frequent monitoring is recommended (Dowell effective dosage using immediate-release opioids
[CDC 2016]). Use with caution in the elderly; may be (instead of extended-release/long-acting opioids). Risk
more sensitive to adverse effects. Decrease initial dose. associated with use increases with higher opioid dos-
Use opioids for chronic pain with caution in this age ages. Risks and benefits should be re-evaluated when
group; monitor closely due to an increased potential for increasing dosage to ≥50 morphine milligram equiva-
risks, including certain risks such as falls/fracture, cog- lents (MME)/day orally; dosages ≥90 MME/day orally
nitive impairment, and constipation. Clearance may should be avoided unless carefully justified (Dowell
also be reduced in older adults (with or without renal [CDC 2016]).
impairment) resulting in a narrow therapeutic window
[US Boxed Warning]: Buccal film, buccal tablet,
and increasing the risk for respiratory depression or
intranasal, sublingual tablet, sublingual spray, and
overdose (Dowell [CDC 2016]). Consider the use of
lozenge preparations contain an amount of medi-
alternative nonopioid analgesics in these patients.
cation that can be fatal to children. Keep all used
Use caution with adrenal insufficiency (including Addi- and unused products out of the reach of children at
son disease), biliary tract impairment (including acute all times and discard products properly. Patients and
pancreatitis), bradycardia or bradyarrhythmias, head caregivers should be counseled on the dangers to
injuries, intracranial lesions, elevated intracranial pres- children including the risk of exposure to partially-con-
sure, history of seizure disorders, morbid obesity, thy- sumed products. [US Boxed Warning]: Prolonged
roid dysfunction, delirium tremens, toxic psychosis, use of opioids during pregnancy can cause neo-
prostatic hyperplasia and/or urinary stricture. Use with natal withdrawal syndrome in the newborn which
caution in patients with renal or hepatic impairment; may be life-threatening if not recognized and
avoid transdermal (patch) in patients with severe hep- treated according to protocols developed by neo-
atic impairment. Concurrent use of mixed agonist/ natology experts. If opioid use is required for a
antagonist analgesics (eg, pentazocine, nalbuphine, prolonged period in a pregnant woman, advise the
butorphanol) or partial agonist (eg, buprenorphine) patient of the risk of neonatal opioid withdrawal
analgesics may precipitate withdrawal symptoms and/ syndrome and ensure that appropriate treatment
or reduced analgesic efficacy in patients following pro- will be available. Signs and symptoms include irrita-
longed therapy with mu opioid agonists. Abrupt discon- bility, hyperactivity and abnormal sleep pattern, high
tinuation following prolonged use may also lead to pitched cry, tremor, vomiting, diarrhea and failure to
withdrawal symptoms. Taper dose gradually when dis- gain weight. Onset, duration and severity depend on
continuing. Use opioids with caution for chronic pain the drug used, duration of use, maternal dose, and rate
and titrate dosage cautiously in patients with risk factors of drug elimination by the newborn. Use with caution in
for sleep-disordered breathing, including HF and obe- cachectic or debilitated patients; there is a greater
sity. Avoid opioids in patients with moderate to severe potential for critical respiratory depression, even at
sleep-disordered breathing (Dowell [CDC 2016]). May therapeutic dosages. Consider the use of alternative
cause severe hypotension (including orthostatic hypo- nonopioid analgesics in these patients. Avoid use in
tension and syncope); use with caution in patients with patients with impaired consciousness or coma as these
hypovolemia, cardiovascular disease (including acute patients are susceptible to intracranial effects of CO2
MI), or drugs which may exaggerate hypotensive effects retention.
(including phenothiazines or general anesthetics). Mon- [US Boxed Warning]: Serious, life-threatening, or
itor for symptoms of hypotension following initiation or fatal respiratory depression may occur, including
dose titration. Avoid use in patients with circulatory following use in opioid non-tolerant patients and
shock. Opioids decrease bowel motility; monitor for improper dosing. Monitor closely for respiratory
decreased bowel motility in postop patients receiving depression, especially during initiation or dose
opioids. Use with caution in the perioperative setting; escalation. Abstral, Actiq, Duragesic, Fentora, Laz-
individualize treatment when transitioning from paren- anda, Onsolis, or Subsys should only be prescribed
teral to oral analgesics. Opioids may obscure diagnosis for opioid-tolerant patients. Risk of respiratory depres-
or clinical course of patients with acute abdominal sion usually occurs after administration of initial dose in
conditions. nontolerant patients or when given with other drugs that
Chronic pain (outside of end-of-life or palliative care, depress respiratory function. Carbon dioxide retention
active cancer treatment, sickle cell disease, or medi- from opioid-induced respiratory depression can exacer-
cation-assisted treatment for opioid use disorder) in bate the sedating effects of opioids. Use with caution
outpatient setting in adults: Opioids should not be used and monitor for respiratory depression in patients with
as first-line therapy for chronic pain management (pain significant chronic obstructive pulmonary disease or cor
>3-month duration or beyond time of normal tissue pulmonale, and those with a substantially decreased
healing) due to limited short-term benefits, undeter- respiratory reserve, hypoxia, hypercapnia, or preexist-
mined long-term benefits, and association with serious ing respiratory depression, particularly when initiating
risks (eg, overdose, MI, auto accidents, risk of devel- and titrating therapy; critical respiratory depression may
occur, even at therapeutic dosages. Consider the use of
oping opioid use disorder). Preferred management
alternative nonopioid analgesics in these patients.
includes nonpharmacologic therapy and nonopioid ther-
apy (eg, NSAIDs, acetaminophen, certain anticonvul- Transmucosal (buccal film/tablet, sublingual spray/tab-
sants and antidepressants). If opioid therapy is initiated, let, lozenge) and intranasal: [US Boxed Warning]:
it should be combined with nonpharmacologic and non- Transmucosal and nasal fentanyl formulations are
opioid therapy, as appropriate. Prior to initiation, known contraindicated in the management of acute or
risks of opioid therapy should be discussed and realistic postoperative pain and in opioid nontolerant
treatment goals for pain/function should be established, patients. Should be used only for the care of opioid-
including consideration for discontinuation if benefits do tolerant cancer patients with breakthrough pain and is
not outweigh risks. Therapy should be continued only if intended for use by specialists who are knowledgeable
clinically meaningful improvement in pain/function out- in treating cancer pain. [US Boxed Warning]: Sub-
weighs risks. Therapy should be initiated at the lowest stantial differences exist in the pharmacokinetic
580
FENTANYL
profile of fentanyl products that result in clinically Radio Frequency Identification (RFID) transmitters can
important differences in the extent of absorption of damage the device. Depending on the rated maximum
fentanyl. When prescribing or dispensing fentanyl, output power and frequency of the transmitter, the
do not convert patients on a mcg-per-mcg basis recommended separation distance between the device
from one fentanyl product to another fentanyl prod- and communications equipment or the RFID transmitter
uct; the substitution of one fentanyl product for ranges between 0.12 and 23 meters. The low-level
another fentanyl product may result in a fatal over- electrical current provided by the device does not result
dose. Death has been reported in children who have in electromagnetic interference with other electrome-
accidentally ingested transmucosal immediate- chanical devices like pacemakers or electrical monitor-
release fentanyl products. Strict adherence to the ing equipment. If exposure to the procedures listed
recommended handling and disposal instructions above, electronic security systems, electrostatic dis-
is of the utmost importance to prevent accidental charge, communications equipment, or RFID transmit-
exposure. [US Boxed Warning]: Available only ters occurs, and if the device does not appear to
through the TIRF REMS ACCESS program, a function normally, remove and replace with a new
restricted distribution program with outpatients, device. Topical skin reactions (erythema, sweating,
prescribers who prescribe to outpatients, pharma- vesicles, papules/pustules) may occur with use and
cies (inpatient and outpatient), and distributor- are typically limited to the application site area. If a
required enrollment. Titration of intranasal fentanyl is severe skin reaction is observed, remove device and
not recommended during use of nasal decongestants discontinue further use.
(eg, oxymetazoline). Avoid use of sublingual spray in
Transdermal patch (Duragesic): [US Boxed Warning]:
cancer patients with grade 2 or higher mucositis (fen-
Transdermal patch is contraindicated for use as an
tanyl exposure increased); use with caution in patients
as-needed analgesic, in acute or postoperative
with grade 1 mucositis, and closely monitor for respira-
pain, or in patients who are opioid nontolerant.
tory and CNS depression. Application site reactions,
Monitor closely for respiratory depression during
ranging from paresthesia to ulcerations and bleeding,
use, particularly during initiation of therapy or after
occurred with buccal tablet (Fentora).
dose increases. Should only be prescribed by health
Transdermal iontophoretic system (Ionsys): [US Boxed care professionals who are knowledgeable in the use of
Warning]: Available only through a restricted pro- potent opioids in the management of chronic pain. [US
gram under a Risk Evaluation and Mitigation Strat- Boxed Warning]: Exposure of application site and
egy (REMS) called the Ionsys REMS Program. surrounding area to direct external heat sources
Healthcare facilities that dispense Ionsys must be (eg, heating pads, electric blankets, heat or tanning
certified in this program and comply with the REMS lamps, sunbathing, hot baths, hot tubs, heated
requirements. [US Boxed Warning]: For use only in water beds, saunas) may increase fentanyl absorp-
patients in the hospital. Discontinue treatment tion and has resulted in fatalities. Warn patients to
before patients leave the hospital. Only the patient avoid exposing the application site and surround-
should activate Ionsys dosing. Accidental exposure ing area to direct external heat sources. Serum
to an intact Ionsys device or to the hydrogel com- fentanyl concentrations may increase by approximately
ponent, especially by children, through contact with one-third for patients with a body temperature of 40°C
skin or contact with mucous membranes, can result (104°F) secondary to a temperature-dependent
in a fatal overdose of fentanyl. Following accidental increase in fentanyl release from the patch and
contact with the device or its components, immediately increased skin permeability. [US Boxed Warning]:
rinse the affected area thoroughly with water. Do not Deaths due to a fatal overdose of fentanyl have
use soap, alcohol, or other solvent because they may occurred when children and adults were acciden-
enhance the drug's ability to penetrate the skin; monitor tally exposed to fentanyl transdermal patch. Strict
for signs of respiratory or CNS depression. If the device adherence to recommended handling and disposal
is not handled correctly using gloves, healthcare pro- instructions is necessary to prevent accidental
fessionals are at risk of accidental exposure to a fatal exposures. Avoid unclothed/unwashed application site
overdose of fentanyl. Ionsys device is considered mag- exposure, inadvertent person-to-person patch transfer
netic resonance unsafe. The device contains metal (eg, while hugging), incidental exposure (eg, sharing
parts and must be removed and properly disposed of same bed, sitting on patch), intentional exposure (eg,
before an MRI procedure to avoid injury to the patient chewing), or accidental exposure by caregivers when
and damage to device. It is unknown if exposure to an applying/removing patch. [US Boxed Warning]: To
MRI procedure increases release of fentanyl from the ensure that the benefits of opioid analgesics out-
device. Monitor any patients wearing the device with weigh the risks of addiction, abuse, and misuse, the
inadvertent exposure to an MRI for signs of CNS and FDA has required a Risk Evaluation and Mitigation
respiratory depression. Use of Ionsys device during Strategy (REMS) for these products. Under the
cardioversion, defibrillation, X-ray, CT, or diathermy requirements of the REMS, drug companies with
can damage the device from the strong electromagnetic approved opioid analgesic products must make
fields set up by these procedures. The device contains REMS-compliant education programs available to
radio-opaque components and may interfere with an X- health care providers. Health care providers are
ray image or CT scan. Remove and properly dispose of strongly encouraged to complete a REMS-compli-
the device prior to cardioversion, defibrillation, X-ray, ant education program; counsel patients and/or
CT, or diathermy. Avoid contact with synthetic materials their caregivers, with every prescription, on safe
(such as carpeted flooring) to reduce the possibility of use, serious risks, storage, and disposal of these
electrostatic discharge and damage to the device. products; emphasize to patients and their care-
Avoid exposing the device to electronic security sys- givers the importance of reading the Medication
tems to reduce the possibility of damage. Use near Guide every time it is provided by their pharmacist;
communications equipment (eg, base stations for radio and consider other tools to improve patient, house-
telephones and land mobile radios, amateur radio, AM hold, and community safety. Should be applied only
and FM radio broadcast and TV broadcast Radio) and to intact skin. Use of a patch that has been cut,
581
FENTANYL
damaged, or altered in any way may result in over- Cannabis; Chlormethiazole; Chlorphenesin Carba-
dosage. Patients who experience adverse reactions mate; Clofazimine; CNS Depressants; Conivaptan;
should be monitored for at least 24 hours after removal Crizotinib; CYP3A4 Inhibitors (Moderate); CYP3A4
of the patch. Drug continues to be absorbed from the Inhibitors (Strong); Dapoxetine; Dimethindene (Top-
skin for 24 hours or more following removal of the patch. ical); Dronabinol; Droperidol; Fosaprepitant; Fusidic
May contain conducting metal (eg, aluminum); remove Acid (Systemic); Idelalisib; Kava Kava; Larotrectinib;
patch prior to MRI. Lofexidine; Magnesium Sulfate; Methotrimeprazine;
Warnings: Additional Pediatric Considerations Methylene Blue; Methylphenidate; MiFEPRIStone;
Opioid withdrawal may occur after conversion of one Minocycline; Nabilone; Oxomemazine; Palbociclib;
dosage form to another or after dosage adjustment; Perampanel; PHENobarbital; Primidone; Rufinamide;
with prolonged use, taper dose to prevent withdrawal Simeprevir; Sodium Oxybate; Stiripentol; Succinylcho-
symptoms. Neonates who receive a total fentanyl dose line; Tapentadol; Tetrahydrocannabinol; Tetrahydro-
>1.6 mg/kg or continuous infusion duration >5 days are cannabinol and Cannabidiol
more likely to develop opioid withdrawal symptoms; for Decreased Effect
infants and children 1 week to 22 months of age, those FentaNYL may decrease the levels/effects of: Anti-
who receive a total dose of 1.5 mg/kg or duration >5 platelet Agents (P2Y12 Inhibitors); Diuretics; Gastro-
days have a 50% chance of developing opioid with- intestinal Agents (Prokinetic); Ioflupane I 123;
drawal and those receiving a total dose >2.5 mg/kg or Pegvisomant; Sincalide
duration of infusion >9 days have a 100% chance of
The levels/effects of FentaNYL may be decreased by:
developing withdrawal.
Alpha-/Beta-Agonists (Indirect-Acting); Alpha1-Ago-
Dosage form specific: nists; CYP3A4 Inducers (Moderate); CYP3A4
Use transdermal patch in pediatric patients only if they Inducers (Strong); Enzalutamide; Nalmefene; Naltrex-
are opioid-tolerant, receiving at least 60 mg oral mor- one; Opioids (Mixed Agonist / Antagonist); PHENo-
phine equivalents per day, and ≥2 years of age. barbital; Primidone; St John's Wort
Use of Actiq was evaluated in a clinical trial of 15 Dietary Considerations Transmucosal lozenge con-
opioid-tolerant pediatric patients (age: 5 to 15 years) tains 2 g sugar per unit.
with breakthrough pain; 12 of the 15 patients Pharmacodynamics/Kinetics
received doses of 200 mcg to 600 mcg; no conclu- Onset of Action
sions about safety and efficacy could be drawn due Children 3 to 12 years: Intranasal: 5 to 10 minutes
to the small sample size. (Borland 2002)
Adults: Analgesic: IM: 7 to 8 minutes; IV: Almost
immediate (maximal analgesic and respiratory
depressant effects may not be seen for several
minutes); Transdermal patch (initial placement): 6
hours; Transmucosal: 5 to 15 minutes
Duration of Action IM: 1 to 2 hours; IV: 0.5 to 1 hour;
Transdermal (removal of patch/no replacement):
Related to blood level; some effects may last 72 to
ity, lactic acidosis, seizures, and respiratory depression;
96 hours due to extended half-life and absorption from
use caution (AAP 1997; Shehab 2009).
Drug Interactions the skin, fentanyl concentrations decrease by ~50% in
20 to 27 hours; Transmucosal: Related to blood level;
respiratory depressant effect may last longer than
CYP3A4 (major); Note: Assignment of Major/Minor
analgesic effect
substrate status based on clinically relevant drug
interaction potential Half-life Elimination
Avoid Concomitant Use IV:
Pediatric patients 5 months to 4.5 years: 2.4 hours
Avoid concomitant use of FentaNYL with any of the
Pediatric patients 6 months to 14 years (after long-
following: Azelastine (Nasal); Bromperidol; Conivap-
term continuous infusion): ~21 hours (range: 11 to
tan; Crizotinib; Dapoxetine; Eluxadoline; Enzaluta-
36 hours)
mide; Fusidic Acid (Systemic); Idelalisib; Methylene
Adults: 2 to 4 hours; when administered as a con-
Blue; MiFEPRIStone; Monoamine Oxidase Inhibitors;
tinuous infusion, the half-life prolongs with infusion
Opioids (Mixed Agonist / Antagonist); Orphenadrine;
duration due to the large volume of distribution
Oxomemazine; Paraldehyde; Thalidomide
(Sessler 2008)
SubQ bolus injection: 10 hours (Capper 2010)
FentaNYL may increase the levels/effects of: Alvimo-
Transdermal device: Terminal: ~16 hours
pan; Azelastine (Nasal); Beta-Blockers; Blonanserin;
Transdermal patch: 20 to 27 hours (apparent half-life
Calcium Channel Blockers (Nondihydropyridine); Des-
is influenced by continued fentanyl absorption
mopressin; Diuretics; Eluxadoline; Flunitrazepam;
from skin)
HYDROcodone; Methotrimeprazine; Metoclopramide;
Transmucosal products: 3 to 14 hours (dose
MetyroSINE; Monoamine Oxidase Inhibitors; Opioid
dependent)
Agonists; Orphenadrine; OxyCODONE; Paraldehyde;
Intranasal: 15 to 25 hours (based on a multiple-dose
Piribedil; Pramipexole; Ramosetron; ROPINIRole;
pharmacokinetic study when doses are administered
Rotigotine; Selective Serotonin Reuptake Inhibitors;
in the same nostril and separated by a 1-, 2-, or 4-
Serotonin Modulators; Suvorexant; Thalidomide; Zol-
hour time lapse)
pidem
Buccal film: ~14 hours
The levels/effects of FentaNYL may be increased by: Buccal tablet: 100 to 200 mcg: 3 to 4 hours; 400 to 800
Alizapride; Amphetamines; Anticholinergic Agents; mcg: 11 to 12 hours
Antiemetics (5HT3 Antagonists); Brimonidine (Top- Time to Peak
ical); Bromopride; Bromperidol; Cannabidiol; Buccal film: 0.75 to 4 hours (median: 1 hour)
582
FENTANYL
Buccal tablet: 20 to 240 minutes (median: 47 minutes) Current guidelines note that nonopioid analgesics are
Lozenge: 20 to 480 minutes (median: 20 to 40 preferred for postpartum pain in breastfeeding women.
minutes) Fentanyl may be used when an opioid is needed
Intranasal: Median: 15 to 21 minutes (Montgomery 2012).
Sublingual spray: 10 to 120 minutes (median: 90 When opioids are needed in breastfeeding women, the
minutes) lowest effective dose for the shortest duration of time
Sublingual tablet: 15 to 240 minutes (median: 30 to 60 should be used to limit adverse events in the mother
minutes) and breastfeeding infant. In general, a single occa-
SubQ bolus injection: 10 to 30 minutes (median: 15 sional dose of an opioid analgesic may be compatible
minutes) (Capper 2010)
with breastfeeding (WHO 2002). Breastfeeding
Transdermal patch: 20 to 72 hours; steady state
women using opioids for postpartum pain or for the
serum concentrations are reached after two sequen-
tial 72-hour applications treatment of chronic maternal pain should monitor
Pregnancy Considerations their infants for drowsiness, sedation, feeding difficul-
Fentanyl crosses the placenta (Leuschen 1990). ties, or limpness (ACOG 177 2017; Montgomery
2012; Sachs 2013). Withdrawal symptoms may occur
Maternal use of opioids may be associated with birth when maternal use is discontinued or breastfeeding is
defects (including neural tube defects, congenital heart stopped
defects, and gastroschisis), poor fetal growth, stillbirth, Product Availability Onsolis: Reformulated product
and preterm delivery (CDC [Dowell 2016]). Opioids may FDA approved August 2015; availability anticipated in
temporarily affect the fetal heart rate (ACOG 177 2017).
the first half of 2018.
Transient muscular rigidity has been observed in the
neonate following maternal administration of IV fen- Controlled Substance C-II
tanyl; symptoms of respiratory or neurological depres- Prescribing and Access Restrictions
sion were not different than those observed in infants of As a requirement of the REMS program, access is
untreated mothers following IV or epidural use during restricted.
labor. Transmucosal immediate-release fentanyl products (eg,
sublingual tablets and spray, oral lozenges, buccal
[US Boxed Warning]: Prolonged use of opioids
tablets and soluble film, intranasal) are only available
during pregnancy can cause neonatal withdrawal
through the Transmucosal Immediate-Release Fen-
syndrome, which may be life-threatening if not
recognized and treated according to protocols tanyl (TIRF) REMS ACCESS program. Enrollment in
developed by neonatology experts. If opioid use is the program is required for outpatients, prescribers for
required for a prolonged period in a pregnant outpatient use, pharmacies (inpatient and outpatient),
woman, advise the patient of the risk of neonatal and distributors. Enrollment is not required for inpa-
opioid withdrawal syndrome and ensure that appro- tient administration (eg, hospitals, hospices, long-term
priate treatment will be available. care facilities), inpatients, and prescribers who pre-
scribe to inpatients. Further information is available at
If chronic opioid exposure occurs in pregnancy, adverse
1-866-822-1483 or at www.TIRFREMSaccess.com
events in the newborn (including withdrawal) may occur
Note: Effective December, 2011, individual REMs pro-
(Chou 2009). Symptoms of neonatal abstinence syn-
grams for TIRF products were combined into a single
drome (NAS) following opioid exposure may be auto-
n o m i c ( e g , f e v e r, t e m p e r a t u r e i n s t a b i l i t y ) , access program (TIRF REMS Access). Prescribers
gastrointestinal (eg, diarrhea, vomiting, poor feeding/ and pharmacies that were enrolled in at least one
weight gain), or neurologic (eg, high-pitched crying, individual REMS program for these products will auto-
hyperactivity, increased muscle tone, increased wake- matically be transitioned to the single access program.
fulness/abnormal sleep pattern, irritability, sneezing, Dosage Forms: US
seizure, tremor, yawning) (Dow 2012; Hudak 2012). Injection, solution [preservative free]:
Opioids may cause respiratory depression and psycho- Sublimaze: 100 mcg/2 mL (2 mL); 250 mcg/5 mL
physiologic effects in the neonate; newborns of mothers (5 mL)
receiving opioids during labor should be monitored. Generic: 100 mcg/2 mL (2 mL); 250 mcg/5 mL (5 mL);
Fentanyl IM and IV injection are commonly used to treat 500 mcg/10 mL (10 mL); 1000 mcg/ 20 mL (20 mL);
maternal pain during labor and immediately postpartum; 1250 mcg/250 mL (250 mL); 2500 mcg/50 mL
the intranasal route has also been studied (ACOG (50 mL)
177 2017). Other routes of administration are not rec- Liquid, sublingual, [spray]:
ommended; use of shorter acting opioids or other Subsys: 100 mcg (30s); 200 mcg (30s); 400 mcg
analgesic techniques is recommended immediately (30s); 600 mcg (30s); 800 mcg (30s)
prior to and during labor. Lozenge, oral:
Actiq: 200 mcg (30s); 400 mcg (30s); 600 mcg (30s);
Long-term opioid use may cause secondary hypogo-
800 mcg (30s); 1200 mcg (30s); 1600 mcg (30s)
nadism, which may lead to sexual dysfunction or infer-
tility in men and women (Brennan 2013). Generic: 200 mcg (30s); 400 mcg (30s); 600 mcg
Breastfeeding Considerations (30s); 800 mcg (30s); 1200 mcg (30s); 1600
Fentanyl and norfentanyl are present in breast milk mcg (30s)
(Cohen 2009). Patch, transdermal:
The actual amount received by a breastfeeding infant Duragesic: 12 [delivers 12.5 mcg/hr] (5s); 25 [delivers
varies. Reports are available following IV or epidural 25 mcg/hr] (5s); 50 [delivers 50 mcg/hr] (5s); 75
use during labor (Goma 2008; Leuschen 1990; Nitsun [delivers 75 mcg/hr] (5s); 100 [delivers 100 mcg/
2006; Steer 1992), or chronic maternal use of the hr] (5s)
transdermal patch (Cohen 2009). Not all studies eval- Ionsys: 40 mcg/actuation (6s) [iontophoretic transder-
uated concentrations of the active metabolite. mal system]
583
FENTANYL
Generic: 12 [delivers 12.5 mcg/hr] (5s); 25 [delivers 25 Central nervous system: Headache (9%), fatigue
mcg/hr] (5s); 37.5 [delivers 37.5 mcg/hr]; 50 [delivers (4%), dizziness
50 mcg/hr] (5s); 62.5 [delivers 62.5 mcg/hr]; 75 Dermatologic: Pruritus
[delivers 75 mcg/hr] (5s); 87.5 [delivers 87.5 mcg/ Gastrointestinal: Constipation, nausea
hr] (5s); 100 [delivers 100 mcg/hr] (5s) Genitourinary: Urinary tract infection (5%)
Powder, for prescription compounding: USP: Neuromuscular & skeletal: Muscle spasm (10%), limb
100% (1 g) pain (7%), back pain (5%), weakness (4%)
Solution, intranasal, as citrate [spray]: Respiratory: Dyspnea (6%)
Lazanda: 100 mcg/spray (5 mL); 300 mcg/spray (5 Miscellaneous: Fever (5%)
mL); 400 mcg/spray (5 mL) [delivers 8 metered <1%, postmarketing, and/or case reports: Anaphylaxis,
sprays] hypersensitivity
Tablet, for buccal application: Mechanism of Action Iron in the form of ferric pyro-
Fentora: 100 mcg (28s); 200 mcg (28s); 400 mcg phosphate citrate and added to hemodialysate solution
(28s); 600 mcg (28s); 800 mcg (28s) is administered to patients by transfer across the dia-
Tablet, sublingual:
lyzer membrane. Iron delivered into the circulation
Abstral: 100 mcg (12s, 32s); 200 mcg (12s, 32s); 300
binds to transferrin for transport to erythroid precursor
mcg (12s, 32s); 400 mcg (12s, 32s); 600 mcg (32s);
cells to be incorporated into hemoglobin.
800 mcg (32s)
Dosage Forms: Canada Patch, transdermal, as base: Half-life Elimination ~1.48 hours
37 mcg/hr (5s)
Dental Health Professional Considerations Trans-
Adverse events were observed in some animal repro-
dermal fentanyl should not be used as a pain reliever in
duction studies.
dentistry due to danger of hypoventilation
Actiq is a solid formulation of fentanyl with a high sugar Maternal iron requirements increase during pregnancy.
content of 2 g hydrated dextrates per unit. Frequent use Adequate iron concentrations to the fetus can be main-
of Actiq could result in significant dental problems tained regardless of maternal iron status, except in
including risk of dental decay. Dry mouth caused by severe cases of anemia (IOM 2001).
fentanyl could add to the risk of caries. Oral adverse The manufacturer recommends effective contraception
reactions reported in clinical trials have included tooth during therapy and for at least 2 weeks after treatment
caries, gum hemorrhage, mouth ulcerations, oral mon- is complete in females of reproductive potential.
iliasis, dry mouth, and cheilitis.
Sedation: There is a subsequent slow release from Ferrous Sulfate (FER us SUL fate)
muscle and fat which results in a terminal half-life that
is beyond that of morphine. Fentanyl does not induce Brand Names: US BProtected Pedia Iron [OTC]; Fer-
the release of histamine; therefore, fentanyl is prefera- In-Sol [OTC]; Fer-Iron [OTC] [DSC]; FeroSul [OTC];
ble in patients with a predisposition to bronchospasm. Ferro-Bob [OTC] [DSC]; FerrouSul [OTC]; Iron Supple-
Fentanyl is a good choice for use in cardiac patients ment Childrens [OTC]; Iron Supplement [OTC]; Slow Fe
because it lacks direct myocardial depression. The [OTC]; Slow Iron [OTC]
incidence of nausea is less than that reported with Brand Names: Canada Fer-In-Sol; Ferodan
morphine or meperidine. The clinician should wait 2 to Pharmacologic Category Iron Salt
3 minutes between doses to allow time for observation Use Iron-deficiency anemia: Prevention and treatment
of the clinical effects of each administered dose.
of iron-deficiency anemias
Ferric Pyrophosphate Citrate No information available to require special precautions
(FER ik pye roe FOS fate SIT rate) Effects on Dental Treatment Do not prescribe tetra-
Brand Names: US Triferic cyclines simultaneously with iron since GI tract absorp-
Pharmacologic Category Iron Salt tion of both tetracycline and iron may be inhibited.
Use Liquid preparations may temporarily stain the teeth.
Iron replacement therapy in hemodialysis-depend- Effects on Bleeding No information available to
ent patients: Replacement of iron to maintain hemo- require special precautions
globin in adult patients with hemodialysis-dependent Adverse Reactions
chronic kidney disease (HDD-CKD) >10%: Gastrointestinal: Darkening of stools (≤80%;
Limitations of use: Not intended for use in patients Tolkien 2015), abdominal pain (≤70%; Tolkien 2015),
receiving peritoneal dialysis; has not been studied in heartburn (1% to 68%; Tolkien 2015), nausea (≤63%;
patients receiving home hemodialysis Tolkien 2015), constipation (≤39%; Tolkien 2015), flat-
Local Anesthetic/Vasoconstrictor Precautions ulence (≤36%; Tolkien 2015), vomiting (≤34%; Tolkien
No information available to require special precautions 2015), diarrhea (≤23%; Tolkien 2015)
Effects on Dental Treatment No significant effects or <1%, postmarketing, and/or case reports: Abdominal
complications reported discomfort (Tolkien 2015)
Effects on Bleeding No information available to Mechanism of Action Replaces iron, found in hemo-
require special precautions globin, myoglobin, and other enzymes; allows the trans-
Adverse Reactions Note: Frequency not always portation of oxygen via hemoglobin
defined. Pharmacodynamics/Kinetics
>10%: Cardiovascular: Procedural hypotension (22%) Onset of Action Hematologic response: Oral: ~3 to
1% to 10%: 10 days
Cardiovascular: Peripheral edema (7%), clotted AV Peak effect: Reticulocytosis: 5 to 10 days; hemoglobin
fistula (3%), dialysis access hemorrhage (3%) increases within 2 to 4 weeks
584
FESOTERODINE
Pregnancy Considerations storage pools or is transported via plasma transferrin for

Maternal iron requirements increase during pregnancy. incorporation into hemoglobin.
Adequate iron concentrations to the fetus can be main- Pharmacodynamics/Kinetics
tained regardless of maternal iron status, except in Half-life Elimination ~15 hours; ferumoxytol is not
severe cases of anemia (IOM 2001). Untreated iron removed by hemodialysis
deficiency and iron deficiency anemia (IDA) in a preg- Pregnancy Considerations
nant female may be associated with adverse events, Maternal iron requirements increase during pregnancy.
including low birth weight, preterm birth, or increased Adequate iron concentrations to the fetus can be main-
perinatal mortality (ACOG 95 2008; IOM 2001; Pavord tained regardless of maternal iron status, except in
2012). severe cases of anemia (IOM 2001). Untreated iron
deficiency and iron deficiency anemia (IDA) in a preg-
In general, treatment of iron deficiency or IDA in preg-
nant female may be associated with adverse events,
nancy is the same as in non-pregnant females. The
including low birth weight, preterm birth, or increased
majority of studies note iron therapy improves maternal
perinatal mortality (ACOG 95 2008; IOM 2001; Pavord
hematologic parameters; however, information related
2012).
to clinical outcomes in the mother and neonate is limited
(Peña-Rosas 2015; Reveiz 2011; Siu 2015). Oral prep- In general, treatment of iron deficiency or IDA in preg-
arations are generally sufficient; however, parenteral nancy is the same as in non-pregnant females. The
iron therapy may be used in females who cannot majority of studies note iron therapy improves maternal
tolerate or will not take oral iron, in cases of severe iron hematologic parameters; however, information related
deficiency, or when malabsorption is present (ACOG to clinical outcomes in the mother and neonate is limited
95 2008; Pavord 2012). Ferrous sulfate has been eval- (Siu 2015). Oral preparations are generally sufficient;
uated in multiple studies as an iron supplement or for however, parenteral iron therapy may be used in
the treatment of IDA in pregnancy (Peña-Rosas 2015; females who cannot tolerate or will not take oral iron,
Reveiz 2011). Enteric-coated and slow/sustained- in cases of severe iron deficiency, or when malabsorp-
release preparations may be less effective (ACOG tion is present (ACOG 95 2008; Pavord 2012). Due to
95 2008). limited safety data in early pregnancy, use of intra-
venous iron products is generally not started until the
second or third trimester (Breymann 2017; Pav-
Ferumoxytol (fer ue MOX i tol)
ord 2012).
Brand Names: US Feraheme
Pharmacologic Category Iron Salt Fesoterodine (fes oh TER oh deen)
Use Iron-deficiency anemia: Treatment of iron-defi-
ciency anemia in adults with an intolerance or unsat- Brand Names: US Toviaz
isfactory response to oral iron or who have chronic Brand Names: Canada Toviaz
kidney disease Pharmacologic Category Anticholinergic Agent
Local Anesthetic/Vasoconstrictor Precautions Use Overactive bladder: Treatment of patients with an
No information available to require special precautions overactive bladder with symptoms of urinary frequency,
Effects on Dental Treatment No significant effects or urgency, or urge incontinence.
Adverse Reactions related to dental treatment: Prolonged use will cause
1% to 10%: significant xerostomia (normal salivary flow resumes
Cardiovascular: Hypotension (≤3%), edema (2%), upon discontinuation).
peripheral edema (2%), chest pain (1%), hyperten- Effects on Bleeding No information available to
sion (1%) require special precautions
Central nervous system: Dizziness (2% to 3%), head- Adverse Reactions
ache (2% to 3%), fatigue (2%) >10%: Gastrointestinal: Xerostomia (19% to 35%;
Dermatologic: Pruritus (1%), skin rash (1%) dose-related)
Gastrointestinal: Diarrhea (1% to 4%), nausea (2% to 1% to 10%:
3%), constipation (2%), vomiting (2%), abdominal Cardiovascular: Peripheral edema (1%)
pain (1%) Central nervous system: Insomnia (1%)
Hypersensitivity: Hypersensitivity reaction (≤4%; seri- Dermatological: Skin rash (1%)
ous hypersensitivity: <1%) Endocrine & metabolic: Increased gamma-glutamyl
Neuromuscular & skeletal: Back pain (1%), muscle transferase (1%)
spasm (1%) Gastrointestinal: Constipation (4% to 6%), dyspepsia
Respiratory: Cough (1%), dyspnea (1%) (2%), nausea (1% to 2%), abdominal pain (1%)
Miscellaneous: Fever (1%) Genitourinary: Urinary tract infection (3% to 4%),
<1%, postmarketing, and/or case reports: Anaphylaxis, dysuria (1% to 2%), urinary retention (1%)
angioedema, cardiac arrhythmia, cardiac failure, cya- Hepatic: Increased serum ALT (1%)
nosis, ischemic heart disease, loss of consciousness, Neuromuscular & skeletal: Back pain (1% to 2%)
syncope, tachycardia, unresponsive to stimuli, urtica- Ophthalmic: Dry eye syndrome (1% to 4%)
ria, wheezing Respiratory: Upper respiratory tract infection (2% to
Mechanism of Action Superparamagnetic iron oxide 3%), cough (1% to 2%), dry throat (1% to 2%)
coated with a low molecular weight semisynthetic car- <1%, postmarketing, and/or case reports: Angina pec-
bohydrate; iron-carbohydrate complex enters the retic- toris, angioedema, blurred vision, chest pain, divertic-
uloendothelial system macrophages of the liver, spleen, u lit is , di zz in es s , dr ows ine s s, f ac ia l e de ma ,
and bone marrow where the iron is released from the gastroenteritis, headache, heat exhaustion, hypersen-
complex. The released iron is either transported into sitivity reaction, increased heart rate (dose-related),
585
FESOTERODINE
irritable bowel syndrome, palpitations, prolonged Q-T Pharmacodynamics/Kinetics

interval on ECG, pruritus, urticaria Onset of Action 2 hours (Simons 2004)
Mechanism of Action Fesoterodine acts as a prodrug Duration of Action 24 hours (Simons 2004)
and is converted to an active metabolite, 5-hydroxy- Half-life Elimination 14.4 hours (59% longer in
methyl tolterodine (5-HMT); 5-HMT is responsible for patients with mild to moderate renal impairment [CrCl
fesoterodine’s antimuscarinic activity and acts as a 41 to 80 mL/minute]; 72% longer in patients with
competitive antagonist of muscarinic receptors. severe renal impairment [CrCl 11 to 40 mL/minute])
Urinary bladder contractions are mediated by muscar- (Markham 1998; Simons 2004)
inic receptors; fesoterodine inhibits the receptors in the Time to Peak Serum: ODT: 2 hours (4 hours with high-
bladder preventing symptoms of urgency and fre- fat meal); Tablet: ~2.6 hours (Simons 2004); Suspen-
quency. sion: ~1 hour
Pharmacodynamics/Kinetics Pregnancy Considerations Limited information is
Half-life Elimination ~7 hours available related to the use of fexofenadine in preg-
Time to Peak Plasma: 5-HMT: ~5 hours; Cmax higher nancy. When a second generation antihistamine is
in poor CYP2D6 metabolizers needed, other agents with more information available
Pregnancy Considerations Adverse effects have regarding their use in pregnancy are currently preferred
been observed in some animal reproduction studies. (Murase 2014; Powell 2015; Scadding 2008; Wallace
2008; Zuberbier 2014).
Fexofenadine (feks oh FEN a deen)

Fibrinogen Concentrate (Human)
Brand Names: US Allegra Allergy Childrens [OTC]; (fi BRIN o gin KON suhn trate HYU man)
Allegra Allergy [OTC]; Allergy 24-HR [OTC]; Allergy
Brand Names: US Fibryga; RiaSTAP
Relief [OTC]; Fexofenadine HCl Childrens [OTC]
[DSC]; Mucinex Allergy [OTC]
Brand Names: Canada Fibryga; RiaSTAP
Brand Names: Canada Allegra 12 Hour (OTC); Alle- Pharmacologic Category Blood Product Derivative
gra 24 Hour (OTC) Use Congenital fibrinogen deficiency: Treatment of
Pharmacologic Category Histamine H1 Antagonist; acute bleeding episodes in patients with congenital
Histamine H1 Antagonist, Second Generation; Piperi- fibrinogen deficiency, including afibrinogenemia and
dine Derivative hypofibrinogenemia.
Use Upper respiratory allergies: Temporary relief of Local Anesthetic/Vasoconstrictor Precautions
runny nose, sneezing, itching of the nose or throat, and/ No information available to require special precautions
or itchy, watery eyes due to hay fever or other upper Effects on Dental Treatment No significant effects or
respiratory allergies. complications reported
Local Anesthetic/Vasoconstrictor Precautions Effects on Bleeding Serious thromboembolism and
No information available to require special precautions thrombosis have been reported.
Effects on Dental Treatment No significant effects or Adverse Reactions
complications reported 1% to 10%:
Effects on Bleeding No information available to Central nervous system: Headache (>1%)
require special precautions Dermatologic: Erythema (≤8%), pruritus (≤8%)
Adverse Reactions Gastrointestinal: Vomiting (>5%)
>10%: Neuromuscular & skeletal: Weakness (>5%)
Central nervous system: Headache (5% to 11%) Miscellaneous: Fever (>5%)
Gastrointestinal: Vomiting (children 6 months to 5 <1%, postmarketing, and/or case reports: Anaphylaxis,
years: 4% to 12%) arterial thrombosis, chills, deep vein thrombosis, dysp-
1% to 10%: nea, hypersensitivity reaction, myocardial infarction,
Central nervous system: Drowsiness (1% to 3%), nausea, pulmonary embolism, skin rash, throm-
fatigue (1% to 3%), dizziness (2%), pain (2%) boembolism
Gastrointestinal: Diarrhea (3% to 4%), nausea (2%), Mechanism of Action Fibrinogen (coagulation factor
dyspepsia (1% to 2%) I), a protein found in normal plasma, is required to clot
Genitourinary: Dysmenorrhea (2%) blood. Fibrinogen concentrate made from pooled
Infection: Viral infection (3%) human plasma replaces this protein which is missing
Neuromuscular & skeletal: Myalgia (3%), back pain or reduced in patients with a congenital fibrinogen
(2% to 3%), limb pain (2%) deficiency.
Otic: Otitis media (2% to 4%) Pharmacodynamics/Kinetics
Respiratory: Upper respiratory tract infection (3% to Half-life Elimination Similar to biological fibrinogen
4%), cough (2% to 4%), rhinorrhea (1% to 2%) Biological fibrinogen: 100 hours (Kamath 2003)
Miscellaneous: Fever (2%) Fibryga: Patients 12 to 53 years: 75.9 ± 23.8 (40 to
<1%, postmarketing, and/or case reports: Hypersensi- 157 hours)
tivity reaction (including anaphylaxis, angioedema, RiaSTAP:
chest tightness, dyspnea, flushing, pruritus, skin rash, Patients <16 years: 69.9 ± 8.5 hours
urticaria), insomnia, nervousness, nightmares, sleep Patients ≥16 years: 82.5 ± 20 hours
disorder Pregnancy Considerations Pregnant patients with
Mechanism of Action Fexofenadine is an active congenital fibrinogen deficiency may have an increased
metabolite of terfenadine and like terfenadine it com- risk of bleeding, thrombosis, and pregnancy loss; there-
petes with histamine for H1-receptor sites on effector fore, close surveillance is recommended. Maternal fibri-
cells in the gastrointestinal tract, blood vessels and nogen concentrations increase during pregnancy but do
respiratory tract; it appears that fexofenadine does not not protect against potential complications. Prophylaxis
cross the blood-brain barrier to any appreciable degree, throughout pregnancy may be needed and higher
resulting in a reduced potential for sedation doses may be required as pregnancy progresses.
586
FIDAXOMICIN
Replacement therapy may be initiated prior to concep- Respiratory: Pleural effusion (23%)
tion. Plasma derived fibrinogen concentrate may be 1% to 10%:
used for treatment or prevention of bleeding in patients Cardiovascular: Bradycardia (≥5%), peripheral edema
with severe deficiency (RCOG [Pavord 2017]). (≥5%), thromboembolism (≤3%), deep vein thrombo-
sis (≤1%)
Dermatologic: Pruritus (1%)
Fibrin Sealant (FI brin SEEL ent)
Immunologic: Graft complications (skin graft failure in
Related Information burn patients: 3%)
Antiplatelet and Anticoagulation Considerations in Den- Infection: Localized infection (grafts: ≥5%)
Miscellaneous: Postoperative complication (bile leak-
tistry on page 1454
age after hepatic surgery; 7%), fever (6% to 7%),
Brand Names: US Artiss; Evarrest; Evicel; Raplixa
procedural complications (seroma; ≤4%)
[DSC]; TachoSil; Tisseel
Brand Names: Canada Artiss; Evicel; Tisseel Hematologic & oncologic: Decreased hemoglobin,
Pharmacologic Category Blood Product Derivative; hematoma
Hemostatic Agent Infection: Abscess (abdomen), staphylococcal
Use infection
Colonic anastomosis sealing (Tisseel only): As an Local: Incision site hemorrhage
adjunct to standard surgical techniques (such as <1%, postmarketing, and/or case reports: Abdominal
suture and ligature) to prevent leakage from colonic distension, anaphylactic shock, anaphylactoid reac-
anastomoses following the reversal of temporary tion, anaphylaxis, angioedema, ascites, bile leakage
colostomies (postprocedural), bronchospasm, catheter complica-
Facial rhytidectomy (Artiss only): To adhere tissue tion, cerebral embolism, cerebral infarction, chest dis-
flaps during facial rhytidectomy surgery (face lift) comfort, chills, dyspnea, edema, eosinophilia,
Hemostasis, adjunct: erythema, flushing, gastrointestinal hemorrhage, gran-
Artiss: Not indicated as an adjunct to hemostasis uloma, hemorrhage (internal, postprocedural), hemo-
Evarrest, Evicel: As an adjunct to hemostasis for use thorax, hepatitis C, hypersensitivity reaction,
in patients undergoing surgery when control of hypotension, inflammation, ischemic bowel disease,
bleeding by conventional surgical techniques (such laryngeal edema, local hemorrhage (spleen), multi-
as suture, ligature, and cautery) is ineffective or organ failure, mydriasis, nerve compression, paraly-
impractical sis, parathyroid disease, paresthesia, procedural
Raplixa: As an adjunct to hemostasis for mild to complications (thoracic cavity drainage), pulmonary
moderate bleeding in adults undergoing surgery embolism, renal artery thrombosis, renal failure, res-
when control of bleeding by standard surgical tech- piratory distress, tachycardia, thrombosis, urticaria,
niques (such as suture, ligature, and cautery) is wheezing
ineffective or impractical Mechanism of Action Formation of a biodegradable
TachoSil: As an adjunct to hemostasis for use with adhesive is done by duplicating the last step of the
manual compression in adults and pediatric patients coagulation cascade, the formation of fibrin from fibri-
≥1 month in cardiovascular and hepatic surgery nogen. Fibrinogen is the main component of the sealant
when control of bleeding by standard surgical tech- solution. The solution also contains thrombin, which
niques (such as suture, ligature, or cautery) is inef- transforms fibrinogen from the sealer protein solution
fective or impractical into fibrin, and fibrinolysis inhibitor (aprotinin), which
Tisseel: As an adjunct to hemostasis in adult and prevents the premature degradation of fibrin. When
pediatric patients (≥1 month) undergoing surgery mixed as directed, a viscous solution forms that sets
when control of bleeding by conventional surgical into an elastic coagulum. Patches contain fibrinogen
techniques, including suture, ligature, and cautery, and thrombin that, in contact with bleeding surfaces,
is ineffective or impractical. Tisseel is effective in hydrate, form active fibrin, then produce a fibrin clot.
heparinized patients. Pharmacodynamics/Kinetics
Skin graft adhesion (Artiss only): To adhere autolo- Onset of Action Artiss: Full adherence achieved: ~2
gous skin grafts to surgically prepared wound beds hours
resulting from burns in adults and pediatric patients Time to hemostasis: Evarrest: 4 minutes; Evicel: 4 to
≥1 year 10 minutes; Raplixa: 5 minutes; TachoSil: 3 to 6
Local Anesthetic/Vasoconstrictor Precautions minutes; Tisseel: 5 minutes
No information available to require special precautions Pregnancy Risk Factor C (manufacturer dependent)
Effects on Dental Treatment No significant effects or Pregnancy Considerations Animal reproduction
complications reported studies have not been conducted.
require special precautions Fidaxomicin (fye DAX oh mye sin)
Adverse Reactions Frequency may vary by product
and patient age. Brand Names: US Dificid
>10%: Brand Names: Canada Dificid
Cardiovascular: Atrial fibrillation (29%), hypertension Pharmacologic Category Antibiotic, Macrolide
(children: 17%) Use
Gastrointestinal: Nausea (30%), diarrhea (chil- Treatment of Clostridioides (formerly Clostridium) diffi-
dren: 17%) cile infection (CDI) in adults
Hematologic & oncologic: Anemia (23%) Note: The 2017 Infectious Diseases Society of America
Hepatic: Increased serum transaminases (chil- (IDSA) and Society for Healthcare Epidemiology of
dren: 11%) America (SHEA) guidelines for Clostridioides (formerly
Immunologic: Antibody development (equine collagen: Clostridium) difficile Infection in adults and children
26% human thrombin: 2%, human fibrinogen: 1%) recommend fidaxomicin as a treatment option for the
587
FIDAXOMICIN
initial episode of CDI (non-severe and severe), first Peripheral blood progenitor cell collection and ther-
recurrence (if vancomycin given for the initial epi- apy (filgrastim and filgrastim biosimilars): Mobili-
sode), and second or subsequent recurrence (IDSA/ zation of autologous hematopoietic progenitor cells
SHEA [McDonald 2018]). into the peripheral blood for apheresis collection
Local Anesthetic/Vasoconstrictor Precautions Severe chronic neutropenia (filgrastim and filgras-
No information available to require special precautions tim biosimilars): Long-term administration to reduce
Effects on Dental Treatment No significant effects or the incidence and duration of neutropenic complica-
complications reported tions (eg, fever, infections, oropharyngeal ulcers) in
Effects on Bleeding No information available to symptomatic patients with congenital, cyclic, or idio-
require special precautions pathic neutropenia
Note: Filgrastim-aafi (Nivestym) and filgrastim-sndz
Adverse Reactions
(Zarxio) are approved as biosimilars to filgrastim
>10%: Gastrointestinal: Nausea (11%)
(Neupogen). In Canada, Grastofil is a biosimilar to
2% to 10%:
filgrastim (Neupogen).
Gastrointestinal: Gastrointestinal hemorrhage (4%),
abdominal pain, vomiting
Hematologic & oncologic: Anemia (2%), neutrope-
nia (2%)
distention, abdominal tenderness, angioedema,
require special precautions. Medical consultation may
decreased platelet count, decreased serum bicarbon-
be considered to confirm adequate platelet counts.
ate, dyspepsia, dysphagia, dyspnea, fixed drug erup-
Adverse Reactions
tion, flatulence, hepatotoxicity (idiosyncratic)
>10%:
(Chalasani, 2014), hyperglycemia, hypersensitivity
Cardiovascular: Chest pain (5% to 13%)
reaction, increased liver enzymes, increased serum
Central nervous system: Fatigue (20%), dizziness
alkaline phosphatase, intestinal obstruction, megaco-
(14%), pain (12%)
lon, metabolic acidosis, pruritus, skin rash
Mechanism of Action Inhibits RNA polymerase sigma Gastrointestinal: Nausea (43%)
subunit resulting in inhibition of protein synthesis and Hematologic & oncologic: Thrombocytopenia (5% to
cell death in susceptible organisms including C. difficile; 38%), splenomegaly (≥5%; severe chronic neutrope-
bactericidal nia: 30%)
Pregnancy Considerations The limited systemic Hepatic: Increased serum alkaline phosphatase (6%
absorption of fidaxomicin may limit potential fetal expo- to 11%)
sure. Neuromuscular & skeletal: Ostealgia (11% to 30%),
back pain (2% to 15%)
Filgrastim (fil GRA stim) Respiratory: Epistaxis (≥5%), cough (14%), dysp-
nea (13%)
Brand Names: US Granix; Neupogen; Nivestym; Zar- Miscellaneous: Fever (8% to 48%)
xio 1% to 10%:
Brand Names: Canada Grastofil; Neupogen Cardiovascular: Peripheral edema (≥5%), hyperten-
Pharmacologic Category Colony Stimulating Factor; sion (≥5%)
Hematopoietic Agent Central nervous system: Headache (6% to 10%),
Use hypoesthesia (≥5%), insomnia (≥5%), malaise
(≥5%), mouth pain (≥5%)
Myelosuppressive chemotherapy recipients with
Dermatologic: Alopecia (≥5%), erythema (≥2%), mac-
nonmyeloid malignancies:
ulopapular rash (≥2%)
Filgrastim and filgrastim biosimilars: To decrease
Endocrine & metabolic: Increased lactate dehydrogen-
the incidence of infection (neutropenic fever) in
ase (6%)
patients with nonmyeloid malignancies receiving
Gastrointestinal: Vomiting (≥5%), decreased appetite
myelosuppressive chemotherapy associated with a
(≥5%), constipation (≥2%), diarrhea (≥2%)
significant incidence of severe neutropenia with fever Genitourinary: Urinary tract infection (≥5%)
Tbo-filgrastim: To decrease the duration of severe Hematologic & oncologic: Anemia (≥5%), decreased
neutropenia in adult and pediatric patients ≥1 month hemoglobin (≥5%), leukocytosis (≤2%)
of age with nonmyeloid malignancies receiving mye- Hypersensitivity: Transfusion reaction (≥2%), hyper-
losuppressive chemotherapy associated with a clin- sensitivity reaction (≥5%)
ically significant incidence of neutropenic fever Immunologic: Antibody development (2% to 3%; no
Acute myeloid leukemia (AML) following induction evidence of neutralizing response)
or consolidation chemotherapy (filgrastim and fil- Infection: Sepsis (≥5%)
grastim biosimilars): To reduce the time to neutrophil Neuromuscular & skeletal: Arthralgia (5% to 9%), limb
recovery and the duration of fever following induction pain (2% to 7%), muscle spasm (≥5%), musculoske-
or consolidation chemotherapy in adults with AML letal pain (≥5%) asthenia (≥5%)
Bone marrow transplantation (filgrastim and filgras- Respiratory: Bronchitis (≥5%), oropharyngeal pain
tim biosimilars): To reduce the duration of neutrope- (≥5%), upper respiratory tract infection (≥5%)
nia and neutropenia-related events (eg, neutropenic <1%, postmarketing, and/or case reports: Acute respi-
fever) in patients with nonmyeloid malignancies ratory distress syndrome, anaphylaxis, capillary leak
receiving myeloablative chemotherapy followed by syndrome, decreased bone mineral density, glomer-
marrow transplantation ulonephritis, hemoptysis, hypersensitivity angiitis,
Hematopoietic radiation injury syndrome, acute (fil- myalgia, osteoporosis, pulmonary alveolar hemor-
grastim only): To increase survival in patients acutely rhage, pulmonary infiltrates, sickle cell crisis, splenic
exposed to myelosuppressive doses of radiation rupture, Sweet syndrome, vasculitis (aortitis)
588
FINASTERIDE
Mechanism of Action Filgrastim, filgrastim biosimi- Limitations of use: Not approved for the prevention of
lars, and tbo-filgrastim are granulocyte colony stimulat- prostate cancer.
ing factors (G-CSF) produced by recombinant DNA Local Anesthetic/Vasoconstrictor Precautions
technology. G-CSFs stimulate the production, matura- No information available to require special precautions
tion, and activation of neutrophils to increase both their Effects on Dental Treatment No significant effects or
migration and cytotoxicity. complications reported
Pharmacodynamics/Kinetics Effects on Bleeding No information available to
Onset of Action require special precautions
Filgrastim: 1 to 2 days Adverse Reactions Note: "Combination therapy"
Tbo-filgrastim: Time to maximum ANC: 3 to 5 days refers to finasteride and doxazosin.
Duration of Action >10%:
Filgrastim: Neutrophil counts generally return to base- Cardiovascular: Orthostatic hypotension (combination
line within 4 days therapy 18%)
Tbo-filgrastim: ANC returned to baseline by 21 days Central nervous system: Dizziness (combination ther-
after completion of chemotherapy apy 23%; monotherapy 7%)
Half-life Elimination Endocrine & metabolic: Decreased libido (combination
Neonates: 4.4 ± 0.4 hours (Gillan 1994) therapy 12%; monotherapy 2% to 10%)
Adults: Filgrastim: ~3.5 hours; Tbo-filgrastim: 3 to 3.5 Genitourinary: Impotence (combination therapy 23%;
hours monotherapy 5% to 19%), ejaculatory disorder (com-
Time to Peak Serum: Filgrastim: SubQ: 2 to 8 hours; bination therapy 14%; monotherapy <1% to 7%)
Tbo-filgrastim: 4 to 6 hours Neuromuscular & skeletal: Weakness (combination
therapy 17%; monotherapy 5%)
1% to 10%:
Filgrastim crosses the placenta.
Cardiovascular: Edema (combination therapy 3%;
Available data do not suggest an association between monotherapy 1%)
the use of filgrastim during pregnancy and an increased Central nervous system: Drowsiness (combination
risk of miscarriage, preterm labor, or adverse fetal out- therapy 3%; monotherapy 2%)
comes (birth weight or infection) following maternal use Dermatologic: Skin rash (monotherapy 1%)
for severe chronic neutropenia. Information related to Endocrine & metabolic: Gynecomastia (monotherapy
the use of granulocyte-colony stimulating factor (G- 1% to 2%)
CSF) in pregnant patients with congenital, cyclic, or Genitourinary: Decreased ejaculate volume (mono-
idiopathic neutropenia (Boxer 2015; Zeidler 2014) and therapy 2% to 4%), breast tenderness (monotherapy
G-CSF-induced allogeneic peripheral blood stem cells ≤1%)
donation is limited (Leitner 2001; Shibata 2003). Respiratory: Dyspnea (combination therapy 2%;
monotherapy 1%), rhinitis (combination therapy 2%;
Data collected from the Severe Chronic Neutropenia monotherapy 1%)
International Registry (SCNIR) note dosing for chronic <1%, postmarketing, and/or case reports: Altered men-
conditions may need adjusted in pregnant women; the tal status, attempted suicide (Welk 2017), change in
lowest effective dose to maintain the absolute neutro- libido, decreased testicular size, depression, disturbed
phil count is recommended (Zeidler 2014). An interna- sleep, hypersensitivity (angioedema, facial swelling,
tional consensus panel has published guidelines for pharyngeal edema, pruritus, skin rash, swelling of
hematologic malignancies during pregnancy that sug- the lips, swollen tongue, urticaria), male infertility
gest that although data are limited, administration of (temporary), malignant neoplasm of the male breast,
granulocyte growth factors during pregnancy may be prostate cancer - high grade, prostatitis, reduction in
acceptable (Lishner 2016). One review suggests when penile curvature, reduction in penile size, sexual dis-
utilizing for hematopoietic stem cell mobilization (in order (may not be reversible with discontinuation),
healthy donors; not a labeled use) avoiding use during suicidal ideation (Welk 2017), testicular pain
the first trimester until additional outcome information is Mechanism of Action Finasteride competitively inhib-
available (Pessach 2013). its type II 5-alpha reductase, resulting in inhibition of the
conversion of testosterone to dihydrotestosterone and
markedly suppresses serum dihydrotestosterone levels
Finasteride (fi NAS teer ide)
Brand Names: US Propecia; Proscar Duration of Action Dihydrotestosterone levels return
Brand Names: Canada Propecia; Proscar to normal within 14 days of discontinuation of treat-
ment; BPH: Prostate volume returns to baseline within
Pharmacologic Category 5 Alpha-Reductase Inhib-
~3 months after discontinuation; Male pattern bald-
itor
ness: Reversal of increased hair count within 12
Use months
Androgenetic alopecia (Propecia): Treatment of male
Half-life Elimination 5 to 6 hours (range: 3 to 16
pattern hair loss in men only.
hours); Elderly (≥70 years): 8 hours (range: 6 to 15
Limitations of use: Efficacy in bitemporal recession hours)
has not been established; not indicated for use in
Time to Peak Serum: 1 to 2 hours
women.
Pregnancy Risk Factor X
Benign prostatic hyperplasia (Proscar): Treatment
(monotherapy) of symptomatic benign prostatic hyper-
Use is contraindicated in females of childbearing poten-
plasia (BPH) to improve symptoms, reduce the risk of
tial.
acute urinary retention, and to reduce the risk of need
for BPH-related surgery); used in combination with an Abnormalities of external male genitalia were reported
alpha-blocker (doxazosin) to reduce the risk of symp- in animal reproduction studies. Pregnant females are
tomatic progression. advised to avoid contact with crushed or broken tablets.
589
FINASTERIDE
Adequate contraception is recommended if used off- pneumonia, progressive multifocal leukoencephalop-

label in the management hirsutism in females associ- athy, prolonged QT interval on ECG, reversible poste-
ated with PCOS (ACOG 194 2018). rior leukoencephalopathy syndrome, skin rash, status
epilepticus, syncope, T-cell lymphoma (including cuta-
neous T-cell lymphoma and mycosis fungoides), urti-
Fingolimod (fin GOL i mod)
caria
Brand Names: US Gilenya Mechanism of Action Fingolimod-phosphate, active
Brand Names: Canada Gilenya metabolite of fingolimod, binds to sphingosine 1-phos-
Pharmacologic Category Sphingosine 1-Phosphate phate receptors 1, 3, 4, and 5. Fingolimod-phosphate
(S1P) Receptor Modulator blocks the lymphocytes' ability to emerge from lymph
nodes; therefore, the amount of lymphocytes available
Use Multiple sclerosis: Treatment of relapsing forms of
to the central nervous system is decreased, which
multiple sclerosis (MS) in patients ≥10 years to reduce
reduces central inflammation.
the frequency of clinical exacerbations and to delay the
accumulation of physical disability.
Half-life Elimination 6 to 9 days; prolonged by
approximately 50% in patients with moderate or
severe hepatic impairment
related to dental treatment: Increased blood pressure
may occur with fingolimod; assess and plan treatment Pregnancy Considerations Adverse events have
according to patient's blood pressure. Fingolimod been observed in animal reproduction studies. Elimina-
causes immune suppression; medical consult needed tion of fingolimod takes approximately 2 months; to
prior to dental surgery. avoid potential fetal harm, women of childbearing
potential should use effective contraception to avoid
pregnancy during and for 2 months after discontinuing
treatment. Data collection to monitor pregnancy and
Adverse Reactions As reported in adults, unless infant outcomes following exposure to fingolimod is
otherwise noted.
ongoing. Health care providers are encouraged to enroll
>10%:
pregnant women, or pregnant women may enroll them-
selves, in the Gilenya Pregnancy Registry
(1-877-598-7237 or https://www.-
transfer (≤15%)
gilenyapregnancyregistry.com).
Gastrointestinal: Diarrhea (13%), nausea (13%),
abdominal pain (11%)
Hepatic: Increased serum alanine aminotransferase Flecainide (fle KAY nide)
(≤15%), increased serum aspartate transami-
nase (≤15%) Related Information
Infection: Influenza (11%) Clinical Risk Related to Drugs Prolonging QT Interval
Neuromuscular & skeletal: Back pain (10%) on page 1462
Respiratory: Cough (12%), sinusitis (11%) Brand Names: Canada Apo-Flecainide; Tambocor
1% to 10%: Pharmacologic Category Antiarrhythmic Agent,
Cardiovascular: Hypertension (8%), first degree atrio- Class Ic
ventricular block (5%), second degree atrioventricu- Use
lar block (4%), bradycardia (3%) Paroxysmal atrial fibrillation/flutter and paroxysmal
Central nervous system: Seizure (children and ado- supraventricular tachycardias (prevention): For
lescents: 6%), migraine (6%) the prevention of paroxysmal atrial fibrillation/flutter
Dermatologic: Alopecia (3%), actinic keratosis (2%), associated with disabling symptoms and paroxysmal
pityriasis versicolor (2%) supraventricular tachycardias (PSVT), including atrio-
Endocrine & metabolic: Increased serum triglycer- ventricular nodal reentrant tachycardia, atrioventricu-
ides (3%) lar reentrant tachycardia, and other supraventricular
Hematologic & oncologic: Lymphocytopenia (7%), tachycardias of unspecified mechanism associated
cutaneous papilloma (3%), leukopenia (2%), basal with disabling symptoms in patients without structural
cell carcinoma (2%) heart disease.
Infection: Herpes virus infection (9%), herpes zoster Guideline recommendations: Due to safety risks, fle-
infection (2%) cainide should be reserved for symptomatic supra-
Neuromuscular & skeletal: Limb pain (10%), asthe- ventricular tachycardias (SVTs) in patients without
nia (2%) structural or ischemic heart disease who are not
Ophthalmic: Blurred vision (4%) candidates for, or prefer not to undergo, catheter
Respiratory: Dyspnea (9%), bronchitis (8%), ablation and in whom other therapies have failed or
decreased lung function (3%; diffusion lung capacity are contraindicated (ACC/AHA/HRS [Page 2015]).
for carbon monoxide), reduced forced expiratory Ventricular arrhythmias (prevention): Prevention of
volume (3%) documented life-threatening ventricular tachyarrhyth-
<1%, postmarketing, and/or case reports: Angioedema, mias (eg, sustained ventricular tachycardia) in patients
arthralgia, asystole, bacterial infection, cerebrovascu- without structural heart disease.
lar accident, cholestatic hepatitis, complete atrioven- Guideline recommendations: Flecainide is an appro-
tricular block, cryptococcosis, fungal infection, priate adjunctive therapy in patients with type 3 long
hepatocellular hepatitis, herpes simplex encephalitis, QT syndrome or catecholaminergic polymorphic ven-
hypersensitivity reaction, JC virus infection, Kaposi tricular tachycardia who are already taking a max-
sarcoma, macular edema, malignant lymphoma imally tolerated beta blocker but still experiencing
(including B-cell), malignant melanoma, Merkel cell symptoms (AHA/ACC/HRS [Al-Khatib 2017]; Ben-
carcinoma, multiorgan failure, myalgia, neoplasm, horin 2000; Chorin 2018; Van der Werf 2011; Wata-
non-Hodgkin lymphoma, peripheral arterial disease, nabe 2013)
590
FLOCTAFENINE
Limitations of use: Use of flecainide is not recom- Mechanism of Action Class Ic antiarrhythmic; slows
mended in patients with less severe ventricular conduction in cardiac tissue by altering transport of ions
arrhythmias, even if symptomatic. Because of the across cell membranes; causes slight prolongation of
proarrhythmic effects of flecainide, its use should be refractory periods; decreases the rate of rise of the
reserved for patients in whom the benefits of treatment action potential without affecting its duration; increases
outweigh the risks. Flecainide should not be used in electrical stimulation threshold of ventricle, His-Purkinje
patients with chronic atrial fibrillation (not adequately system; possesses local anesthetic and moderate neg-
studied) or recent MI. No evidence from controlled ative inotropic effects
trials have demonstrated favorable effects of flecai- Pharmacodynamics/Kinetics
nide on survival or the incidence of sudden death. Half-life Elimination
Local Anesthetic/Vasoconstrictor Precautions Newborns: Up to ≤29 hours; 3 months: 11 to 12 hours;
Flecainide is one of the drugs confirmed to prolong 12 months: 6 hours
the QT interval and is accepted as having a risk of Children: ~8 hours
causing torsade de pointes. The risk of drug-induced Adolescents 12 to 15 years: ~11 to 12 hours
torsade de pointes is extremely low when a single QT Adults: ~20 hours (range: 12 to 27 hours); increased in
interval prolonging drug is prescribed. In terms of epi- patients with heart failure (NYHA Class III) or renal
nephrine, it is not known what effect vasoconstrictors in dysfunction
the local anesthetic regimen will have in patients with a Time to Peak Serum: ~3 hours (range: 1 to 6 hours)
known history of congenital prolonged QT interval or in Pregnancy Risk Factor C
patients taking any medication that prolongs the QT Pregnancy Considerations Adverse events have
interval. Until more information is obtained, it is sug- been observed in some animal reproduction studies.
gested that the clinician consult with the physician prior Flecainide is recommended in the treatment of fetal
to the use of a vasoconstrictor in suspected patients, tachycardia determined to be SVT. Flecainide may be
and that the vasoconstrictor (epinephrine, mepivacaine also used for the ongoing management of SVT in highly
and levonordefrin [Carbocaine® 2% with Neo-Cobe- symptomatic pregnant patients. The lowest effective
frin®]) be used with caution. dose is recommended; avoid use during the first trimes-
Effects on Dental Treatment No significant effects or ter if possible (Page [ACC/AHA/HRS 2015]). Additional
complications reported guidelines are available for management of cardiovas-
Effects on Bleeding No information available to cular diseases during pregnancy (ESG [Regitz-Zagro-
require special precautions sek 2011]).
Adverse Reactions Dental Health Professional Considerations See
Central nervous system: Dizziness (19% to 30%)
Ocular: Visual disturbances (16%) Floctafenine (flok ta FEN een)
Respiratory: Dyspnea (~10%)
1% to 10%: Related Information
Cardiovascular: Palpitation (6%), chest pain (5%), Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
edema (3.5%), tachycardia (1% to 3%), proarrhyth- on page 1484
mic (4% to 12%), sinus node dysfunction (1.2%), Pharmacologic Category Analgesic, Nonopioid; Non-
syncope steroidal Anti-inflammatory Drug (NSAID), Oral
Central nervous system: Headache (4% to 10%), Use Note: Not approved in the US
fatigue (8%), nervousness (5%) additional symptoms Pain: Short-term management of acute, mild-to-moder-
occurring at a frequency between 1% and 3%: fever, ate pain
malaise, hypoesthesia, paresis, ataxia, vertigo, som- Local Anesthetic/Vasoconstrictor Precautions
nolence, tinnitus, anxiety, insomnia, depression No information available to require special precautions
Dermatologic: Rash (1% to 3%) Effects on Dental Treatment Key adverse event(s)
Gastrointestinal: Nausea (9%), constipation (1%), related to dental treatment: Xerostomia and changes in
abdominal pain (3%), anorexia (1% to 3%), diarrhea salivation (normal salivary flow resumes upon discon-
(0.7% to 3%) tinuation), bitter taste. See Effects on Bleeding.
Neuromuscular & skeletal: Tremor (5%), weakness Effects on Bleeding Nonselective NSAIDs are known
(5%), paresthesia (1%) to reversibly decrease platelet aggregation via mecha-
Ophthalmic: Diplopia (1% to 3%), blurred vision nisms different than observed with aspirin. Platelet
<1% (Limited to important or life-threatening): Brady- function is restored as the drug is eliminated from the
cardia, paradoxical increase in ventricular rate in atrial body. Dental professionals should be aware that rec-
fibrillation/flutter, heart block, increased P-R, QRS ommendations differ between dental and general med-
duration, ventricular arrhythmia, CHF, flushing, AV ical surgery. NSAIDs should be avoided (if possible) in
block, angina, hyper-/hypotension, amnesia, confu- general medical surgery patients for 3 to 5 half-lives of
sion, decreased libido, depersonalization, euphoria, the drug (usually 1 to 3 days) prior to surgery to reduce
apathy, nervousness, twitching, neuropathy, weak- the risk of excessive bleeding. However, there is no
ness, taste disturbance, urticaria, exfoliative dermati- scientific evidence to warrant discontinuance of NSAIDs
tis, pruritus, alopecia, flatulence, xerostomia, blood prior to dental surgery. In medically complicated
dyscrasias, possible hepatic dysfunction, paresthesia, patients or extensive oral surgery, the decision to inter-
eye pain, photophobia, bronchospasm, pneumonitis, rupt therapy must be based on the risk to benefit in an
swollen lips/tongue/mouth, arthralgia, myalgia, polyu- individual patient and a medical consult is suggested.
ria, urinary retention, leukopenia, granulocytopenia, Routine interruption of NSAID therapy for most dental
thrombocytopenia, metallic taste, alters pacing procedures is not warranted. If therapy is continued
threshold without interruption, the clinician should anticipate the
Postmarketing and/or case reports: Tardive dyskinesia, potential for slower clotting times.
corneal deposits Adverse Reactions Frequency not defined.
591
FLOCTAFENINE
Cardiovascular: Edema, flushing, tachycardia Hematologic & oncologic: Anemia, bone marrow
Central nervous system: Bitter taste, depression, dizzi- depression (nadir: 7-10 days; may be dose limiting),
ness, drowsiness, fatigue, headache, insomnia, irrita- leukopenia, thrombocytopenia
bility, malaise, nervousness, vertigo 1% to 10%:
Dermatologic: Diaphoresis, pruritus, skin rash, urticaria Dermatologic: Alopecia, dermatitis, localized eryth-
Endocrine & metabolic: Fluid retention, hyperkalemia, ema, skin hyperpigmentation, skin photosensitivity
increased thirst Gastrointestinal: Anorexia, biliary sclerosis, cholecys-
Gastrointestinal: Abdominal pain, constipation, diar- titis
rhea, dyspepsia, flatulence, gastrointestinal hemor- Hepatic: Jaundice
rhage, gastrointestinal perforation (with gross <1%, postmarketing, and/or case reports: Abdominal
bleeding), gastrointestinal ulcer, heartburn, nausea, cramps, abdominal pain, BSP abnormality, change in
vomiting, xerostomia prothrombin time, decreased erythrocyte sedimenta-
Genitourinary: Burning sensation on urination, cystitis, tion rate, decreased serum total protein, duodenal
dysuria, hematuria ulcer, duodenitis, enteritis, fever, gastritis, gastroenter-
Hematologic & oncologic: Agranulocytosis, aplastic itis, gastrointestinal hemorrhage, gastrointestinal
anemia, hemorrhage, leukopenia, neutropenia, throm- ulcer, glossitis, hemorrhage, hepatic abscess,
increased erythrocyte sedimentation rate, increased
bocytopenia
lactate dehydrogenase, increased serum alkaline
Hepatic: Hepatotoxicity, increased liver enzymes
phosphatase, increased serum bilirubin, increased
Hypersensitivity: Anaphylaxis, angioedema
serum total protein, increased serum transaminases,
Ophthalmic: Blurred vision, vision loss
infusion related reaction (arterial aneurysm; arterial
Otic: Tinnitus
ischemia; arterial thrombosis; embolism; fibromyositis;
Renal: Interstitial nephritis, polyuria, renal insufficiency thrombophlebitis; hepatic necrosis; abscesses; infec-
(acute, reversible; with or without oliguria or anuria), tion at catheter site; bleeding at catheter site; catheter
urethritis, urine abnormality (strong smell) blocked, displaced, or leaking), ischemic heart dis-
Respiratory: Dyspnea (asthmatic-type) ease, lethargy, malaise, nausea, pharyngitis, skin
Mechanism of Action Reversibly inhibits cyclooxyge- rash, vomiting, weakness
nase-1 and 2 (COX-1 and 2) enzymes, which results in Mechanism of Action Floxuridine is catabolized to
decreased formation of prostaglandin precursors; has fluorouracil after intra-arterial administration, resulting
antipyretic, analgesic, and anti-inflammatory properties in activity similar to fluorouracil; inhibits thymidylate
Other proposed mechanisms not fully elucidated (and synthetase and disrupts DNA and RNA synthesis.
possibly contributing to the anti-inflammatory effect to Pregnancy Risk Factor D
varying degrees), include inhibiting chemotaxis, altering Pregnancy Considerations Teratogenic effects have
lymphocyte activity, inhibiting neutrophil aggregation/ been observed in animal reproduction studies. Medica-
activation, and decreasing proinflammatory cytokine tions that inhibit DNA synthesis are known to be terato-
levels. genic in humans. Women of childbearing potential
Pharmacodynamics/Kinetics should avoid pregnancy.
Duration of Action 6 to 8 hours
Half-life Elimination Initial phase (distribution): 1 Fluconazole (floo KOE na zole)
hour; second phase (elimination): 8 hours
Time to Peak Plasma: Floctafenic acid: 1 to 2 hours Related Information
Pregnancy Considerations Floctafenic acid, the Clinical Risk Related to Drugs Prolonging QT Interval
active metabolite of floctafenine crosses the placenta. on page 1462
In late pregnancy, NSAIDs may cause premature clo- Fungal Infections on page 1538
sure of the ductus arteriosus. Related Sample Prescriptions
Product Availability Not available in the US Fungal Infections - Sample Prescriptions on page 39
Brand Names: US Diflucan
Brand Names: Canada CanesOral; Diflucan; Diflucan
Floxuridine (floks YOOR i deen) injection; Diflucan One; Diflucan PWS; Dom-Flucona-
zole; Fluconazole Injection; Fluconazole Injection SDZ;
Brand Names: Canada FUDR®
Fluconazole Omega; Monicure
metabolite; Antineoplastic Agent, Antimetabolite (Pyri-
midine Analog)
Pharmacologic Category Antifungal Agent, Oral;
Antifungal Agent, Parenteral
Use Colorectal cancer, hepatic metastases: Palliative
Dental Use Treatment of susceptible fungal infections
management of hepatic metastases of colorectal can-
in the oral cavity including candidiasis, oral thrush, and
cer (administered by continuous regional intra-arterial
chronic mucocutaneous candidiasis treatment of
infusion) in select patients considered incurable by esophageal and oropharyngeal candidiasis caused by
surgical resection or other means. Candida species; treatment of severe, chronic mucocu-
Local Anesthetic/Vasoconstrictor Precautions taneous candidiasis caused by Candida species
No information available to require special precautions Use Treatment of candidiasis (esophageal, oropharyng-
Effects on Dental Treatment Key adverse event(s) eal, peritoneal, urinary tract, vaginal); systemic candida
related to dental treatment: Stomatitis. infections (eg, candidemia, disseminated candidiasis,
Effects on Bleeding Thrombocytopenia and anemia pneumonia); and cryptococcal meningitis; and antifun-
can occur. gal prophylaxis in allogeneic hematopoietic cell trans-
Adverse Reactions plant recipients
Gastrointestinal: Diarrhea (may be dose limiting), sto- Fluconazole is one of the drugs confirmed to prolong
matitis the QT interval and is accepted as having a risk of
592
FLUCONAZOLE
causing torsade de pointes. The risk of drug-induced Candidemia (neutropenic and non-neutropenic
torsade de pointes is extremely low when a single QT patients):
interval prolonging drug is prescribed. In terms of epi- Initial therapy (alternative to echinocandin if no
nephrine, it is not known what effect vasoconstrictors in previous azole exposure, noncritically ill, and not
the local anesthetic regimen will have in patients with a at high risk of fluconazole-resistant isolate): IV,
known history of congenital prolonged QT interval or in Oral: Loading dose of 800 mg (12 mg/kg) on day
patients taking any medication that prolongs the QT 1, then 400 mg (6 mg/kg) once daily; if flucona-
interval. Until more information is obtained, it is sug- zole-susceptible Candida glabrata isolated, tran-
gested that the clinician consult with the physician prior sition to 800 mg (12 mg/kg) once daily (IDSA
to the use of a vasoconstrictor in suspected patients, [Pappas 2016]).
and that the vasoconstrictor (epinephrine, mepivacaine Step-down therapy:
and levonordefrin [Carbocaine® 2% with Neo-Cobe- Isolates other than C. glabrata: Oral: 400 mg
frin®]) be used with caution. (6 mg/kg) once daily (IDSA [Pappas 2016])
Effects on Dental Treatment Key adverse event(s) Isolates of C. glabrata (if fluconazole-susceptible
or susceptible dose-dependent): Oral: 800 mg
related to dental treatment: Abnormal taste.
(12 mg/kg) once daily (IDSA [Pappas 2016];
Kauffman 2018a)
Duration: Continue for ≥14 days after first negative
Adverse Reactions blood culture and resolution of signs/symptoms
>10%: Central nervous system: Headache (adults: 2% (longer duration required in patients with meta-
to 13%) static complications); step-down therapy to oral
1% to 10%: fluconazole (eg, after initial therapy with an echi-
Central nervous system: Dizziness (adults: 1%) nocandin) is recommended after 5 to 7 days in
Dermatologic: Skin rash (adults: 2%) stable patients with negative repeat cultures and
Gastrointestinal: Nausea (adults: 4% to 7%; children fluconazole-susceptible isolates (IDSA [Pappas
and adolescents: 2%), abdominal pain (2% to 6%), 2016]; Kauffman 2018a).
vomiting (2% to 5%), diarrhea (2% to 3%), dysgeusia Candidiasis, invasive (empiric therapy) and/or crit-
(adults: 1%), dyspepsia (adults: 1%) ically ill non-neutropenic patients in the ICU at risk
Frequency not defined: Hepatic: Fulminant hepatitis, of invasive candidiasis with fever and unidentified
hepatitis, increased serum alkaline phosphatase, etiology (alternative to echinocandin if no previous
increased serum aspartate aminotransferase, azole exposure and not colonized with fluconazole-
increased serum transaminases, jaundice resistant isolate): IV, Oral: Loading dose of 800 mg
<1%, postmarketing, and/or case reports: Acute gener- (12 mg/kg) on day 1, then 400 mg (6 mg/kg) once
alized exanthematous pustulosis, agranulocytosis, daily; continue for ≥14 days in patients with clinical
alopecia, anaphylaxis, angioedema, asthenia, choles- improvement. Consider discontinuing after 4 to 5
tasis, diaphoresis, DRESS syndrome, drowsiness, days in patients with no clinical response and no
exfoliative dermatitis, fatigue, fever, fixed drug erup- evidence of invasive candidiasis (IDSA [Pappas
tion, hepatic failure, hepatotoxicity, hypercholesterole- 2016]; Kauffman 2018a).
mia, hypertriglyceridemia, hypokalemia, insomnia, Cardiac device infection (eg, implantable cardiac
leukopenia, malaise, myalgia, neutropenia, paresthe- defibrillator, pacemaker, ventricular assist device
sia, prolonged QT interval on ECG, seizure, Stevens- [VAD]): Step-down therapy: IV, Oral: 400 to
Johnson syndrome, thrombocytopenia, torsades de 800 mg (6 to 12 mg/kg) once daily for 4 to 6 weeks
pointes, toxic epidermal necrolysis, tremor, vertigo, after device removal (4 weeks for infections limited
xerostomia to generator pockets and ≥6 weeks for infections
Dental Usual Dosage Candidiasis: Adults: involving wires). Note: If VAD cannot be removed,
chronic suppressive therapy with fluconazole 400 to
Usual dosage range: 200 to 400 mg/day; duration and
800 mg (6 to 12 mg/kg) once daily should be used
dosage depends on severity of infection
(IDSA [Pappas 2016]).
Oropharyngeal (long-term suppression): 200 mg/day;
Chronic, disseminated (hepatosplenic): Step-down
chronic therapy is recommended in immunocompro-
therapy: Oral: 400 mg (6 mg/kg) once daily; con-
mised patients with history of oropharyngeal candidia-
tinue until lesion resolution (usually several months)
sis (OPC)
and through periods of immunosuppression (IDSA
Dosing
[Pappas 2016]).
Adult & Geriatric CNS: Step-down therapy (fluconazole-susceptible
Blastomycosis (off-label use): isolates): IV, Oral: 400 to 800 mg (6 to 12 mg/kg)
CNS disease (alternative agent): Step-down therapy: once daily; continue until signs/symptoms and CSF/
Oral: 800 mg once daily for ≥12 months and until radiologic abnormalities have resolved (IDSA [Pap-
resolution of cerebrospinal (CSF) abnormalities pas 2016]; IDSA [Tunkel 2017]).
(Bradsher 2018; IDSA [Chapman 2008]) Endocarditis, native or prosthetic valve: Step-down
Pulmonary disease (alternative agent if unable to therapy (fluconazole-susceptible isolates): IV, Oral:
tolerate itraconazole): Oral: 400 to 800 mg once 400 to 800 mg (6 to 12 mg/kg) once daily for ≥6
daily for 6 to 12 months (IDSA [Chapman 2008]; weeks after valve replacement surgery (longer
Pappas 1997) durations recommended in patients with perivalvu-
Candidiasis, treatment: Note: Consider weight- lar abscesses or other complications). Note: In
based dosing for patients <50 kg or >90 kg (Rex patients who cannot undergo valve replacement
1994; Rex 2003). A maximum dose has not been surgery or with prosthetic valve endocarditis,
established, but based on a small number of chronic suppressive therapy with fluconazole 400
patients, doses up to 1,600 mg/day appear to be to 800 mg (6 to 12 mg/kg) once daily should be
well tolerated (Anaissie 1995). used (IDSA [Pappas 2016]).
593
FLUCONAZOLE
Endophthalmitis, endogenous (with or without vitritis) before and after the procedure (IDSA [Pap-
(fluconazole-susceptible isolates): IV, Oral: Loading pas 2016])
dose of 800 mg (12 mg/kg) on day 1, then 400 to Cystitis (symptomatic): Oral: 200 mg (3 mg/kg)
800 mg (6 to 12 mg/kg) once daily for ≥4 to 6 once daily for 2 weeks (IDSA [Pappas 2016])
weeks and until examination indicates resolution Pyelonephritis: Oral: 200 to 400 mg (3 to 6 mg/kg)
(longer duration may be needed for patients with once daily for 2 weeks (IDSA [Pappas 2016])
vitritis); for patients with vitritis or macular involve- UTI associated with fungus balls: Oral: 200 to
ment, intravitreal antifungal therapy is also recom- 400 mg (3 to 6 mg/kg) once daily; concomitant
mended (IDSA [Pappas 2016]; Kauffman 2018b). amphotericin B deoxycholate irrigation via neph-
Esophageal: IV, Oral: Loading dose of 400 mg rostomy tubes, if present, is also recommended,
(6 mg/kg) on day 1, then 200 to 400 mg (3 to along with surgical management (IDSA [Pap-
6 mg/kg) once daily for 14 to 21 days; for HIV- pas 2016]).
infected patients with recurrent infections who have Vaginal/Vulvovaginal:
not attained immune reconstitution on antiretroviral Uncomplicated: Oral: 150 mg as a single dose
therapy, chronic suppressive therapy of 100 to (manufacturer's labeling)
200 mg 3 times weekly may be used (IDSA [Pap- Complicated or severe: Oral: 150 mg every 72
pas 2016]; Kauffman 2018c). hours for 2 or 3 doses (CDC [Workowski 2015];
Intertrigo, refractory to topical therapy (off-label use): IDSA [Pappas 2016])
Oral: 150 mg once weekly for 4 weeks (Brodell Recurrent: Oral: 150 mg every 72 hours for 10 to 14
2018; Nozickova 1998; Stengel 1994) days, followed by 150 mg once weekly for 6
Intra-abdominal infections (alternative to echinocan- months (IDSA [Pappas 2016]; Sobel 2004) or
din if no previous azole exposure, noncritically ill, 100 mg, 150 mg, or 200 mg every 72 hours for
and not at high risk of fluconazole-resistant isolate): 3 doses, then 100 mg, 150 mg, or 200 mg once
IV, Oral: Loading dose of 800 mg (12 mg/kg) on weekly for 6 months (CDC [Workowski 2015]).
day 1, then 400 mg (6 mg/kg) once daily; duration Candidiasis, prophylaxis:
is for ≥2 weeks and until all signs of infection have Hematologic malignancy patients (off-label use) or
resolved. Step-down therapy (after patient has hematopoietic cell transplant (HCT) recipients who
responded to initial therapy [eg, echinocandin]) with do not warrant mold-active prophylaxis (off-label
fluconazole is recommended in stable patients with use): Oral: 400 mg once daily. Duration is at least
a fluconazole-susceptible isolate (IDSA [Pappas until resolution of neutropenia and/or through day
75 in allogeneic HCT recipients (ASBMT [Tomblyn
2016]; Kauffman 2018d).
2009]; ASCO/IDSA [Taplitz 2018]; Glasmacher
Oropharyngeal: IV, Oral: Loading dose of 200 mg on
2006; Wingard 2018).
day 1, then 100 to 200 mg once daily for 7 to 14
ICU patients (high risk) in units with a high rate (>5%)
days; recommended for patients unresponsive to
of invasive candidiasis (off-label use): Oral, IV:
topical therapy or those with moderate to severe
Loading dose of 800 mg (12 mg/kg) once on day
infection, recurrent infection, or risk for esophageal
1, then 400 mg (6 mg/kg) once daily (IDSA [Pap-
candidiasis (eg, HIV-infected patients with CD4
pas 2016]). Note: Some experts do not routinely
counts <100 cells/mm3). In patients with recurrent
use prophylaxis in this setting (Kauffman 2018a).
infection, chronic suppressive therapy (100 mg 3
Peritoneal dialysis-associated infection (concurrently
times weekly) may be considered, but is usually treated with antibacterials), prevention of secon-
unnecessary (IDSA [Pappas 2016]; Kauffman dary fungal infection: Oral: 200 mg every other
2018c). day or 100 mg once daily (Burkart 2018; Glickman
Osteoarticular (osteomyelitis or septic arthritis) (flu- 2018; Restrepo 2010)
conazole-susceptible isolates): Initial or step-down Solid organ transplant recipients (selected patients at
therapy: IV, Oral: 400 mg (6 mg/kg) once daily. high-risk for Candida infection) (off-label use): Oral,
Duration for osteomyelitis is 6 to 12 months and IV: 400 mg (6 mg/kg) given perioperatively and
for septic arthritis is 6 weeks. Course may include 2 continued once daily postoperatively; indications
weeks of initial treatment with a lipid formulation of and duration vary among transplant centers
amphotericin B or an echinocandin. For prosthetic (ASHP/IDSA/SIS/SHEA [Bratzler 2013]; Fishman
joints that cannot be removed, chronic suppressive 2018; Silveira 2013; Winston 2002).
therapy with fluconazole 400 mg (6 mg/kg) once Coccidioidomycosis, treatment (off-label use):
daily is recommended (IDSA [Pappas 2016]). Bone and/or joint infection: Initial or step-down ther-
Peritonitis, associated with peritoneal dialysis: Note: apy: Oral: 800 mg once daily for ≥3 years; in some
Use for empiric treatment if no prior azole exposure cases, lifelong treatment is needed; duration
or for directed therapy against fluconazole-suscep- depends on severity and host immunocompetence
tible isolates: Oral: 200 mg on day 1, then 100 to (IDSA [Galgiani 2016]).
200 mg once daily for 2 to 4 weeks (Chen 2004; Meningitis: Oral: 400 to 1,200 mg once daily,
Glickman 2018; ISPD [Li 2016]; Wang 2000). depending on severity; continue lifelong as there
Thrombophlebitis, suppurative: Initial or step-down is a high relapse rate when the dose is decreased
therapy: IV, Oral: 400 to 800 mg (6 to 12 mg/kg) or treatment is discontinued (HHS [OI adult 2018];
once daily for ≥2 weeks after candidemia (if IDSA [Galgiani 2016]).
present) has cleared (IDSA [Pappas 2016]). Pneumonia, primary infection: Note: Only for
Urinary tract infection (UTI): patients with significantly debilitating illness, exten-
Candiduria (asymptomatic): sive pulmonary involvement, concurrent diabetes,
Patients with neutropenia: Treat as if patient has frailty due to age or comorbidities, or HIV (HHS [OI
candidemia (Georgiadou 2013; IDSA [Pap- adult 2018]; IDSA [Galgiani 2016]):
pas 2016]). Oral: Usual dose: 400 mg once daily; IDSA guide-
Patients undergoing a urologic procedure: Oral: lines state that some experts recommend 800 mg
400 mg (6 mg/kg) once daily several days once daily. Duration of therapy is 3 to 6 months for
594
FLUCONAZOLE
immunocompetent patients; immunocompro- receiving any other induction regimen should

mised patients require a longer duration of ther- receive 800 mg once daily for ≥8 weeks (Cox
apy (sometimes lifelong) (HHS [adult OI 2018]; 2018a; IDSA [Perfect 2010]; WHO 2018).
IDSA [Galgiani 2016]). Maintenance (suppression): Oral: 200 mg once
Pneumonia, symptomatic chronic cavitary and/or daily for ≥12 months; may discontinue if com-
cavitary disease in immunocompromised patients: pleted induction, consolidation, and ≥12 months
Oral: 400 mg once daily for ≥12 months. In patients of maintenance therapy, patient remains asymp-
with ruptured cavities, the duration may be shorter, tomatic, and CD4 count has been ≥100 cells/mm3
but depends upon the postoperative course (IDSA for ≥3 months and HIV RNA is suppressed in
[Galgiani 2016]; Jaroszewski 2018). response to effective antiretroviral therapy (HHS
Soft tissue infection (not associated with bone infec-
[OI adult 2018]).
tion): Oral: 400 mg once daily; some experts give
HIV-uninfected patients:
up to 800 mg once daily; duration is for ≥6 to 12
Induction (alternative regimens): Oral:
months (IDSA [Galgiani 2016]).
Coccidioidomycosis, prophylaxis (off-label use): If flucytosine is unavailable or not tolerated:
HIV-infected patients: Note: Primary prophylaxis is 800 mg once daily in combination with ampho-
not recommended; yearly or twice-yearly serologic tericin B for 2 weeks (Cox 2018b); or
testing should be performed in patients living in If amphotericin B is unavailable or not tolerated:
endemic areas. 800 to 1,200 mg once daily in combination with
Patients with a CD4 count <250 cells/mm3 who flucytosine for 2 to 10 weeks, depending on
have a new positive serology: Oral: 400 mg once severity and respons e to therapy (Cox
daily until antiretroviral therapy has fully sup- 2018b); or
pressed HIV replication and the CD4 count is If amphotericin B and flucytosine are unavailable
≥250 cells/mm3 (HHS [OI adult 2018]). or not tolerated: 800 to 1,200 mg once daily as
Solid organ transplant recipients: monotherapy for ≥10 weeks (Cox 2018b)
Seronegative patients in endemic areas (regardless Consolidation: Oral: 400 to 800 mg once daily for 8
of clinical history of coccidioidomycosis): Oral: weeks (800 mg once daily preferred for patients
200 mg once daily for 6 to 12 months following who receive a 2-week induction course) (Baddley
transplantation (Ampel 2018; IDSA [Gal- 2013; Cox 2018b; IDSA [Perfect 2010])
giani 2016]) Maintenance (suppression): Oral: 200 to 400 mg
Seropositive patients in endemic areas: Oral: once daily for 6 to 12 months (Baddley 2013;
400 mg once daily for 6 to 12 months following IDSA [Perfect 2010]) (a longer duration may be
transplantation (IDSA [Galgiani 2016]) warranted for patients on high-dose steroids or
Cryptococcal meningitis: Note: Treatment involves biologic agent [eg, alemtuzumab], or with radio-
induction, consolidation, and maintenance phases of
graphic evidence of cryptococcoma [Cox 2018b])
therapy.
Cryptococcosis, pulmonary infection (off-label
HIV-infected patients:
use):
Induction: Oral:
Resource-rich settings, alternative regimens: Mild to moderate symptoms (if severe pneumonia,
If flucytosine is unavailable or not tolerated: treat like CNS infection): Immunocompetent or
800 mg once daily in combination with ampho- immunocompromised patients without diffuse pul-
tericin B (lipid formulation preferred) for ≥2 monary infiltrates or disseminated infection: Oral:
weeks (HHS [OI adult 2018]); or 400 mg (6 mg/kg) once daily for 6 to 12 months
If amphotericin B is unavailable or not tolerated: (Cox 2018c; IDSA [Perfect 2010]); for HIV-infected
800 to 1,200 mg once daily in combination with patients, some experts recommend a duration of 12
flucytosine for ≥2 weeks (IDSA [Perfect 2010]; months (HHS [OI adult 2018]). Chronic suppressive
Molloy 2018; Nussbaum 2010); or therapy may be warranted for patients with ongoing
If flucytosine and amphotericin B are unavailable immunosuppression (Cox 2018c; HHS [OI
or not tolerated: 1,200 mg once daily as mono- adult 2018]).
therapy for ≥2 weeks (HHS [OI adult 2018]). Tinea:
Resource-limited settings: Tinea corporis or cruris: Oral: 150 to 200 mg once
Amphotericin B deoxycholate in combination weekly for 2 to 4 weeks (Goldstein 2018; Kotogyan
with flucytosine for 1 week followed by flucona- 1996; Montero-Gei 1992; Stary 1998)
zole 1,200 mg once daily for 1 week (preferred Tinea pedis: Oral: 150 mg once weekly for 2 to 6
regimen) (WHO 2018); or weeks (Gupta 2008; Kotogyan 1996; Montero-
If IV therapy is difficult to administer: 1,200 mg Gei 1992)
once daily as a 2-week induction regimen in Tinea versicolor: Oral: 300 mg once weekly for 2
combination with flucytosine for 2 weeks (WHO
weeks (Karakas 2005)
2018); or
If flucytosine is unavailable: 1,200 mg once daily
in combination with amphotericin B deoxycho- Manufacturer's labeling: Note: Renal function esti-
late for 2 weeks (WHO 2018) mated using the Cockcroft-Gault formula
Note: Induction therapy should be continued No adjustment for vaginal candidiasis single-dose
beyond the durations listed above if clinical therapy
improvement is not observed and/or if CSF For multiple dosing, administer loading dose of 50 to
cultures remain positive (Cox 2018a). 400 mg, then adjust daily doses as follows:
Consolidation: Oral: 400 mg once daily for ≥8 CrCl >50 mL/minute: No dosage adjustment nec-
weeks following induction with the preferred regi- essary
men of amphotericin B and flucytosine (HHS [OI CrCl ≤50 mL/minute (no dialysis): Reduce dose
adult 2018]; IDSA [Perfect 2010]); patients by 50%
595
FLUCONAZOLE
End-stage renal disease on intermittent hemodialysis Candidiasis, chronic, disseminated (hepatos-

(IHD): plenic), step-down therapy : Infants, Children,
Manufacturer's labeling: 100% of daily dose (accord- and Adolescents: Oral: 6 mg/kg/dose once daily
ing to indication) after each dialysis session; on following several weeks of initial therapy with an
nondialysis days, patient should receive a reduced amphotericin B lipid formulation or an echinocandin;
dose according to their CrCl. treatment should continue until lesion resolution
Alternate recommendations: Doses of 200 to 400 mg (usually several months); maximum dose: 400 mg/
every 48 to 72 hours or 100 to 200 mg every 24 dose (IDSA [Pappas 2016])
hours have been recommended. Note: Dosing Candidiasis, CNS candidiasis, step-down therapy :
dependent on the assumption of 3 times/week, Infants, Children, and Adolescents: Oral, IV:
complete IHD sessions (Heintz 2009). 12 mg/kg/dose once daily following initial therapy
Continuous renal replacement therapy (CRRT) with liposomal amphotericin B (with or without flucy-
(Heintz 2009; Trotman 2005): Drug clearance is tosine); maximum dose: 800 mg/dose; treatment
highly dependent on the method of renal replace- should continue until all signs, symptoms, and CSF
ment, filter type, and flow rate. Appropriate dosing and radiological abnormalities have resolved (IDSA
requires close monitoring of pharmacologic [Pappas 2016]; IDSA [Tunkel 2017]; Red Book
response, signs of adverse reactions due to drug [AAP 2018])
accumulation, as well as drug concentrations in Candidiasis, endophthalmitis, treatment: Oral, IV:
relation to target trough (if appropriate). The follow- Infants, Children, and Adolescents: 12 mg/kg/dose
ing are general recommendations only (based on on day 1 followed by 6 to 12 mg/kg/dose once daily
dialysate flow/ultrafiltration rates of 1 to 2 L/hour for at least 4 to 6 weeks until examination indicates
and minimal residual renal function) and should not resolution; maximum dose 800 mg/dose. Note: Use
supersede clinical judgment: in combination with intravitreal injection of voricona-
CVVH: Loading dose of 400 to 800 mg followed by zole or amphotericin B deoxycholate when vitritis or
200 to 400 mg every 24 hours macular involvement is present (IDSA [Pap-
CVVHD/CVVHDF: Loading dose of 400 to 800 mg pas 2016]).
followed by 400 to 800 mg every 24 hours (CVVHD Candidiasis, esophageal, treatment:
or CVVHDF) or 800 mg every 24 hours (CVVHDF) Non-HIV-exposed/-positive: Infants, Children, and
Note: Higher maintenance doses of 400 mg every 24 Adolescents: IV, Oral: 6 mg/kg/dose once daily for
hours (CVVH), 800 mg every 24 hours (CVVHD), 14 to 21 days. Note: Usual adult dose is 200 to
and 500 to 600 mg every 12 hours (CVVHDF) may 400 mg/day (IDSA [Pappas 2016]; Red Book
be considered when treating resistant organisms [AAP 2018]).
and/or when employing combined ultrafiltration and HIV-exposed/-positive:
dialysis flow rates of ≥2 L/hour for CVVHD/CVVHDF Infants and Children: IV, Oral: 6 to 12 mg/kg/dose
(Heintz 2009; Trotman 2005). once daily for 14 days following symptom reso-
Hepatic Impairment: Adult There are no dosage lution (minimum duration: 21 days); maximum
adjustments provided in the manufacturer's labeling; dose: 600 mg/dose (HHS [OI pediatric 2018])
use with caution. Adolescents: IV, Oral: 100 to 400 mg once daily for
Pediatric 14 to 21 days; may follow with chronic suppres-
General dosing, susceptible infection: Infants, Chil- sive therapy of 100 to 200 mg once daily for
dren, and Adolescents: IV, Oral: Initial: 6 to patients with frequent or severe recurrences
12 mg/kg/dose, followed by 3 to 12 mg/kg/dose once (HHS [OI adult 2018])
daily; duration and dosage depends on severity of Candidiasis, oropharyngeal:
infection; the manufacturer suggests limiting dose to Non-HIV-exposed/-positive: Infants, Children, and
600 mg/dose. Adolescents: IV, Oral: 6 mg/kg/dose on day 1 fol-
Candida infections, prophylaxis: lowed by 3 to 6 mg/kg/dose once daily for ≥14
Oncology patients at high risk of invasive candidiasis days. Note: Usual adult dose is 100 to 200 mg/day
(eg, AML, recurrent ALL, myelodysplastic syn- (Red Book [AAP 2018]).
drome [MDS], HSCT recipients): Limited data avail- HIV-exposed/-positive:
able: Infants, Children, and Adolescents: IV, Oral: 6 Treatment:
to 12 mg/kg/dose once daily; maximum dose: Infants and Children: IV, Oral: 6 to 12 mg/kg/dose
400 mg/dose; duration dependent upon type of once daily for 7 to 14 days; maximum dose:
transplant and/or chemotherapy, consult institu- 400 mg/dose (HHS [OI pediatric 2018])
tion-specific protocols (ESCMID [Hope 2012]; Sci- Adolescents: Oral: 100 mg once daily for 7 to 14
ence 2014) days; may follow with chronic suppressive ther-
Surgical prophylaxis, high-risk patients undergoing apy of 100 mg once daily or 3 times weekly for
liver, pancreas, kidney, or pancreas-kidney trans- patients with frequent or severe recurrences
plantation: Infants, Children, and Adolescents: IV: (HHS [OI adult 2018])
6 mg/kg as a single dose 60 minutes before proce- Secondary prophylaxis, recurrent severe: Infants
dure; maximum dose: 400 mg/dose; time of initia- and Children: Oral: 3 to 6 mg/kg/dose once daily;
tion and duration varies with transplant type, maximum dose: 200 mg/dose (HHS [OI pedia-
consult institution-specific protocols (ASHP/IDSA tric 2018])
[Bratzler 2013]) Candidiasis, peritoneal dialysis-related infections
Candidiasis, systemic (including Candidemia and (ISPD [Warady 2012]):
invasive candidiasis), treatment: Infants, Children, Peritonitis:
and Adolescents: IV, Oral: 12 mg/kg/dose once daily; Treatment: Intraperitoneal, IV, Oral: 6 to 12 mg/kg/
maximum dose: 800 mg/dose; continue treatment for dose every 24 to 48 hours; maximum dose:
14 days after documented clearance and resolution 400 mg/dose
of symptoms (ESCMID [Hope 2012]; IDSA [Pappas Prophylaxis for high-risk situations (eg, during anti-
2016]; Red Book [AAP 2018]) biotic therapy or PEG placement): IV, Oral: 3 to
596
FLUCONAZOLE
6 mg/kg/dose every 24 to 48 hours; maximum CNS, severe pulmonary or disseminate infection,

dose: 200 mg/dose treatment:
Exit-site or tunnel infection, treatment: Oral: 6 mg/kg/ Induction therapy: HIV-exposed/-positive (not first-
dose every 24 to 48 hours; maximum dose: line therapy):
400 mg/dose Infants and Children: IV: 12 mg/kg on day 1, then
Candidiasis, vulvovaginal infection: 10 to 12 mg/kg/dose once daily in combination
Uncomplicated infections, treatment (independent of with amphotericin B or flucytosine for ≥14 days;
maximum dose: 800 mg/dose (HHS [OI pedia-
HIV status): Adolescents: Oral: 150 mg as a single
tric 2018])
dose (CDC [Workowski 2015]; HHS [OI adult 2018])
Adolescents: IV, Oral: 400 to 800 mg once daily in
Severe infections, treatment:
combination with flucytosine for ≥14 days or
Non-HIV-exposed/-positive: Adolescents: Oral: 800 mg once daily in combination with ampho-
150 mg every 72 hours for 2 to 3 doses (CDC tericin for ≥14 days or 1,200 mg once daily as
[Workowski 2015]; IDSA [Pappas 2016]) monotherapy for at least 2 weeks (HHS [OI
HIV-exposed/-positive: Adolescents: Oral: 100 to adult 2018])
200 mg once daily for ≥7 days; may follow with Consolidation:
chronic suppressive therapy of 150 mg once Non-HIV-exposed/-positive: Infants, Children, and
weekly (HHS [OI adult 2018]) Adolescents: IV, Oral: 10 to 12 mg/kg/day once
Recurrent infection, treatment: daily or in divided doses twice daily for 8 weeks;
Non HIV-exposed/-positive: Adolescents: Oral: Ini- maximum dose: 800 mg/dose (IDSA [Perfect
tial: 100 to 200 mg every 72 hours for 3 doses; 2010]; Red Book [AAP 2018])
followed by maintenance of 100 to 200 mg once HIV-exposed/-positive:
weekly for 6 months (CDC [Workowski 2015]; Infants and Children: IV, Oral: 12 mg/kg on day
IDSA [Pappas 2016]) 1, then 10 to 12 mg/kg/day once daily for ≥8
weeks; maximum daily dose: 800 mg/dose
HIV-exposed/-positive: Adolescents: Oral: 100 to
(HHS [OI pediatric 2018])
200 mg once daily for ≥ 7 days; may follow with
Adolescents: IV, Oral: 400 mg once daily for ≥8
chronic suppressive therapy of 150 mg once
weeks (HHS [OI adult 2018])
weekly (HHS [OI adult 2018]) Secondary prophylaxis/chronic suppressive main-
Coccidioidomycosis (HIV-exposed/-positive) (HHS tenance therapy:
[OI adult 2018]; HHS [OI pediatric 2018]): Non-HIV-exposed/-positive: Infants, Children, and
Mild to moderate non-meningeal infection (eg, focal Adolescents: Oral: 6 mg/kg/dose once daily for 6
pneumonia): to 12 months; maximum dose: 200 mg/dose
Infants and Children: IV, Oral: 6 to 12 mg/kg/dose (IDSA [Perfect 2010])
once daily; maximum dose: 400 mg/dose HIV-exposed/-positive: Infants, Children, and Ado-
Adolescents: Oral: 400 mg once daily for ≥6 lescents: Oral: 6 mg/kg/dose once daily for ≥12
months months; maximum dose: 200 mg/dose (HHS [OI
Severe illness (diffuse pulmonary or disseminated adult 2018]; HHS [OI pediatric 2018])
non-meningitic disease) initial therapy if unable to Histoplasmosis: HIV-exposed/-positive patients,
use amphotericin or as step-down therapy: Infants alternative therapy (HHS [OI adult 2018]; HHS [OI
and Children: IV, Oral: 12 mg/kg/dose once daily; pediatric 2018]):
Pulmonary, acute primary disease: Infants and Chil-
maximum dose: 800 mg/dose for a total of 1 year of
dren: Oral: 3 to 6 mg/kg/dose once daily; maximum
treatment followed by secondary prophylaxis
dose: 200 mg/dose
Meningeal infection: Disseminated disease, mild to moderate:
Infants and Children: IV, Oral: 12 mg/kg/dose once Infants and Children: IV, Oral: 5 to 6 mg/kg/dose
daily; maximum dose: 800 mg/dose, followed by twice daily for 12 months; maximum dose:
lifelong secondary prophylaxis 300 mg/dose
Adolescents: IV, Oral: 400 to 800 mg once daily, Adolescents: Oral: 800 mg once daily
followed by lifelong suppressive therapy Secondary prophylaxis/chronic suppressive therapy:
Secondary prophylaxis/chromic suppressive ther- Infants and Children: Oral: 3 to 6 mg/kg/dose once
apy: Infants, Children, and Adolescents: Oral: daily for ≥12 months; maximum dose:
6 mg/kg/dose once daily; maximum dose: 200 mg/dose
400 mg/dose Adolescents: Oral: 400 mg once daily for ≥12
Cryptococcal infection: months
Mild to moderate localized infection including pneu- Renal Impairment: Pediatric
monia (not CNS), treatment: Infants, Children, and Adolescents:
Non HIV-exposed/-positive: Infants, Children, and For multiple dosing, administer usual load then
Adolescents: Oral: 6 to 12 mg/kg/dose once daily adjust daily doses as follows; based upon Schwartz
calculations:
for 6 to 12 months. Usual adult dose is 400 mg/
CrCl >50 mL/minute/1.73 m2: No adjustment nec-
dose (IDSA [Perfect 2010]).
essary.
HIV-exposed/-positive:
CrCl 10 to 50 mL/minute/1.73 m2: Administer 50%
Infants and Children: IV, Oral: 12 mg/kg on day 1, of recommended dose at the normal interval.
then 6 to 12 mg/kg/dose once daily; maximum CrCl ≤10 mL/minute/1.73 m2: Administer 50% of
dose: 600 mg/dose; duration depends on recommended dose every 48 hours (Aron-
severity and clinical response (HHS [OI pediatric off 2007).
2018]) Intermittent hemodialysis: Dialyzable (50%): May
Adolescents: Oral: 400 mg daily for 12 months administer 100% of daily dose (according to indi-
(HHS [OI adult 2018]) cation) after each dialysis session; on nondialysis
597
FLUCONAZOLE
days, patient should receive a reduced dose binding sites (Ahlfors 2001); avoid or use dosage forms
according to their CrCl; some experts have sug- containing benzyl alcohol derivative with caution in neo-
gested the following: Administer 50% of dose nates. See manufacturer’s labeling.
every 48 hours; on dialysis days administer dose Drug Interactions
after dialysis session (Aronoff 2007) Metabolism/Transport Effects Inhibits CYP2C19
Peritoneal dialysis: Administer 50% of recom- (strong), CYP2C9 (moderate), CYP3A4 (moderate)
mended dose every 48 hours (Aronoff 2007) Avoid Concomitant Use
Continuous renal replacement (CRRT): 6 mg/kg/ Avoid concomitant use of Fluconazole with any of the
dose every 24 hours (Aronoff 2007) following: Aprepitant; Astemizole; Asunaprevir; Bosu-
Adolescents: No adjustment required for vaginal can- tinib; Budesonide (Systemic); Cobimetinib; Domperi-
didiasis single-dose therapy. done; Erythromycin (Systemic); Flibanserin;
Hepatic Impairment: Pediatric There are no dos- Fosaprepitant; Ivabradine; Lomitapide; Mizolastine;
age adjustments provided in manufacturer's labeling; Naloxegol; Neratinib; Ospemifene; Pimozide; QuiNI-
use with caution. Dine; Saccharomyces boulardii; Simeprevir; Siponi-
Mechanism of Action Interferes with fungal cyto- mod; Ulipristal; Voriconazole
chrome P450 activity (lanosterol 14-α-demethylase), Increased Effect/Toxicity
decreasing ergosterol synthesis (principal sterol in fun- Fluconazole may increase the levels/effects of: Abe-
gal cell membrane) and inhibiting cell membrane for- maciclib; Acalabrutinib; Alfentanil; Amiodarone; Ami-
mation triptyline; AmLODIPine; Apixaban; Aprepitant;
Contraindications Hypersensitivity to fluconazole or ARIPiprazole; Astemizole; Asunaprevir; AtorvaSTA-
any component of the formulation (cross-reaction with Tin; Avanafil; Avatrombopag; Benzhydrocodone; Blo-
other azole antifungal agents may occur, but has not nanserin; Bosentan; Bosutinib; Brexpiprazole;
been established; use caution); coadministration of Brigatinib; Bromocriptine; Budesonide (Systemic);
terfenadine in adult patients receiving multiple doses Budesonide (Topical); Busulfan; Calcium Channel
of 400 mg or higher or with CYP3A4 substrates which Blockers; Cannabidiol; Cannabis; CarBAMazepine;
may lead to QTc prolongation (eg, astemizole, cisapr- Carvedilol; Ceritinib; Cilostazol; Citalopram; Cobimeti-
ide, erythromycin, pimozide, or quinidine) nib; Colchicine; Crizotinib; CycloSPORINE (Sys-
Warnings/Precautions Serious (and sometimes fatal) temic); CYP2C19 Substrates (High risk with
hepatic toxicity (eg, hepatitis, cholestasis, fulminant Inhibitors); CYP2C9 Substrates (High risk with Inhib-
hepatic failure) has been observed. Use with caution itors); CYP3A4 Substrates (High risk with Inhibitors);
in patients with renal and hepatic dysfunction or pre- Dabigatran Etexilate; Dapoxetine; Deflazacort; Diclo-
vious hepatotoxicity from other azole derivatives. fenac (Systemic); Domperidone; DOXOrubicin (Con-
Patients who develop abnormal liver function tests ventional); Dronabinol; Dronedarone; Eletriptan;
during fluconazole therapy should be monitored closely Eliglustat; Encorafenib; Eplerenone; Erythromycin
and discontinued if symptoms consistent with liver (Systemic); Estrogen Derivatives; Etravirine; Everoli-
disease develop. Rare exfoliative skin disorders have mus; FentaNYL; Flibanserin; Fluvastatin; Fosaprepi-
been observed; fatal outcomes have been reported in tant; Fosphenytoin; GuanFACINE; Haloperidol;
patients with serious concomitant diseases. Monitor HYDROcodone; Ibrutinib; Imatinib; Ivabradine; Ivacaf-
patients with deep seated fungal infections closely for tor; Ivosidenib; Lesinurad; Levomethadone; Lomita-
rash development and discontinue if lesions progress. pide; Lornoxicam; Lovastatin; Lurasidone;
In patients with superficial fungal infections who Manidipine; Methadone; Mirodenafil; Mizolastine; Nal-
develop a rash attributable to fluconazole, treatment demedine; Nalfurafine; Nalmefene; Naloxegol; Nate-
should also be discontinued. Cases of QTc prolongation glinide; Neratinib; Nevirapine; NiMODipine; Olaparib;
and torsade de pointes associated with fluconazole use Ospemifene; OxyCODONE; Parecoxib; Phenytoin;
have been reported (usually high dose or in combina- Pimecrolimus; Pimozide; PredniSONE; Proton Pump
tion with agents known to prolong the QT interval); use Inhibitors; QT-prolonging Antipsychotics (Moderate
caution in patients with concomitant medications or Risk); QT-prolonging Class IA Antiarrhythmics (High-
conditions which are arrhythmogenic. Anaphylaxis has est Risk); QT-prolonging Class III Antiarrhythmics
been reported rarely; use with caution in patients with (Highest Risk); QT-prolonging Kinase Inhibitors (High-
hypersensitivity to other azoles. Potentially significant est Risk); QT-prolonging Kinase Inhibitors (Moderate
drug-drug interactions may exist, requiring dose or Risk); QT-prolonging Miscellaneous Agents (Highest
frequency adjustment, additional monitoring, and/or Risk); QT-prolonging Miscellaneous Agents (Moderate
selection of alternative therapy. May occasionally cause Risk); QT-prolonging Moderate CYP3A4 Inhibitors
dizziness or seizures; use caution driving or operating (Moderate Risk); QT-prolonging Strong CYP3A4
machines. Inhibitors (Moderate Risk); QuiNIDine; Ramelteon;
Ranolazine; Red Yeast Rice; Rifamycin Derivatives;
Powder for oral suspension contains sucrose; use Rupatadine; Ruxolitinib; Salmeterol; SAXagliptin; Sil-
caution with fructose intolerance, sucrose-isomaltase denafil; Silodosin; Simeprevir; Simvastatin; Siponi-
deficiency, or glucose-galactose malabsorption. mod; Sirolimus; Solifenacin; Sonidegib;
Sulfonylureas; SUNItinib; Suvorexant; Tacrolimus
(Systemic); Tadalafil; Tamsulosin; Telithromycin; Tem-
sirolimus; Terfenadine; Tetrahydrocannabinol; Tetra-
hydrocannabinol and Cannabidiol; Tezacaftor;
Theophylline Derivatives; Ticagrelor; Tipranavir; Tofa-
citinib; Tolvaptan; Torsemide; Trabectedin; Udenafil;
Ulipristal; Vardenafil; Venetoclax; Vilazodone; Vin-
CRIStine; Vindesine; Vitamin K Antagonists; Vorico-
nazole; Zidovudine; Zopiclone; Zuclopenthixol
intracranial hemorrhage), hypotension, and cardiovas-
cular collapse (AAP 1997; CDC 1982); some data The levels/effects of Fluconazole may be increased
suggests that benzoate displaces bilirubin from protein by: Amitriptyline; Ceritinib; Domperidone; Encorafenib;
598
FLUCYTOSINE
Etravirine; Ivosidenib; Methadone; Ondansetron; Pen- Although the manufacturer recommends that caution be
tamidine (Systemic); Pimozide; QT-prolonging Antide- exercised when administering fluconazole to breast-
pressants (Moderate Risk); QT-prolonging Class IC feeding women, existing recommendations state that
Antiarrhythmics (Moderate Risk); QT-prolonging Class fluconazole is considered compatible with breastfeed-
III Antiarrhythmics (Highest Risk); QT-prolonging Kin- ing when used in usual recommended doses (WHO
ase Inhibitors (Highest Risk); QT-prolonging Miscella- 2002). Treatment of breastfeeding women with nipple
neous Agents (Highest Risk); QT-prolonging or breast candidiasis with oral fluconazole is common,
Quinolone Antibiotics (Moderate Risk) especially in persistent or recurring infections (Brent
Decreased Effect 2001). Untreated candida nipple or breast infections
Fluconazole may decrease the levels/effects of: may be painful for the mother and can contribute to
Amphotericin B; Clopidogrel; Codeine; Ifosfamide; premature weaning (Brent 2001). The amount of
Losartan; Saccharomyces boulardii fluconazole contained in the breast milk is not suffi-
cient to treat mucocutaneous candidiasis in the infant
The levels/effects of Fluconazole may be decreased (Force 1995; Schilling 1993); concurrent treatment of
by: Didanosine; Etravirine; Rifamycin Derivatives both the breastfeeding infant and mother may be
required (Chetwynd 2002).
Half-life Elimination Normal renal function: ~30
Dosage Forms: US
hours (range: 20 to 50 hours); Elderly: 46.2 hours;
Solution, Intravenous:
Neonates (gestational age 26 to 29 weeks): 73.6 to
Generic: 200 mg (100 mL); 200 mg/100 mL in NaCl
46.6 hours (decreases with increasing postnatal age);
0.9% (100 mL); 400 mg (200 mL)
Pediatric patients 9 months to 15 years: 19.5 to 25
Solution, Intravenous [preservative free]:
hours
Generic: 200 mg (100 mL); 200 mg/100 mL in NaCl
Time to Peak Oral: 1 to 2 hours 0.9% (100 mL); 400 mg (200 mL); 400 mg/200 mL in
Pregnancy Considerations NaCl 0.9% (200 mL)
Following exposure during the first trimester, malforma- Suspension Reconstituted, Oral:
tions have been noted in humans when fluconazole was Diflucan: 10 mg/mL (35 mL); 40 mg/mL (35 mL)
used in higher doses (≥400 mg/day). Abnormalities Generic: 10 mg/mL (35 mL); 40 mg/mL (35 mL)
reported include brachycephaly, abnormal facies, Tablet, Oral:
abnormal calvarial development, cleft palate, femoral Diflucan: 50 mg, 100 mg, 150 mg, 200 mg
bowing, thin ribs and long bones, arthrogryposis, and Generic: 50 mg, 100 mg, 150 mg, 200 mg
congenital heart disease. Use of lower doses (150 mg Dental Health Professional Considerations See
as a single dose) suggest increased risks to the fetus,
however, additional study is needed.
Use of oral fluconazole for vaginal candidiasis is not Flucytosine (floo SYE toe seen)
recommended in pregnant women (HHS [OI adult
2017]; Workowski [CDC 2015]). Most azole antifungals, Brand Names: US Ancobon
including fluconazole, are recommended to be avoided Pharmacologic Category Antifungal Agent, Oral
during the first trimester of pregnancy (IDSA [Pap- Use Candida/Cryptococcus infections: Adjunctive
pas 2016]). treatment of systemic fungal infections (eg, septicemia,
The manufacturer recommends females of childbearing endocarditis, UTI, meningitis, or pulmonary) caused by
potential taking higher doses (≥400 mg/day) use effec- susceptible strains of Candida or Cryptococcus
tive contraception during therapy and for ~1 week after Local Anesthetic/Vasoconstrictor Precautions
the final fluconazole dose. No information available to require special precautions
Breastfeeding Considerations Effects on Dental Treatment No significant effects or
Fluconazole is present in breast milk at concentrations complications reported
similar to maternal plasma concentrations (Force Effects on Bleeding No information available to
1995; Schilling 1993). require special precautions
The relative infant dose (RID) of fluconazole is 5% to Adverse Reactions Frequency not defined.
21% when calculated using the highest breast milk Cardiovascular: Cardiotoxicity, chest pain, ventricular
concentration located and compared to an infant ther- dysfunction
apeutic dose of 3 to 12 mg/kg/day. Central nervous system: Ataxia, confusion, fatigue,
In general, breastfeeding is considered acceptable hallucination, headache, paresthesia, parkinsonian-
when the RID is <10%; when an RID is >25% breast- like syndrome, peripheral neuropathy, psychosis,
feeding should generally be avoided (Anderson 2016; sedation, seizure, vertigo
Ito 2000). Dermatologic: Pruritus, skin photosensitivity, skin rash,
The RID of fluconazole was calculated using a milk toxic epidermal necrolysis, urticaria
concentration of 4.1 mcg/mL, providing an estimated Endocrine & metabolic: Hypoglycemia, hypokalemia
daily infant dose via breast milk of 0.62 mg/kg/day. Gastrointestinal: Abdominal pain, anorexia, diarrhea,
This milk concentration was obtained following mater- duodenal ulcer, enterocolitis, gastrointestinal hemor-
nal administration of oral fluconazole 200 mg daily for rhage, nausea, ulcerative colitis, vomiting, xerostomia
18 days; the apparent elimination half-life of flucona- Genitourinary: Azotemia, crystalluria
zole in breast milk was 26.9 hours (Schilling 1993). Hematologic & oncologic: Agranulocytosis, anemia,
Serious adverse events in breastfeeding infants have aplastic anemia, bone marrow aplasia, eosinophilia,
not been reported following maternal use of flucona- leukopenia, pancytopenia, thrombocytopenia
zole for nipple or breast candidiasis (Bodley 1997; Hepatic: Hepatic injury (acute), hepatic insufficiency,
Chetwynd 2002; Moorhead 2011); flushed cheeks, hepatic necrosis, increased liver enzymes, increased
GI upset, loose stools, mucous feces, and somno- serum bilirubin, jaundice
lence have been reported in breastfed infants (Moor- Hypersensitivity: Hypersensitivity reaction
head 2011). Neuromuscular & skeletal: Weakness
599
FLUCYTOSINE
Otic: Hearing loss Respiratory: Cough (10% to 44%), pneumonia (16%

Renal: Increased blood urea nitrogen, increased serum to 22%), dyspnea (9% to 22%), upper respiratory
creatinine, renal failure tract infection (2% to 16%)
Respiratory: Dyspnea Miscellaneous: Fever (60% to 69%)
Miscellaneous: Fever 1% to 10%:
Mechanism of Action Penetrates fungal cells and is Cardiovascular: Angina pectoris (≤6%), cardiac
converted to fluorouracil which competes with uracil arrhythmia (≤3%), cardiac failure (≤3%), cerebrovas-
interfering with fungal RNA and protein synthesis cular accident (≤3%), myocardial infarction (≤3%),
Pharmacodynamics/Kinetics supraventricular tachycardia (≤3%), deep vein
Half-life Elimination Neonates: 4 to 34 hours (Baley, thrombosis (1% to 3%), phlebitis (1% to 3%), aneur-
1990); Infants: 7.4 hours; Adults: 2 to 5 hours; Anuria: ysm (≤1%), transient ischemic attacks (≤1%)
85 hours (range: 30 to 250); End-stage renal disease Central nervous system: Malaise (6% to 8%), head-
(ESRD): 75 to 200 hours ache (≤3%), sleep disorder (1% to 3%), cerebellar
Time to Peak Serum: Neonates: 2.5 ± 1.3 hours; syndrome (≤1%), depression (≤1%), difficulty think-
Adults: ~1 to 2 hours ing (≤1%)
Dermatologic: Alopecia (≤3%), pruritus (1% to 3%),
seborrhea (≤1%)
Endocrine & metabolic: Hyperglycemia (1% to 6%),
Flucytosine is metabolized to fluorouracil which may
dehydration (≤1%)
cause adverse events if administered during preg-
Gastrointestinal: Stomatitis (≤9%), cholelithiasis
nancy; refer to the Fluorouracil (Systemic) monograph
(≤3%), esophagitis (≤3%), constipation (1% to 3%),
for additional information.
mucositis (≤2%), dysphagia (≤1%)
Genitourinary: Dysuria (3% to 4%), urinary hesitancy
Fludarabine (floo DARE a been) (≤3%), hematuria (2% to 3%), proteinuria (≤1%)
Hematologic & oncologic: Hemorrhage (≤1%), tumor
Brand Names: Canada Fludara; Fludarabine Phos- lysis syndrome (≤1%)
phate for Injection; Fludarabine Phosphate for Injection, Hepatic: Abnormal hepatic function tests (1% to 3%),
USP; Fludarabine Phosphate Injection, PPC STD. hepatic failure (≤1%)
Pharmacologic Category Antineoplastic Agent, Anti- Hypersensitivity: Anaphylaxis (≤1%)
metabolite; Antineoplastic Agent, Antimetabolite Neuromuscular & skeletal: Osteoporosis (≤2%),
(Purine Analog) arthralgia (≤1%)
Use Chronic lymphocytic leukemia (refractory or Otic: Hearing loss (2% to 6%)
progressive): Treatment of B-cell chronic lymphocytic Renal: Renal failure (≤1%), renal function test abnor-
leukemia (CLL) in adults who have not responded to or mality (≤1%)
have progressed during treatment with at least one Respiratory: Pharyngitis (≤9%), hypersensitivity pneu-
standard regimen containing an alkylating agent. monitis (≤6%), hemoptysis (1% to 6%), sinusitis
Local Anesthetic/Vasoconstrictor Precautions (≤5%), bronchitis (≤1%), epistaxis (≤1%), hypo-
No information available to require special precautions xia (≤1%)
Effects on Dental Treatment Key adverse event(s) <1%, postmarketing, and/or case reports: Acquired
related to dental treatment: Stomatitis. blood coagulation disorder, acute myelocytic leukemia
Effects on Bleeding Thrombocytopenia (nadir: 16 (usually associated with prior or concurrent treatment
days) and anemia reported in the majority of patients. with other anticancer agents), adult respiratory dis-
tress syndrome, agitation, autoimmune hemolytic ane-
Adverse Reactions
mia, autoimmune thrombocytopenia, blindness, bone
Frequency not always defined.
marrow aplasia (trilineage), bone marrow depression
>10%:
(trilineage), cerebral hemorrhage, coma, confusion,
Cardiovascular: Edema (8% to 19%) Epstein-Barr-associated lymphoproliferative disorder,
Central nervous system: Fatigue (10% to 38%), neu- erythema multiforme, Evans syndrome, flank pain,
rological signs and symptoms (doses >96 mg/m2/ hemorrhagic cystitis, herpes zoster (reactivation),
day for 5 to 7 days: 36%; doses <125 mg/m2 /cycle: hyperkalemia, hyperphosphatemia, hyperuricemia,
<1%; characterized by cortical blindness, coma, and hypocalcemia, immune thrombocytopenia (autoim-
paralysis; symptom onset may be delayed for 3 to 4 mune), increased liver enzymes, interstitial pneumo-
weeks), pain (20% to 22%), chills (11% to 19%), nitis, malignant neoplasm of skin (new-onset or
paresthesia (4% to 12%) exacerbation), metabolic acidosis, myelodysplastic
Dermatologic: Skin rash (15%), diaphoresis (1% syndrome (usually associated with prior or concurrent
to 13%) treatment with other anticancer agents), myelofibrosis,
Gastrointestinal: Nausea and vomiting (31% to 36%), opportunistic infection, optic neuritis, optic neuropathy,
anorexia (7% to 34%), diarrhea (13% to 15%), gas- pancreatic disease (pancreatic enzymes abnormal),
trointestinal hemorrhage (3% to 13%) pancytopenia, pemphigus, pericardial effusion, periph-
Genitourinary: Urinary tract infection (2% to 15%) eral neuropathy, pneumonitis, progressive multifocal
Hematologic & oncologic: Anemia (60%), neutropenia leukoencephalopathy (PML), pulmonary fibrosis, pul-
(grade 4: 59%; nadir: ~13 days), thrombocytopenia monary hemorrhage, reactivation of latent Epstein-
(55%; nadir: ~16 days), bone marrow depression Barr virus, respiratory distress, respiratory failure,
(nadir: 10 to 14 days; recovery: 5 to 7 weeks; seizure, Stevens-Johnson syndrome, toxic epidermal
dose-limiting toxicity) necrolysis, urate crystalluria, wrist-drop
Infection: Infection (33% to 44%) Mechanism of Action Fludarabine inhibits DNA syn-
Neuromuscular & skeletal: Weakness (9% to 65%), thesis by inhibition of DNA polymerase and ribonucleo-
myalgia (4% to 16%) tide reductase; also inhibits DNA primase and DNA
Ophthalmic: Visual disturbance (3% to 15%) ligase I
600
FLUDROCORTISONE
Pharmacodynamics/Kinetics suggested; an antihypertensive may be necessary

Half-life Elimination 2-fluoro-ara-A: Adults: ~20 if hypertension remains uncontrolled (Endocrine
hours Society [Bornstein 2016]).
Time to Peak Oral: 1 to 2 hours Manufacturer's labeling: Dosing in the prescribing
Pregnancy Risk Factor D information may not reflect current clinical practice.
Pregnancy Considerations Adverse events were 0.1 mg daily; if transient hypertension develops,
observed in animal reproduction studies. Based on reduce dose to 0.05 mg daily; maintenance dosage
the mechanism of action, fludarabine may cause fetal range: 0.1 mg 3 times weekly to 0.2 mg daily.
harm if administered during pregnancy. Effective con- Congenital adrenal hyperplasia, classic (salt-los-
traception should be used to avoid pregnancy during ing adrenogenital syndrome): Oral: 0.05 to
and after treatment for women and men with female 0.2 mg/day in 1 or 2 divided doses (in combination
partners of reproductive potential. with glucocorticoid therapy) (Endocrine Society [Spe-
iser 2018])
Orthostatic hypotension (off-label use; Kearney
Fludrocortisone (floo droe KOR ti sone)
2009; Lahrmann 2006; Lanier 2011): Oral: Initial:
Brand Names: Canada Florinef 0.1 mg daily in conjunction with a high-salt diet and
Generic Availability (US) Yes adequate fluid intake; may be increased in incre-
ments of 0.1 mg per week; maximum dose: 1 mg
Pharmacologic Category Corticosteroid, Systemic
daily. Note: Doses exceeding 0.3 mg daily may not
Use be beneficial and predispose patient to unwanted
Adrenal insufficiency, primary (Addison disease):
side effects (eg, hypertension, hypokalemia).
Partial replacement therapy for primary adrenocortical
Septic shock (off-label use): Note: Corticosteroids
insufficiency
should only be used for septic shock that is not
Congenital adrenal hyperplasia, classic (salt-losing
responsive to volume resuscitation and vasopres-
adrenogenital syndrome): Treatment of classic con-
sors (Rhodes 2017; SCCM/ESICM [Annane 2017]).
genital adrenal hyperplasia (salt-losing adrenogenital
Oral: 0.05 mg once daily (via nasogastric tube) for 7
syndrome)
days (in combination with IV hydrocortisone)
Local Anesthetic/Vasoconstrictor Precautions (Annane 2002; Annane 2018).
Renal Impairment: Adult There are no dosage
use with caution.
Adverse Reactions Frequency not defined. use with caution.
Cardiovascular: Cardiac failure, cardiomegaly, edema,
Pediatric
hypertension
Note: Dosing should be individualized to lowest effec-
Central nervous system: Delirium, depression, emo-
tive dose.
tional lability, euphoria, hallucination, headache,
Adrenal insufficiency, autoimmune (aldosterone
increased intracranial pressure, insomnia, malaise,
deficiency component Addison’s disease);
nervousness, personality changes, pseudotumor cer-
replacement therapy: Limited data available: Oral:
ebri, psychiatric disturbance, psychosis, seizure,
0.05 to 0.2 mg daily (Betterle, 2002; Klieg-
vertigo
man, 2011)
Dermatologic: Acne vulgaris, atrophic striae, diaphore-
sis, erythema, hyperpigmentation, maculopapular Congenital adrenal hyperplasia (salt losers) (eg,
rash, skin atrophy, skin rash, suppression of skin test 21-hydroxylase deficiency): Limited data avail-
reaction, urticaria able: Note: Use in combination with glucocorticoid
Endocrine & metabolic: Cushing’s syndrome, diabetes therapy (eg, hydrocortisone); concurrent sodium
mellitus, glycosuria, growth suppression, hirsutism, replacement therapy may be required, particularly
HPA-axis suppression, hyperglycemia, hypokalemia, in young infants. Oral: Maintenance therapy:
hypokalemic alkalosis, impaired glucose tolerance, Infants, Children, and Adolescents (actively grow-
menstrual disease, negative nitrogen balance ing): Usual range: 0.05 to 0.2 mg daily in 1 or 2
Gastrointestinal: Abdominal distention, esophageal divided doses; doses as high as 0.3 mg/day may
ulcer, pancreatitis, peptic ulcer be necessary (AAP, 2000; AAP, 2010; Spe-
Hematologic & oncologic: Bruise, petechia, purpura iser, 2010)
Hypersensitivity: Anaphylaxis (generalized) Adolescents (fully grown): 0.05 to 0.2 mg once
Local: Lipoatrophy at injection site daily (AAP, 2010; Speiser, 2010)
Neuromuscular & skeletal: Amyotrophy, bone fracture, Renal Impairment: Pediatric There are no dosage
myasthenia, myopathy, osteonecrosis (femoral and adjustments provided in the manufacturer's labeling;
humeral heads), osteoporosis, vertebral compression use with caution.
fracture Hepatic Impairment: Pediatric There are no dos-
Ophthalmic: Cataract, exophthalmos, glaucoma, age adjustments provided in the manufacturer's label-
increased intraocular pressure ing.
Miscellaneous: Wound healing impairment Mechanism of Action Very potent mineralocorticoid
Dosing with high glucocorticoid activity; used primarily for its
Adult & Geriatric mineralocorticoid effects. Promotes increased reab-
Adrenal insufficiency, primary (Addison disease): sorption of sodium and loss of potassium from renal
Oral: Initial: 0.05 to 0.1 mg once daily in the morning distal tubules.
(in combination with hydrocortisone or cortisone). Contraindications
Usual maintenance dose: 0.05 to 0.2 mg once daily. Hypersensitivity to fludrocortisone or any component of
If hypertension develops, dose reduction is the formulation; systemic fungal infections
601
FLUDROCORTISONE
Documentation of allergenic cross-reactivity for cortico- cardiomyopathy has been reported in premature neo-
steroids is limited. However, because of similarities in nates.
chemical structure and/or pharmacologic actions, the Drug Interactions
possibility of cross-sensitivity cannot be ruled out with Metabolism/Transport Effects None known.
certainty. Avoid Concomitant Use
Warnings/Precautions May cause hypercortisolism or Avoid concomitant use of Fludrocortisone with any of
suppression of hypothalamic-pituitary-adrenal (HPA) the following: Aldesleukin; BCG (Intravesical); Cladri-
axis, particularly in younger children or in patients bine; Desmopressin; Indium 111 Capromab Pende-
receiving high doses for prolonged periods. HPA axis tide; Macimorelin; Mifamurtide; MiFEPRIStone;
suppression may lead to adrenal crisis. Withdrawal and Natalizumab; Pimecrolimus; Tacrolimus (Topical)
discontinuation of a corticosteroid should be done Increased Effect/Toxicity
slowly and carefully. Rare cases of anaphylactoid reac- Fludrocortisone may increase the levels/effects of:
tions have been observed in patients receiving cortico- Acetylcholinesterase Inhibitors; Amphotericin B;
steroids. Androgens; Baricitinib; Deferasirox; Desirudin; Des-
Prolonged use may increase risk of infection, mask mopressin; Fingolimod; Leflunomide; Loop Diuretics;
acute infection (including fungal infections), prolong or Natalizumab; Nicorandil; Nonsteroidal Anti-Inflamma-
exacerbate viral infections, or limit response to killed or tory Agents (COX-2 Selective); Nonsteroidal Anti-
inactivated vaccines. Exposure to chickenpox or mea- Inflammatory Agents (Nonselective); Quinolones;
sles should be avoided. Corticosteroids should not be Ritodrine; Sargramostim; Siponimod; Thiazide and
used for cerebral malaria or viral hepatitis. Close obser- Thiazide-Like Diuretics; Tofacitinib; Vaccines (Live);
vation is required in patients with latent tuberculosis Warfarin
(TB) and/or TB reactivity. Restrict use in active TB (only The levels/effects of Fludrocortisone may be
fulminating or disseminated TB in conjunction with increased by: Aprepitant; Cladribine; CYP3A4 Inhib-
antituberculosis treatment). Amebiasis should be ruled itors (Strong); Denosumab; DilTIAZem; Estrogen
out in any patient with recent travel to tropic climates or Derivatives; Fosaprepitant; Indacaterol; MiFEPRI-
unexplained diarrhea prior to initiation of corticoste- Stone; Neuromuscular-Blocking Agents (Nondepola-
roids. Use with extreme caution in patients with Strong- rizing); Ocrelizumab; Pimecrolimus; Roflumilast;
yloides infections; hyperinfection, dissemination and Salicylates; Tacrolimus (Topical); Trastuzumab
fatalities have occurred.
Decreased Effect
Prolonged treatment with corticosteroids has been Fludrocortisone may decrease the levels/effects of:
associated with the development of Kaposi sarcoma Aldesleukin; Antidiabetic Agents; Axicabtagene Cilo-
(case reports); if noted, discontinuation of therapy leucel; BCG (Intravesical); Calcitriol (Systemic); Coc-
should be considered (Goedert 2002). Acute myopathy cidioides immitis Skin Test; Corticorelin; Cosyntropin;
has been reported with high-dose corticosteroids, usu- Hyaluronidase; Indium 111 Capromab Pendetide; Iso-
ally in patients with neuromuscular transmission disor- niazid; Macimorelin; Mifamurtide; Nivolumab; Pidoti-
ders; may involve ocular and/or respiratory muscles; mod; Salic ylates; Sipuleucel-T; Somatropin;
monitor creatine kinase; recovery may be delayed. Tacrolimus (Systemic); Tertomotide; Tisagenlecleucel;
Corticosteroid use may cause psychiatric disturbances, Urea Cycle Disorder Agents; Vaccines (Inactivated);
including euphoria, insomnia, mood swings, personality Vaccines (Live)
changes, severe depression to psychotic manifestation.
Preexisting psychiatric conditions may be exacerbated The levels/effects of Fludrocortisone may be
by corticosteroid use. decreased by: Antacids; Bile Acid Sequestrants;
CYP3A4 Inducers (Strong); Echinacea; MiFEPRI-
Use with caution in patients with GI diseases (divertic- Stone; Mitotane
ulitis, fresh intestinal anastomoses, active or latent Dietary Considerations Systemic use of mineralocor-
peptic ulcer, ulcerative colitis, abscess or other pyo- ticoids/corticosteroids may require a diet with increased
genic infection) due to perforation risk. Use with caution potassium, vitamins A, B6, C, D, folate, calcium, zinc,
in patients with a history of ocular herpes simplex; and phosphorus, and decreased sodium. With fludro-
corneal perforation has occurred; do not use in active cortisone, a decrease in dietary sodium is often not
ocular herpes simplex. Use with caution in patients with required as the increased retention of sodium is usually
renal impairment; hepatic impairment; history of seizure the desired therapeutic effect.
disorder; myasthenia gravis; osteoporosis; diabetes Pharmacodynamics/Kinetics
mellitus; thyroid disease; HF and/or hypertension; in Half-life Elimination Plasma: ≥3.5 hours; Biological:
patients with cataracts and/or glaucoma; and the eld- 18 to 36 hours
erly. Use with caution following acute MI; corticosteroids Pregnancy Risk Factor C
have been associated with myocardial rupture. Poten- Pregnancy Considerations
tially significant interactions may exist, requiring dose or Animal reproduction studies have not been conducted
frequency adjustment, additional monitoring, and/or with fludrocortisone; adverse events have been
selection of alternative therapy. When discontinuing observed with corticosteroids in animal reproduction
therapy, withdraw therapy with gradual tapering of dose. studies. Some studies have shown an association
Patients may require higher doses when subject to
between first trimester systemic corticosteroid use and
stress (ie, trauma, surgery, severe illness).
oral clefts (Park-Wyllie 2000; Pradat 2003). Systemic
Warnings: Additional Pediatric Considerations corticosteroids may also influence fetal growth
May cause osteoporosis (at any age) or inhibition of (decreased birth weight); however, information is con-
bone growth in pediatric patients. Use with caution in flicting (Lunghi 2010). Hypoadrenalism may occur in
patients with osteoporosis. In a population-based study
newborns following maternal use of corticosteroids in
of children, risk of fracture was shown to be increased
pregnancy; monitor.
with >4 courses of corticosteroids; underlying clinical
condition may also impact bone health and osteoporotic When systemic corticosteroids are needed in preg-
effect of corticosteroids (Leonard, 2007). Hypertrophic nancy, it is generally recommended to use the lowest
602
FLUMAZENIL
effective dose for the shortest duration of time, avoiding hiccups, hyperacusis, hypertension, increased blood
high doses during the first trimester (Leachman 2006; pressure, lack of concentration, panic attack, reversi-
Lunghi 2010). Fludrocortisone may be used to treat ble hearing loss, rigors, seizure (including general-
women during pregnancy who require therapy for con- i z e d ) , s e ns at i o n o f c o ld , s h iv e r i n g , s t u p o r,
genital adrenal hyperplasia or primary adrenal insuffi- tachycardia, tinnitus, tongue edema, ventricular tachy-
ciency (Endocrine Society [Bornstein 2016; cardia, voice disorder, withdrawal syndrome
Speiser 2018]). Dosing
Breastfeeding Considerations It is not known if Adult
fludrocortisone is excreted in breast milk; corticoste- Benzodiazepine reversal when used in conscious
roids are excreted in breast milk. The manufacturer sedation or general anesthesia: IV:
recommends that caution be exercised when adminis- Initial dose: 0.2 mg over 15 seconds
tering fludrocortisone to nursing women. Repeat doses (maximum: 4 doses): If the desired
Dosage Forms: US level of consciousness is not obtained, 0.2 mg may
Tablet, Oral: be repeated at 1-minute intervals.
Generic: 0.1 mg Maximum total cumulative dose: 1 mg (usual total
dose: 0.6 to 1 mg). In the event of resedation:
Repeat doses may be given at 20-minute intervals
Flumazenil (FLOO may ze nil) as needed at 0.2 mg per minute to a maximum of
1 mg total dose and 3 mg in 1 hour.
Brand Names: Canada Anexate; Flumazenil Injection;
Management of benzodiazepine overdose: IV:
Flumazenil Injection, USP; Romazicon
Initial dose: 0.2 mg over 30 seconds; if the desired
Generic Availability (US) Yes level of consciousness is not obtained 30 seconds
Pharmacologic Category Antidote after the dose, 0.3 mg can be given over 30
Use seconds
Benzodiazepine reversal when used in conscious Repeat doses: 0.5 mg over 30 seconds repeated at
sedation or general anesthesia: Complete or partial 1-minute intervals
reversal of the sedative effects of benzodiazepines Maximum total cumulative dose: 3 mg (usual total
used in conscious sedation and general anesthesia. dose: 1 to 3 mg).
Management of benzodiazepine overdose: Treat- Patients with a partial response at 3 mg may require
ment of benzodiazepine overdose. (rare) additional titration up to a total dose of 5 mg
Local Anesthetic/Vasoconstrictor Precautions (although doses >3 mg do not reliably produce
No information available to require special precautions additional effects). If a patient has not responded
Effects on Dental Treatment Key adverse event(s) 5 minutes after a cumulative dose of 5 mg, the
related to dental treatment: Xerostomia (normal salivary major cause of sedation is not likely due to benzo-
flow resumes upon discontinuation). diazepines or may be due to exposure to additional
Effects on Bleeding No information available to CNS depressants (eg, opioids). In the event of
require special precautions resedation, repeat doses may be given at 20-
Adverse Reactions minute intervals if needed, at 0.5 mg per minute
>10%: Gastrointestinal: Vomiting (11%) to a maximum of 1 mg total dose and 3 mg in
1% to 10%: 1 hour.
Cardiovascular: Palpitation (3% to 9%), flushing (1% Geriatric Refer to adult dosing. No differences in
to 3%), thrombophlebitis (1% to 3%), vasodilatation safety or efficacy have been reported; however,
(1% to 3%) increased sensitivity may occur in some elderly
Central nervous system: Ataxia (10%), dizziness patients.
(10%), vertigo (10%), agitation (3% to 9%), anxiety Renal Impairment: Adult No dosage adjustment
(3% to 9%), insomnia (3% to 9%), nervousness (3% provided in manufacturer's labeling; however, pharma-
to 9%), depersonalization (1% to 3%), depression cokinetics are not significantly affected by renal failure
(1% to 3%), dysphoria (1% to 3%), emotional lability (CrCl <10 mL/minute) or hemodialysis.
(1% to 3%; including crying), euphoria (1% to 3%), Hepatic Impairment: Adult Initial reversal: No dos-
fatigue (1% to 3%), headache (1% to 3%), hypoes- age adjustment necessary. Repeat doses: Reduce
thesia (1% to 3%), malaise (1% to 3%), paranoia (1% dose or frequency.
to 3%), paresthesia (1% to 3%) Pediatric
Dermatologic: Dermatological disease (skin abnormal- Benzodiazepine reversal when used in con-
ity: 1% to 3%), diaphoresis (1% to 3%), skin rash (1% scious sedation or general anesthesia: Infants,
to 3%) Children, and Adolescents: IV: Initial dose:
Endocrine & metabolic: Hot flash (1% to 3%) 0.01 mg/kg (maximum dose: 0.2 mg) given over
Gastrointestinal: Xerostomia (3% to 9%), nausea (1% 15 seconds; may repeat 0.01 mg/kg (maximum
to 3%) dose: 0.2 mg) after 45 seconds, and then every
Local: Pain at injection site (3% to 9%), injection site minute to a maximum total cumulative dose of
reaction (1% to 3%) 0.05 mg/kg or 1 mg, whichever is lower; usual total
Neuromuscular & skeletal: Weakness (1% to 3%), dose: 0.08 to 1 mg (mean: 0.65 mg)
tremor Suspected benzodiazepine overdose: Limited
Ophthalmic: Blurred vision (3% to 9%), lacrimation data available: Infants, Children, and Adolescents:
(1% to 3%), visual disturbance (1% to 3%) Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg)
Respiratory: Dyspnea (3% to 9%), hyperventilation with repeat doses of 0.01 mg/kg (maximum dose:
(3% to 9%) 0.2 mg) given every minute to a maximum total
<1%, postmarketing, and/or case reports: Atrial tachy- cumulative dose of 1 mg; as an alternative to
cardia (paroxysmal), auditory disturbance, bradycar- repeat bolus doses, follow up continuous infusions
dia, cardiac arrhythmia, chest pain, confusion, of 0.005-0.01 mg/kg/hour have been used (Clark
decreased blood pressure, delirium, drowsiness, fear, 1995; Richard 1991; Roald 1989; Sugarman 1994)
603
FLUMAZENIL
Renal Impairment: Pediatric There are no dosage dysfunction; repeated doses of the drug should be
adjustments provided in the manufacturer’s labeling; reduced in frequency or amount.
adult pharmacokinetic data suggests drug not signifi- Warnings: Additional Pediatric Considerations
cantly affected by renal failure (CrCl <10 mL/minute) Pediatric patients (especially 1 to 5 years of age) may
or hemodialysis. experience resedation; these patients may require
Hepatic Impairment: Pediatric Initial reversal dose: repeat bolus doses or continuous infusion.
Use normal dose; repeat doses should be decreased Drug Interactions
in size or frequency Metabolism/Transport Effects None known.
Mechanism of Action Competitively inhibits the activ- Avoid Concomitant Use There are no known inter-
ity at the benzodiazepine receptor site on the GABA/ actions where it is recommended to avoid concomitant
benzodiazepine receptor complex. Flumazenil does not use.
antagonize the CNS effect of drugs affecting GABA- Increased Effect/Toxicity There are no known sig-
ergic neurons by means other than the benzodiazepine nificant interactions involving an increase in effect.
receptor (ethanol, barbiturates, general anesthetics) Decreased Effect There are no known significant
and does not reverse the effects of opioids interactions involving a decrease in effect.
Contraindications Hypersensitivity to flumazenil, ben- Dietary Considerations Avoid alcohol for the first 24
zodiazepines, or any component of the formulation; hours after administration or as long as the effects of
patients given benzodiazepines for control of potentially benzodiazepines exist.
life-threatening conditions (eg, control of intracranial Pharmacodynamics/Kinetics
pressure or status epilepticus); patients who may have Onset of Action 1-2 minutes; 80% response within 3
ingested or are showing signs of cyclic-antidepressant minutes; Peak effect: 6-10 minutes
overdosage. Duration of Action Resedation occurs after ~1 hour
Warnings/Precautions [US Boxed Warning]: Ben- (range: 19-50 minutes); duration related to dose given
zodiazepine reversal may result in seizures; seiz- and benzodiazepine plasma concentrations; reversal
ures may occur more frequently in patients on effects of flumazenil may wear off before effects of
benzodiazepines for long-term sedation or follow- benzodiazepine
ing tricyclic antidepressant overdose. Dose should Half-life Elimination
be individualized and practitioners should be pre- Children: Terminal: 20-75 minutes (mean: 40 minutes)
pared to manage seizures. Seizures may also Adults: Alpha: 4-11 minutes; Terminal: 40-80 minutes
develop in patients with concurrent major sedative- Moderate hepatic dysfunction: 1.3 hours
hypnotic drug withdrawal, recent therapy with repeated Severe hepatic impairment: 2.4 hours
doses of parenteral benzodiazepines, myoclonic jerking Pregnancy Risk Factor C
or seizure activity prior to flumazenil administration. Use Pregnancy Considerations Teratogenic effects were
with caution in patients relying on a benzodiazepine for not seen in animal reproduction studies. Embryocidal
seizure control. May cause CNS depression, which may effects were seen at large doses. Use during labor and
impair physical or mental abilities; patients must be delivery is not recommended. In general, medications
cautioned about performing tasks which require mental used as antidotes should take into consideration the
alertness (eg, operating machinery or driving) for 24 health and prognosis of the mother; antidotes should be
hours after discharge. administered to pregnant women if there is a clear
Flumazenil may not reliably reverse respiratory depres- indication for use and should not be withheld because
sion/hypoventilation. Flumazenil is not a substitute for of fears of teratogenicity (Bailey 2003).
evaluation of oxygenation; establishing an airway and Breastfeeding Considerations It is not known if
assisting ventilation, as necessary, is always the initial flumazenil is excreted in breast milk. The manufacturer
step in overdose management. Resedation occurs recommends that caution be used if administering to
more frequently in patients where a large single dose breastfeeding women.
or cumulative dose of a benzodiazepine is administered Dosage Forms: US
along with a neuromuscular-blocking agent and multiple Solution, Intravenous:
anesthetic agents. Flumazenil should be used with Generic: 0.5 mg/5 mL (5 mL); 1 mg/10 mL (10 mL)
caution in the intensive care unit because of increased Dental Health Professional Considerations Seda-
risk of unrecognized benzodiazepine dependence in tion: Patients should be monitored for at least 1 hour
such settings. Should not be used to diagnose benzo- following administration of flumazenil to ensure full
diazepine-induced sedation. Reverse neuromuscular recovery. Flumazenil should only be used in an emer-
blockade before considering use. Flumazenil does not gency situation and not as a means of hastening
antagonize the CNS effects of other GABA agonists recovery from conscious sedation. When used to has-
(such as ethanol, barbiturates, or general anesthetics); ten recovery, emergence can be sudden and unpleas-
nor does it reverse opioids. Flumazenil does not con- ant. Flumazenil should be used with caution in patients
sistently reverse amnesia; patient may not recall verbal routinely taking benzodiazepines for other therapeutic
instructions after procedure. uses, withdrawal symptoms will be induced.
Use with caution in patients with a history of panic
disorder; may provoke panic attacks. Use caution in Flunarizine (floo NAR i zeen)
drug and ethanol-dependent patients; these patients
may also be dependent on benzodiazepines. Not rec- Brand Names: Canada Novo-Flunarizine
ommended for treatment of benzodiazepine depend- Pharmacologic Category Calcium Channel Blocker
ence. Use with caution in patients with a head injury; Use Note: Not approved in the US
may alter cerebral blood flow or precipitate convulsions Migraine: Prophylaxis of migraine (with and without
in patients receiving benzodiazepines. Use caution in aura) in patients with frequent and severe attacks,
patients with mixed drug overdoses; toxic effects of who have not responded satisfactorily to other treat-
other drugs taken may emerge once benzodiazepine ments, and/or do not tolerate other therapy (due to
effects are reversed. Use caution in hepatic unacceptable adverse effects).
604
FLUNISOLIDE (ORAL INHALATION)
Limitation of use: Not indicated for treatment of acute Pregnancy Risk Factor C
attacks. Pregnancy Considerations Adverse effects were
Local Anesthetic/Vasoconstrictor Precautions observed in some animal reproduction studies. Intra-
No information available to require special precautions nasal corticosteroids are recommended for the treat-
Effects on Dental Treatment Key adverse event(s) ment of rhinitis during pregnancy; the lowest effective
related to dental treatment: Xerostomia and changes in dose should be used (NAEPP, 2005; Wallace, 2008).
tinuation).
Flunisolide (Oral Inhalation) (floo NISS oh lide)
require special precautions Related Information
Adverse Reactions Frequency not always defined. Respiratory Diseases on page 1467
Central nervous system: Drowsiness (20%), anxiety, Brand Names: US Aerospan [DSC]
depression, dizziness, extrapyramidal reaction,
Pharmacologic Category Corticosteroid, Inhalant
fatigue, insomnia, motor dysfunction, sedation, sleep
(Oral)
disorder, vertigo
Use Asthma: Maintenance treatment of asthma as
prophylactic therapy in patients ≥6 years.
Endocrine & metabolic: Weight gain (15%), galactor-
Limitations of use: Not indicated for relief of acute
rhea, increased serum prolactin, menstrual disease
bronchospasm.
Gastrointestinal: Heartburn, increased appetite, nau-
Guideline recommendations: A low-dose inhaled cor-
sea, stomach pain, vomiting, xerostomia
ticosteroid (in addition to an as-needed short acting
Neuromuscular & skeletal: Myalgia, weakness
beta2-agonist) is the initial preferred long term control
Mechanism of Action Flunarizine is a selective cal- medication for children, adolescents, and adult
cium channel blocker that prevents cellular calcium
overload by reducing excessive transmembrane cal-
for treatment according to a step-wise treatment
cium influx; also has antihistamine properties. Has
approach (GINA 2018; NAEPP 2007).
greater effect on decreasing the frequency of migraine
attacks than on decreasing the severity or duration of
attacks.
Pharmacodynamics/Kinetics Effects on Dental Treatment Key adverse event(s)
Half-life Elimination Variable; Alpha: ~2.4 to 5.5 related to dental treatment: Candida infections of the
hours (single dose); Beta: ~4 days (single dose), pharynx, sore throat, bitter taste, palpitations, dizziness,
~19 days (multidose) headache, nervousness, GI irritation, sneezing, cough-
ing, upper respiratory tract infection, bronchitis,
increased susceptibility to infections, xerostomia (nor-
mal salivary flow resumes upon discontinuation), dry
throat, loss of taste, and diaphoresis.
Product Availability Not available in the US
Flunisolide (Nasal) (floo NISS oh lide) Adverse Reactions Frequency not always defined.
>10%:
Brand Names: Canada Apo-Flunisolide®; Nasalide®; Central nervous system: Headache (9% to 14%)
Rhinalar® Respiratory: Pharyngitis (17% to 18%), rhinitis (4%
Pharmacologic Category Corticosteroid, Nasal to 16%)
Use Rhinitis: Management of the nasal symptoms 1% to 10%:
associated with seasonal or perennial rhinitis Cardiovascular: Chest pain (1% to 3%), edema (1% to
Local Anesthetic/Vasoconstrictor Precautions 3%), capillary fragility (≥1%), chest tightness (≥1%),
No information available to require special precautions hypertension (≥1%), palpitations (≥1%), peripheral
Effects on Dental Treatment Key adverse event(s) edema (≥1%), tachycardia (≥1%)
related to dental treatment: Candida infections of the Central nervous system: Pain (2% to 5%), dizziness
nose, atrophic rhinitis, sneezing, nasal congestion, (1% to 3%), insomnia (1% to 3%), migraine (1% to
nasal dryness and burning, increased susceptibility to 3%), voice disorder (1% to 3%), anosmia (≥1%),
infections, dry throat, epistaxis anxiety (≥1%), depression (≥1%), fatigue (≥1%),
Effects on Bleeding No information available to hyperactivity (≥1%), hypoactivity (≥1%), irritability
require special precautions (≥1%), malaise (≥1%), mood changes (≥1%), numb-
Adverse Reactions ness (≥1%), shakiness (≥1%), vertigo (≥1%)
Frequency not always defined. Dermatologic: Skin rash (2% to 4%), erythema multi-
>10%: forme (1% to 3%), acne vulgaris (≥1%), diaphoresis
Dermatologic: Burning sensation of the nose (≤13%) (≥1%), eczema (≥1%), pruritus (≥1%), urtica-
Respiratory: Nasal congestion (15%), stinging sensa- ria (≥1%)
tion of the nose (≤13%) Endocrine & metabolic: Weight gain (≥1%), adrenal
1% to 10%: suppression, adrenocortical insufficiency, growth
Central nervous system: Anosmia suppression (children and adolescents), hypercorti-
Respiratory: Dry nose, nasal mucosa irritation, rhinitis, coidism
sneezing Gastrointestinal: Vomiting (≤5%), dyspepsia (2% to
<1%, postmarketing, and/or case reports: Nasal 4%), abdominal pain (1% to 3%), diarrhea (1% to
mucosa ulcer 3%), dysgeusia (1% to 3%), gastroenteritis (1% to
Mechanism of Action Decreases inflammation by 3%), nausea (1% to 3%), oral candidiasis (1% to
suppression of migration of polymorphonuclear leuko- 3%), ageusia (≥1%), constipation (≥1%), decreased
cytes and reversal of increased capillary permeability; appetite (≥1%), epigastric fullness (≥1%), flatulence
does not depress hypothalamus (≥1%), glossitis (≥1%), heartburn (≥1%), mouth
605
FLUNISOLIDE (ORAL INHALATION)
irritation (≥1%), sore throat (≥1%), stomach discom- Use

fort (≥1%), oropharyngeal candidiasis Body oil: Treatment of moderate to severe atopic
Genitourinary: Urinary tract infection (1% to 4%), dermatitis in pediatric patients ≥3 months; treatment
dysmenorrhea (1% to 3%), vaginitis (1% to 3%) of atopic dermatitis in adults
Hematologic & oncologic: Lymphadenopathy (≥1%) Cream, ointment, topical solution: Relief of inflam-
Hypersensitivity: Hypersensitivity reaction (4% to 5%) matory and pruritic manifestations of corticosteroid-
Infection: Bacterial infection (4%), infection (1% to responsive dermatoses
3%), cold symptoms (≥1%), influenza (≥1%) Scalp oil: Treatment of psoriasis of the scalp in adults
Neuromuscular & skeletal: Back pain (1% to 3%), Shampoo: Treatment of seborrheic dermatitis of the
myalgia (1% to 3%), neck pain (1% to 3%), weak- scalp
ness (≥1%), decreased bone mineral density Local Anesthetic/Vasoconstrictor Precautions
Ophthalmic: Conjunctivitis (1% to 3%), blurred vision No information available to require special precautions
(≥1%), eye discomfort (≥1%), eye infection (≥1%), Effects on Dental Treatment No significant effects or
cataract, glaucoma, increased intraocular pressure complications reported
Otic: Otalgia (1% to 3%), otitis (≥1%) Effects on Bleeding No information available to
Respiratory: Cough (9%), sinusitis (7% to 9%), epis- require special precautions
taxis (3%), bronchitis (1% to 3%), laryngitis (1% to Adverse Reactions Frequency not defined.
3%), bronchospasm (≥1%), chest congestion (≥1%), Cardiovascular: Intracranial hypertension (rare)
dry throat (≥1%), dyspnea (≥1%), hoarseness (≥1%), Central nervous system: Telangiectasia
increased bronchial secretions (≥1%), nasal conges- Dermatologic: Acneiform eruptions, allergic contact der-
tion (≥1%), nasal mucosa irritation (≥1%), pleurisy matitis, atopic dermatitis (secondary), burning, dry-
(≥1%), pneumonia (≥1%), rhinorrhea (≥1%), sinus ness, erythema, folliculitis, irritation, itching,
congestion (≥1%), sinus discomfort (≥1%), sinus hypertrichosis, hypopigmentation, keratosis pilaris,
drainage (≥1%), sinus infection (≥1%), sneezing miliaria, papules, perioral dermatitis, pustules, shiny
(≥1%), throat irritation (≥1%), upper respiratory tract skin, skin atrophy, striae
infection (≥1%), wheezing (≥1%), exacerbation of Endocrine & metabolic: Cushing's syndrome, HPA axis
asthma suppression
Miscellaneous: Fever (1% to 7%) Otic: Ear infection
Mechanism of Action Decreases airway inflammation Miscellaneous: Herpes simplex, secondary infection
by suppression of endogenous inflammatory mediators Dental Usual Dosage Inflammatory and pruritic man-
(kinins, histamine, liposomal enzymes, prostaglandins). ifestations: Adults: Topical: Apply to oral lesion 4 times/
Inhibits inflammatory cell migration and reverses day, after meals and at bedtime
increased capillary permeability to decrease access of Dosing
inflammatory cells to the site of inflammation; does not Adult & Geriatric Note: Dosage should be based on
depress hypothalamus. severity of disease and patient response; use smallest
Pharmacodynamics/Kinetics amount for shortest period of time. Therapy should be
Half-life Elimination 1.3-1.7 hours discontinued when control is achieved.
Time to Peak Within 5-10 minutes Atopic dermatitis: Topical: Body oil: Apply thin film to
Pregnancy Considerations affected area 3 times daily
Uncontrolled asthma is associated with adverse events Corticosteroid-responsive dermatoses: Topical:
in pregnancy (increased risk of perinatal mortality, pre- Cream, ointment, solution: Apply a thin layer to
eclampsia, preterm birth, low birth weight infants). affected area 2 to 4 times daily; may use occlusive
Poorly controlled asthma or asthma exacerbations dressings to manage psoriasis or recalcitrant con-
may have a greater fetal/maternal risk than what is ditions
associated with appropriately used asthma medications Scalp psoriasis: Topical: Scalp oil: Massage thor-
(ACOG 2008; GINA 2018). oughly into wet or dampened hair/scalp; cover with
shower cap. Leave on overnight (or for at least 4
Inhaled corticosteroids are recommended for the treat-
hours). Remove by washing hair with shampoo and
ment of asthma during pregnancy (ACOG 2008; GINA
rinsing thoroughly.
2018; Namazy 2016). Pregnant females adequately
Seborrheic dermatitis of the scalp: Topical: Sham-
controlled on flunisolide for asthma may continue ther- poo: Apply no more than 1 ounce to scalp once daily;
apy; if initiating treatment during pregnancy, use of an work into lather and allow to remain on scalp for ~5
agent with more data in pregnant females may be minutes. Remove from hair and scalp by rinsing
preferred (Namazy 2016). thoroughly with water.
Product Availability Aerospan has been discontinued Renal Impairment: Adult There are no dosage
in the US for more than 1 year. adjustments provided in the manufacturer's labeling.
Fluocinolone (Topical) (floo oh SIN oh lone) adjustments provided in the manufacturer's labeling.
Pediatric Note: Dosage should be based on severity
Brand Names: US Capex; Derma-Smoothe/FS Body; of disease and patient response; use smallest amount
Derma-Smoothe/FS Scalp; Synalar; Synalar (Cream); for shortest period of time to avoid HPA axis suppres-
Synalar (Ointment); Synalar TS; Xilapak sion. Therapy should be discontinued when control is
Brand Names: Canada Derma-Smoothe/FS; Synalar achieved.
Generic Availability (US) May be product dependent Atopic dermatitis, moderate to severe:
Pharmacologic Category Corticosteroid, Topical Derma-Smoothe/FS body oil (0.01%): Infants ≥3
Dental Use Relief of inflammatory and pruritic manifes- months, Children, and Adolescents: Topical: Mois-
tations (low, medium, high potency topical corticoste- ten skin; apply a thin film to affected area twice
roid) daily; do not use for longer than 4 weeks
606
FLUOCINOLONE (TOPICAL)
Derma-Smoothe/FS scalp oil (0.01%): Limited data antimicrobial therapy. Not for oral, ophthalmic, or intra-
available: Children ≥2 years and Adolescents: vaginal use; do not apply to the face, axillae, groin, or
Topical: Apply a thin film to affected area twice diaper area unless directed by health care provider. Use
daily; do not use longer than 4 weeks the least amount needed to cover the affected area;
Corticosteroid-responsive dermatoses: Synalar discontinue when control is achieved. If improvement is
cream (0.025%), ointment (0.025%), topical solu- not seen within 2 weeks, reassess.
tion (0.01%): Children and Adolescents: Topical:
Apply thin layer 2 to 4 times daily to affected area; Derma-Smoothe/FS products may contain peanut oil;
may use occlusive dressings to manage psoriasis use caution in peanut-sensitive individuals.
or recalcitrant conditions Shampoo: Has not been proven to be effective in
Renal Impairment: Pediatric There are no dosage corticosteroid responsive dermatoses other than sebor-
adjustments provided in the manufacturer's labeling. rheic dermatitis of the scalp.
Hepatic Impairment: Pediatric There are no dos- Warnings: Additional Pediatric Considerations
age adjustments provided in the manufacturer's label- Topical corticosteroids may be absorbed percutane-
ing. ously. The extent of absorption is dependent on several
Mechanism of Action Topical corticosteroids have factors, including epidermal integrity (intact vs abraded
anti-inflammatory, antipruritic, and vasoconstrictive skin), formulation, age of the patient, prolonged dura-
properties. May depress the formation, release, and tion of use, and the use of occlusive dressings. Percuta-
activity of endogenous chemical mediators of inflam- neous absorption of topical steroids is increased in
mation (kinins, histamine, liposomal enzymes, prosta- neonates (especially preterm neonates), infants, and
glandins) through the induction of phospholipase A2 young children. Hypothalamic-pituitary-adrenal (HPA)
inhibitory proteins (lipocortins) and sequential inhibition suppression may occur, particularly in younger children
of the release of arachidonic acid. Fluocinolone has low or in patients receiving high doses for prolonged peri-
to intermediate range potency (dosage-form depend- ods; acute adrenal insufficiency (adrenal crisis) may
ent). occur with abrupt withdrawal after long-term therapy
Contraindications or with stress. Infants and small children may be more
Hypersensitivity to fluocinolone or any component of susceptible to HPA axis suppression or other systemic
the formulation toxicities due to larger skin surface area to body mass
Documentation of allergenic cross-reactivity for cortico- ratio; use with caution in pediatric patients.
steroids is limited. However, because of similarities in
chemical structure and/or pharmacologic actions, the Some dosage forms may contain propylene glycol; in
possibility of cross-sensitivity cannot be ruled out with neonates large amounts of propylene glycol delivered
certainty. orally, intravenously (eg, >3,000 mg/day), or topically
Canadian labeling: Additional contraindications (not in have been associated with potentially fatal toxicities
US labeling): Viral (eg, herpes, varicella) lesions of the which can include metabolic acidosis, seizures, renal
skin; bacterial or fungal skin infections; parasitic infec- failure, and CNS depression; toxicities have also been
tions; skin manifestations relating to tuberculosis or reported in children and adults including hyperosmolal-
syphilis; eruptions following vaccinations; application ity, lactic acidosis, seizures, and respiratory depression;
to the eye use caution (AAP, 1997; Shehab, 2009).
Warnings/Precautions Topical corticosteroids may be Drug Interactions
absorbed percutaneously. Absorption of topical cortico- Metabolism/Transport Effects None known.
steroids may cause manifestations of Cushing syn- Avoid Concomitant Use
drome, hyperglycemia, or glycosuria. Absorption is Avoid concomitant use of Fluocinolone (Topical) with
increased by the use of occlusive dressings, application any of the following: Aldesleukin
to denuded skin, or application to large surface areas. Increased Effect/Toxicity
May cause hypercortisolism or suppression of hypo- Fluocinolone (Topical) may increase the levels/effects
thalamic-pituitary-adrenal (HPA) axis, particularly in of: Deferasirox; Ritodrine
younger children or in patients receiving high doses Decreased Effect
for prolonged periods. HPA axis suppression may lead
Fluocinolone (Topical) may decrease the levels/effects
to adrenal crisis. HPA axis suppression, intracranial
of: Aldesleukin; Corticorelin; Hyaluronidase
hypertension, and Cushing syndrome have been
reported in children receiving topical corticosteroids.
Prolonged use may affect growth velocity; growth Pregnancy Considerations Adverse events have
should be routinely monitored in pediatric patients. been observed with corticosteroids in animal reproduc-
Allergic contact dermatitis can occur, it is usually diag- tion studies. In general, the use of topical corticoste-
nosed by failure to heal rather than clinical exacerba- roids during pregnancy is not considered to have
tion. Prolonged treatment with corticosteroids has been significant risk; however, intrauterine growth retardation
associated with the development of Kaposi sarcoma in the infant has been reported (rare). The use of large
(case reports); if noted, discontinuation of therapy amounts or for prolonged periods of time should be
should be considered (Goedert 2002). Local adverse avoided (Reed 1997).
reactions may occur (eg, skin atrophy, striae, telangiec- Breastfeeding Considerations Systemic corticoste-
tasias, burning, itching, irritation, dryness, folliculitis, roids are excreted in human milk. It is not known if
acneiform eruptions, hypopigmentation, perioral derma- sufficient quantities of fluocinolone are absorbed follow-
titis, allergic contact dermatitis, secondary infection ing topical administration to produce detectable
miliaria); may be irreversible. Local adverse reactions amounts in breast milk. Hypertension in the breastfeed-
are more likely to occur with occlusive and/or prolonged ing infant has been reported following corticosteroid
use. If irritation develops, discontinued use and institute ointment applied to the nipples (Reed 1997). The
appropriate therapy. Concomitant skin infections may manufacturer recommends that caution be exercised
be present or develop during therapy; discontinue if when administering fluocinolone to breastfeeding
dermatological infection persists despite appropriate women.
607
FLUOCINOLONE (TOPICAL)
Dosage Forms: US Dosing

Cream, External: Adult & Geriatric
Synalar: 0.025% (120 g) Atopic dermatitis: Topical:
Generic: 0.01% (15 g, 60 g); 0.025% (15 g, 60 g) Cream, gel, ointment, solution (0.05%): Apply thin
Kit, External: layer to affected area 2 to 4 times daily.
Synalar (Cream): 0.025% Cream (0.1%): Apply thin layer to affected areas
Synalar (Ointment): 0.025% once daily. Not recommended for use >2 consec-
Synalar TS: 0.01% utive weeks or >60 g/week total exposure. Therapy
Xilapak: 0.01% should be discontinued when control is achieved; if
Oil, External: no improvement is seen within 2 weeks, reassess-
ment of diagnosis may be necessary.
Derma-Smoothe/FS Body: 0.01% (118.28 mL)
Psoriasis: Topical:
Derma-Smoothe/FS Scalp: 0.01% (118.28 mL)
Cream, gel, ointment, solution (0.05%): Apply thin
Generic: 0.01% (118.28 mL)
layer to affected area 2 to 4 times daily.
Ointment, External:
Cream (0.1%): Apply a thin layer once or twice daily
Synalar: 0.025% (120 g)
to affected areas. Not recommended for use >2
Generic: 0.025% (15 g, 60 g) consecutive weeks or >60 g/week total exposure.
Shampoo, External: Therapy should be discontinued when control is
Capex: 0.01% (120 mL) achieved; if no improvement is seen within 2
Solution, External: weeks, reassess diagnosis.
Synalar: 0.01% (60 mL, 90 mL) Other inflammatory and pruritic dermatologic con-
Generic: 0.01% (60 mL) ditions besides atopic dermatitis or psoriasis:
Topical:
Fluocinonide (floo oh SIN oh nide) Cream, gel, ointment, solution (0.05%): Apply thin
layer to affected area 2 to 4 times daily.
Related Information Cream (0.1%): Apply thin layer to affected area once
Ulcerative, Erosive, and Painful Oral Mucosal Disorders or twice daily. Not recommended for use >2 con-
on page 1544 secutive weeks or >60 g/week total exposure.
Related Sample Prescriptions Therapy should be discontinued when control is
Ulcerative and Erosive Disorders - Sample Prescrip- achieved; if no improvement is seen within 2
tions on page 47 weeks, reassess diagnosis.
Brand Names: US Vanos Renal Impairment: Adult There are no dosage
Brand Names: Canada Lidemol; Lidex; Lyderm; Tia-
mol; Topactin; Topsyn
Pediatric
Pharmacologic Category Corticosteroid, Topical Atopic dermatitis:
Dental Use Relief of inflammatory and pruritic manifes- Cream, gel, ointment, topical solution (0.05%):
tations (high potency topical corticosteroid) Children and Adolescents: Topical: Apply thin
Use Inflammatory and pruritic dermatologic condi- layer to affected area 2 to 4 times daily depending
tions: Relief of the inflammatory and pruritic manifes- on the severity of the condition. Note: In children
tations of corticosteroid-responsive dermatoses. <12 years, NICE guidelines recommend applying
Local Anesthetic/Vasoconstrictor Precautions only once or twice daily (NICE 2007).
No information available to require special precautions Cream (0.1%): Children ≥12 years and Adoles-
Effects on Dental Treatment No significant effects or cents: Topical: Apply a thin layer once daily to
complications reported affected areas. Not recommended for use >2
Effects on Bleeding No information available to consecutive weeks or >60 g/week total exposure.
require special precautions Therapy should be discontinued when control is
Adverse Reactions Frequency not defined. achieved; if no improvement is seen within 2
Central nervous system: Intracranial hypertension, weeks, reassessment of diagnosis may be nec-
essary.
localized burning
Corticosteroid-responsive dermatoses (includ-
Dermatologic: Acne vulgaris, allergic dermatitis, atro-
ing psoriasis):
phic striae, contact dermatitis, folliculitis, hypertricho-
Cream, gel, ointment, topical solution (0.05%):
sis, hypopigmentation, maceration of the skin, miliaria,
Children and Adolescents: Topical: Apply thin
perioral dermatitis, pruritus, skin atrophy, telangiecta- layer to affected area 2 to 4 times daily depending
sia, xeroderma on the severity of the condition; may use occlusive
Endocrine & metabolic: Cushing's syndrome, glycosu- dressings to manage psoriasis or recalcitrant con-
ria, growth suppression, HPA-axis suppression, hyper- ditions
glycemia Cream (0.1%): Children ≥12 years and Adoles-
Infection: Secondary infection cents: Topical: Apply a thin layer once or twice
Local: Local irritation daily to affected areas. Not recommended for use
Dental Usual Dosage Pruritus and inflammation: Chil- >2 consecutive weeks or >60 g/week total expo-
dren and Adults: Topical (0.05% cream): Apply thin sure. Therapy should be discontinued when con-
layer to affected area 2-4 times/day depending on the trol is achieved; if no improvement is seen within 2
severity of the condition. Therapy should be discontin- weeks, reassess diagnosis.
ued when control is achieved; if no improvement is Renal Impairment: Pediatric There are no dosage
seen, reassessment of diagnosis may be necessary. adjustments provided in the manufacturer's labeling.
608
FLUOCINONIDE
Hepatic Impairment: Pediatric There are no dos- suppression may occur, particularly in younger children
age adjustments provided in the manufacturer's label- or in patients receiving high doses for prolonged peri-
ing. ods; acute adrenal insufficiency (adrenal crisis) may
Mechanism of Action Topical corticosteroids have occur with abrupt withdrawal after long-term therapy
anti-inflammatory, antipruritic, and vasoconstrictive or with stress. Infants and small children may be more
properties. May depress the formation, release, and susceptible to HPA axis suppression or other systemic
activity of endogenous chemical mediators of inflam- toxicities due to larger skin surface area to body mass
mation (kinins, histamine, liposomal enzymes, prosta- ratio; use with caution in pediatric patients.
glandins) through the induction of phospholipase A2 Some dosage forms may contain propylene glycol; in
inhibitory proteins (lipocortins) and sequential inhibition neonates large amounts of propylene glycol delivered
of the release of arachidonic acid. Fluocinonide is orally, intravenously (eg, >3,000 mg/day), or topically
fluorinated corticosteroid considered to be of high have been associated with potentially fatal toxicities
potency. which can include metabolic acidosis, seizures, renal
Contraindications Hypersensitivity to fluocinonide or failure, and CNS depression; toxicities have also been
any component of the formulation reported in children and adults including hyperosmolal-
Warnings/Precautions May cause hypercortisolism or ity, lactic acidosis, seizures and respiratory depression;
suppression of hypothalamic-pituitary-adrenal (HPA) use caution (AAP 1997; Shehab 2009).
axis, particularly in younger children or in patients Drug Interactions
receiving high doses for prolonged periods. HPA axis Metabolism/Transport Effects None known.
suppression may lead to adrenal crisis. Absorption of Avoid Concomitant Use
topical corticosteroids may cause manifestations of Avoid concomitant use of Fluocinonide with any of the
Cushing syndrome, hyperglycemia, or glycosuria. following: Aldesleukin
Absorption is increased by the use of occlusive dress- Increased Effect/Toxicity
ings, application to denuded skin, or application to large Fluocinonide may increase the levels/effects of: Defer-
surface areas. asirox; Ritodrine
Allergic contact dermatitis can occur, it is usually diag- Decreased Effect
nosed by failure to heal rather than clinical exacerba- Fluocinonide may decrease the levels/effects of: Alde-
tion. Local adverse reactions may occur (eg, skin sleukin; Corticorelin; Hyaluronidase
atrophy, striae, telangiectasias, burning, itching, irrita- Pregnancy Risk Factor C
tion, dryness, folliculitis, acneiform eruptions, hypopig- Pregnancy Considerations Adverse events have
mentation, perioral dermatitis, allergic contact been observed with corticosteroids in animal reproduc-
dermatitis, secondary infection miliaria); may be irrever- tion studies. Topical corticosteroids are preferred over
sible. Local adverse reactions are more likely to occur systemic for treating conditions, such as psoriasis or
with occlusive and/or prolonged use. If irritation devel- atopic dermatitis in pregnant women; high-potency cor-
ops, discontinued use and institute appropriate therapy. ticosteroids are not recommended during the first tri-
Concomitant skin infections may be present or develop mester. Topical products are not recommended for
during therapy; discontinue if dermatological infection extensive use, in large quantities, or for long periods
persists despite appropriate antimicrobial therapy. Pro- of time in pregnant women (Bae 2011; Koutroulis 2011;
longed treatment with corticosteroids has been associ- Leachman 2006). Information specific to the use of
ated with the development of Kaposi sarcoma (case fluocinonide during pregnancy is limited (Valkova 2006).
reports); if noted, discontinuation of therapy should be Breastfeeding Considerations Systemic corticoste-
considered. Lower-strength formulations (0.05%) may roids are excreted in human milk. It is not known if
be used cautiously on face or opposing skin surfaces sufficient quantities of fluocinonide are absorbed follow-
that may rub or touch (eg, skin folds of the groin, axilla, ing topical administration to produce detectable
and breasts); higher-strength (0.1%) should not be amounts in breast milk. Do not apply topical cortico-
used on the face, groin, or axillae. Children may absorb steroids to nipples; hypertension was noted in a breast-
proportionally larger amounts after topical application feeding infant exposed to a topical corticosteroid while
and may be more prone to systemic effects. HPA axis breastfeeding (Leachman 2006).
suppression, intracranial hypertension, and Cushing The manufacturer recommends that caution be exer-
syndrome have been reported in children receiving cised when administering fluocinonide 0.05% to nursing
topical corticosteroids. Prolonged use may affect women. Because maternal use of systemic corticoste-
growth velocity; growth should be routinely monitored roids have the potential to cause adverse events in a
in pediatric patients. Treatment beyond 2 consecutive breastfeeding infant (eg, growth suppression, interfere
weeks with the 0.1% cream is not recommended and with endogenous corticosteroid production), the manu-
the total dosage should not exceed 60 g per week; facturer recommends that a decision be made whether
therapy should be discontinued when control of the to discontinue breastfeeding or to discontinue the drug,
disease is achieved; if no improvement is seen within taking into account the importance of treatment to the
2 weeks, reassess diagnosis; do not use more than half mother when using the fluocinonide 0.1%.
of the 120 g tube per week; should not be used in the Dosage Forms: US
treatment of rosacea or perioral dermatitis. Cream, External:
Warnings: Additional Pediatric Considerations Vanos: 0.1% (30 g, 60 g, 120 g)
Topical corticosteroids may be absorbed percutane- Generic: 0.05% (15 g, 30 g, 60 g, 120 g); 0.1% (30 g,
ously. The extent of absorption is dependent on several 60 g, 120 g)
factors, including epidermal integrity (intact vs abraded Gel, External:
skin), formulation, age of the patient, prolonged dura- Generic: 0.05% (15 g, 30 g, 60 g)
tion of use, and the use of occlusive dressings. Percuta- Ointment, External:
neous absorption of topical steroids is increased in Generic: 0.05% (15 g, 30 g, 60 g)
neonates (especially preterm neonates), infants, and Solution, External:
young children. Hypothalamic-pituitary-adrenal (HPA) Generic: 0.05% (20 mL, 60 mL)
609
FLUORIDE
after thoroughly brushing teeth; do not swallow. For

Fluoride (FLOR ide) maximum benefit with PreviDent rinse, do not eat,
drink, or rinse mouth for at least 30 minutes after
Related Information treatment.
Dentifrices Without Sodium Lauryl Sulfate (SLS)a on Gel-Kam rinse: After diluting solution as directed,
page 1604 rinse with 15 mL for 1 minute at least daily, then
Dentin Hypersensitivity, Acid Erosion, High Caries spit. Repeat with remaining solution.
Index, Management of Alveolar Osteitis, and Xerosto- Lozenge: Lozi-FlurOne lozenge daily regardless of
mia on page 1548 fluoride content of drinking water
Brand Names: US Act Kids [OTC]; Act Restoring Pediatric
[OTC]; Act Total Care Dry Mouth [OTC]; Act Total Care Adequate Intake (AI): (IOM, 1997): Infants, Chil-
Sensitive [OTC]; Act Total Care [OTC]; Act [OTC]; dren, and Adolescents: Oral:
CaviRinse [DSC]; Clinpro 5000; ControlRx [DSC]; 1 to 6 months: 0.01 mg/day; additional supplemen-
Denta 5000 Plus; DentaGel; Fluor-A-Day [DSC]; Fluo- tation is not recommended in infants <6 months
rabon; Fluoridex; Fluoridex Daily Renewal; Fluoridex of age
Enhanced Whitening; Fluorinse; Fluoritab; Flura-Drops; 7 to 12 months: 0.5 mg/day
Gel-Kam Rinse; Gel-Kam [OTC]; Just For Kids [OTC]; 1 to 3 years: 0.7 mg/day
Lozi-Flur [DSC]; NeutraCare; NeutraGard Advanced 4 to 8 years: 1 mg/day
[DSC]; Omni Gel [OTC]; OrthoWash; parodontax 9 to 13 years: 2 mg/day
[OTC]; PerioMed; Phos-Flur; Phos-Flur Rinse [OTC]; 14 to 18 years: 3 mg/day
PreviDent; PreviDent 5000 Booster; PreviDent 5000 Dental caries, prevention:
Booster Plus; PreviDent 5000 Dry Mouth; PreviDent Systemic therapy:
5000 Plus; Sensodyne Repair & Protect [OTC]; Stan- Drops/tablets (Fluorabon, Fluor-A-Day, Fluoritab,
Gard Perio Flura-drops): Oral: The recommended oral daily
Brand Names: Canada Fluor-A-Day dose of fluoride is adjusted in proportion to the
Generic Availability (US) Yes: Excludes lozenge fluoride content of available drinking water:
Pharmacologic Category Nutritional Supplement Birth to 6 months: No supplement required
Dental Use Prevention of dental caries regardless of fluoride content of drinking water
Use Prevention of dental caries 6 months to 3 years:
Local Anesthetic/Vasoconstrictor Precautions <0.3 ppm: 0.25 mg once daily
No information available to require special precautions ≥0.3 ppm: No supplement required
Effects on Dental Treatment Key adverse event(s) 3 to 6 years:
related to dental treatment: Products containing stan- <0.3 ppm: 0.5 mg once daily
nous fluoride may stain teeth. See Dental Health Pro- 0.3 to 0.6 ppm: 0.25 mg once daily
fessional Considerations. >0.6 ppm: No supplement required
Effects on Bleeding No information available to 6 to 16 years:
require special precautions <0.3 ppm: 1 mg once daily
Adverse Reactions Frequency not defined. 0.3 to 0.6 ppm: 0.5 mg once daily
Dermatologic: Skin rash >0.6 ppm: No supplement required
Gastrointestinal: Dental discoloration (with products Lozenges (Lozi-Flur): Children ≥6 years and Ado-
containing stannous fluoride; temporary), nausea lescents: Oral: 1 lozenge daily; allow lozenge to
Hypersensitivity: Hypersensitivity reaction dissolve slowly in the mouth and swallow with
Dosing saliva. Note: For use in areas where the fluoride
Adult & Geriatric content of drinking water is <0.3 ppm.
Cream or paste: Topical therapy:
Clinpro 5000 paste, Control Rx 1.1%, Denta 5000 Dental rinse: Note: Do not eat, drink, or rinse
Plus: Once daily, in place of conventional tooth- mouth for at least 30 minutes after treatment;
paste, brush teeth with a thin ribbon or pea-sized do not swallow.
amount of paste for at least 2 minutes. Brush teeth Acidulated phosphate fluoride rinse (Phos-Flur):
with cream or paste once daily regardless of fluo- Children ≥6 years and Adolescents: Topical: 10
ride content of drinking water mL once daily after brushing; swish between
Prevident 5000 Sensitive: Twice daily, brush teeth teeth for 1 minute, then spit.
with a 1 inch strip of toothpaste for at least 1 minute. Sodium fluoride: Topical:
After brushing, expectorate and rinse mouth thor- 0.02% Sodium fluoride (ACT Restoring, ACT
oughly. Brush teeth twice daily regardless of fluo- Total Care): Children ≥6 years and Adoles-
ride content of drinking water cents: 10 mL swish and spit twice daily after
Dental rinse or gel: brushing
ACT Restoring 0.02% rinse, ACT Total Care 0.02% 0.05% Sodium fluoride (ACT Anticavity Rinse,
rinse: Twice daily after brushing, rinse 10 mL ACT Kids): Children ≥6 years and Adoles-
around and between teeth for 1 minute, then spit. cents: 10 mL swish and spit once daily after
Do not eat, drink, or rinse mouth for at least 30 brushing
minutes after treatment; do not swallow 0.2% Neutral sodium fluoride (CaviRinse, Pre-
ACT 0.05% rinse, Phos-Flur Rinse: Once daily after viDent Rinse): Children ≥6 years and Adoles-
brushing, rinse 10 mL around and between teeth for cents: 10 mL swish and spit once weekly,
1 minute, then spit. Do not eat, drink, or rinse mouth preferably at bedtime after brushing. Note:
for at least 30 minutes after treatment; do not CaviRinse labeling recommends children
swallow and adolescents 6 to 16 years rinse with
Cavirinse, PreviDent rinse: Once weekly, rinse 10 mL water immediately following treatment.
vigorously around and between teeth for 1 minute, Stannous fluoride 0.63% (Gel-Kam): Children
then spit; this should be done preferably at bedtime, ≥12 years and Adolescents: Topical: After
610
FLUORIDE
diluting solution as directed, rinse with 15 mL containing polysorbate 80 in certain individuals (Isaks-
for 1 minute, then spit; repeat with remaining son, 2002; Lucente 2000; Shelley, 1995). Thrombocy-
solution. Use at least once daily. topenia, ascites, pulmonary deterioration, and renal and
Gel: Stannous fluoride 0.4% (Just for Kids): Chil- hepatic failure have been reported in premature neo-
dren ≥6 years and Adolescents: Topical: Once nates after receiving parenteral products containing
daily after brushing, apply a pea-sized amount of polysorbate 80 (Alade, 1986; CDC, 1984). See manu-
gel to teeth and brush thoroughly. Allow gel to facturer’s labeling.
remain on teeth for 1 minute prior to spitting out. Warnings: Additional Pediatric Considerations
Do not eat or drink for 30 minutes after using. Supervise children <12 years of age using topical
Paste: Sodium fluoride 1.1%: Topical: fluoride products, especially children <6 years old, to
Clinpro 5000, Control Rx, Denta 5000 Plus: prevent repeated swallowing; swallowing should be
Children ≥6 years and Adolescents: Once daily, minimized with topical products (eg, creams, gels,
preferably at bedtime, in place of conventional rinses).
toothpaste; brush teeth with a thin ribbon or
pea-sized amount of toothpaste for at least 2 Some dosage forms may contain propylene glycol; in
minutes; after brushing expectorate and rinse neonates large amounts of propylene glycol delivered
mouth thoroughly with water. orally, intravenously (eg, >3,000 mg/day), or topically
PreviDent 5000 Sensitive: Children ≥12 years have been associated with potentially fatal toxicities
and Adolescents: Twice daily, brush teeth with which can include metabolic acidosis, seizures, renal
a 1-inch strip of toothpaste for at least 1 minute. failure, and CNS depression; toxicities have also been
After brushing, expectorate and rinse mouth reported in children and adults including hyperosmolal-
thoroughly. ity, lactic acidosis, seizures, and respiratory depression;
Dental varnish: 5% Sodium Fluoride (2.26% Fluo- use caution (AAP, 1997; Shehab, 2009).
ride ion): Infants (after primary tooth eruption), Drug Interactions
Children and Adolescents: Topical: Apply a thin Metabolism/Transport Effects None known.
layer of varnish to surfaces of teeth at least every Avoid Concomitant Use There are no known inter-
3 to 6 months (ADA [Weyant], 2013). Note: Must actions where it is recommended to avoid concomitant
be professionally applied; USPSTF recommends use.
dental varnish may be applied by primary care Increased Effect/Toxicity There are no known sig-
practitioners to the primary teeth of all infants nificant interactions involving an increase in effect.
and children starting at the age of primary tooth Decreased Effect There are no known significant
eruption through 5 years of age (USPSTF, interactions involving a decrease in effect.
2014): Dietary Considerations Do not administer with dairy
Mechanism of Action Promotes remineralization of products.
decalcified enamel; inhibits the cariogenic microbial Pregnancy Risk Factor B
process in dental plaque; increases tooth resistance Pregnancy Considerations Fluoride crosses the pla-
to acid dissolution centa and can be found in the fetal circulation (IOM,
Contraindications 1997). Adverse events have not been observed in
Fluor-A-Day: When fluoride content of drinking water animal reproduction studies; epidemiological studies in
exceeds 0.6 ppm; patients with arthralgia, GI ulcer- areas with high levels of fluorinated water have not
ation, chronic renal insufficiency and failure, or osteo- shown an increase in adverse effects. Heavy exposure
malacia in utero may be linked to skeletal fluorosis seen later in
Fluorabon: When fluoride content of drinking water childhood.
exceeds 0.6 ppm Breastfeeding Considerations Low concentrations
Fluoritab: Patients with dental fluorosis of fluoride can be found in breast milk and the amount
Flura-Drops, Loziflur: When fluoride content of drinking is not significantly affected by supplementation or con-
water is ≥0.3 ppm centrations in drinking water (IOM, 1997). The manu-
Warnings/Precautions Prolonged ingestion with facturer recommends that caution be exercised when
excessive doses may result in dental fluorosis and administering fluoride to nursing women.
osseous changes; do not exceed recommended dos- Dosage Forms: US
age. Some products contain tartrazine. Cream, oral:
Denta 5000 Plus: 1.1% (51 g)
PreviDent 5000 Plus: 1.1% (51 g)
Gel, oral:
PreviDent 5000 Booster: 1.1% (100 mL)
PreviDent 5000 Booster Plus: 1.1% (100 mL)
PreviDent 5000 Dry Mouth: 1.1% (100 mL)
Gel, topical:
DentaGel: 1.1% (56 g)
Gel-Kam [OTC]: 0.4% (129 g)
intracranial hemorrhage), hypotension, and cardiovas-
Just For Kids [OTC]: 0.4% (122 g)
cular collapse (AAP ["Inactive" 1997]; CDC, 1982);
NeutraCare: 1.1% (60 g)
some data suggests that benzoate displaces bilirubin
Omni Gel [OTC]: 0.4% (122 g); 0.4% (122 g)
from protein binding sites (Ahlfors, 2001); avoid or use
Phos-Flur: 1.1% (51 g)
dosage forms containing benzyl alcohol derivative with
PreviDent: 1.1% (56 g)
caution in neonates. See manufacturer’s labeling.
Paste, oral:
Polysorbate 80: Some dosage forms may contain poly- Clinpro 5000: 1.1% (113 g)
sorbate 80 (also known as Tweens). Hypersensitivity Fluoridex: 1.1% (112 g)
reactions, usually a delayed reaction, have been Fluoridex Enhanced Whitening: 1.1% (112 g)
reported following exposure to pharmaceutical products parodontax [OTC]: 0.454% (96.4 g)
611
FLUORIDE
Sensodyne Repair & Protect [OTC]: 0.454% (96.4 g) ophthalmic drops is not known. If ophthalmic agents
Solution, oral: are needed during pregnancy, the minimum effective
Act [OTC]: 0.05% (532 mL) dose should be used in combination with punctual
Act Kids [OTC]: 0.05% (500 mL, 532 mL) occlusion to decrease potential exposure to the fetus
Act Restoring [OTC]: 0.02% (1000 mL); 0.05% (Samples 1988).
(532 mL)
Act Total Care [OTC]: 0.05% (90 mL, 532 mL,
1000 mL)
Fluorouracil (Systemic) (flure oh YOOR a sil)
Fluorabon: 0.55 mg/0.6 mL (60 mL) Brand Names: US Adrucil

Fluoridex Daily Renewal: 0.63% (248 mL) Brand Names: Canada Fluorouracil Injection
Fluorinse: 0.2% (480 mL) Pharmacologic Category Antineoplastic Agent, Anti-
Fluoritab: 0.275 mg/drop metabolite; Antineoplastic Agent, Antimetabolite (Pyri-
Flura-Drops: 0.55 mg/drop (24 mL) midine Analog)
Gel-Kam Rinse: 0.63% (300 mL)
Use
OrthoWash: 0.044% (480 mL)
Breast cancer: Management of breast cancer
PerioMed: 0.63% (284 mL)
Colon and rectal cancer: Management of colon and
Phos-Flur Rinse [OTC]: 0.044% (473 mL, 500 mL)
rectal cancer
PreviDent: 0.2% (473 mL)
Gastric cancer: Management of stomach (gastric)
StanGard Perio: 0.63% (284 mL)
cancer
Tablet, chewable, oral:
Pancreatic cancer: Management of pancreatic cancer
Fluoritab: 1.1 mg, 2.2 mg
Generic: 0.55 mg, 1.1 mg, 2.2 mg
Dental Health Professional Considerations Neu-
tral pH fluoride preparations are preferred in patients
related to dental treatment: Stomatitis.
with oral mucositis to reduce tissue irritation; long-term
use of acidulated fluorides has been associated with Effects on Bleeding Thrombocytopenia and anemia
enamel demineralization and damage to porcelain can occur during systemic therapy.
crowns Adverse Reactions Frequency not defined. Toxicity
depends on duration of treatment and/or rate of admin-
istration.
Fluorometholone (flure oh METH oh lone) Cardiovascular: Angina pectoris, cardiac arrhythmia,
cardiac failure, cerebrovascular accident, ischemic
Brand Names: US Flarex; FML; FML Forte; FML heart disease, local thrombophlebitis, myocardial
Liquifilm infarction, vasospasm, ventricular ectopy
Brand Names: Canada Flarex; FML; FML Forte; Central nervous system: Cerebellar syndrome (acute),
PMS-Fluorometholone; Sandoz-Fluorometholone confusion, disorientation, euphoria, headache
Pharmacologic Category Corticosteroid, Ophthalmic Dermatologic: Alopecia, changes in nails (including nail
Use Ocular inflammation: Treatment of steroid-respon- loss), dermatitis, hyperpigmentation (supravenous),
sive inflammation of the palpebral and bulbar conjunc- maculopapular rash (pruritic), palmar-plantar erythro-
tiva, cornea, and anterior segment of the eye dysesthesia, skin fissure, skin photosensitivity, Ste-
Local Anesthetic/Vasoconstrictor Precautions vens-Johnson syndrome, toxic epidermal necrolysis,
No information available to require special precautions xeroderma
Effects on Dental Treatment No significant effects or Gastrointestinal: Anorexia, diarrhea, esophagopharyng-
complications reported itis, gastrointestinal hemorrhage, gastrointestinal
Effects on Bleeding No information available to ulcer, mesenteric ischemia (acute), nausea, stomatitis,
require special precautions tissue sloughing (gastrointestinal), vomiting
Adverse Reactions Frequency not defined. Hematologic & oncologic: Agranulocytosis, anemia,
Dermatologic: Skin rash leukopenia (nadir: days 9 to 14; recovery by day 30),
Endocrine & metabolic: Hypercorticoidism (rare) pancytopenia, thrombocytopenia
Gastrointestinal: Dysgeusia Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Hypersensitivity: Hypersensitivity reaction (generalized)
Ophthalmic: Bacterial eye infection (secondary), blurred Ophthalmic: Lacrimal stenosis, lacrimation, nystagmus,
vision, burning sensation of eyes, cataract, decreased photophobia, visual disturbance
visual acuity, erythema of eyelid, eye discharge, eye Respiratory: Epistaxis
irritation, eyelid edema, eye pain, eye pruritus, foreign <1%, postmarketing, and/or case reports: Dysgeusia
body sensation of eye, fungal eye infection (secon- (Syed 2016)
dary), glaucoma, increased intraocular pressure, Mechanism of Action Fluorouracil is a pyrimidine
increased lacrimation, optic nerve damage, stinging analog antimetabolite that interferes with DNA and
of eyes, swelling of eye, viral eye infection (secon- RNA synthesis; after activation, F-UMP (an active
dary), visual field defect, wound healing impairment metabolite) is incorporated into RNA to replace uracil
Mechanism of Action Corticosteroids inhibit the and inhibit cell growth; the active metabolite F-dUMP,
inflammatory response including edema, capillary dila- inhibits thymidylate synthetase, depleting thymidine
tion, leukocyte migration, and scar formation. Fluoro- triphosphate (a necessary component of DNA synthe-
metholone penetrates cells readily to induce the sis).
production of lipocortins. These proteins modulate the Pharmacodynamics/Kinetics
activity of prostaglandins and leukotrienes. Half-life Elimination Following bolus infusion: 8 to 20
Pregnancy Considerations Adverse events were minutes
observed in animal reproduction studies following use Pregnancy Risk Factor D
of ophthalmic fluorometholone. The extent of systemic Pregnancy Considerations Adverse effects
absorption following topical application of the ( i n c r e a s e d r e s o r p t i o n s , e m b r y o l e t h a l i t y, a n d
612
FLUOXETINE
teratogenicity) have been observed in animal reproduc- depression (patients with MDD who do not respond
tion studies. Based on the mechanism of action, fluo- to 2 separate trials of different antidepressants of
rouracil may cause fetal harm if administered during adequate dose and duration in the current episode)
pregnancy (according to the manufacturer’s labeling). in combination with olanzapine or other antipsychotics
Females of reproductive potential and male patients (APA 2010)
with female partners of reproductive potential should Local Anesthetic/Vasoconstrictor Precautions
use effective contraception during treatment and for 3 Although caution should be used in patients taking
months following cessation of fluorouracil therapy. tricyclic antidepressants, no interactions have been
Chemotherapy, if indicated, may be administered to reported with vasoconstrictors and fluoxetine, a non-
pregnant women with breast cancer as part of a combi- tricyclic antidepressant which acts to increase seroto-
nation chemotherapy regimen (common regimens nin; no precautions appear to be needed. Fluoxetine is
administered during pregnancy include doxorubicin [or one of the drugs confirmed to prolong the QT interval
epirubicin], cyclophosphamide, and fluorouracil); che- and is accepted as having a risk of causing torsade de
motherapy should not be administered during the first pointes. The risk of drug-induced torsade de pointes is
trimester, after 35 weeks' gestation, or within 3 weeks of extremely low when a single QT interval prolonging
planned delivery (Amant 2010; Loibl 2006). The Euro- drug is prescribed. In terms of epinephrine, it is not
pean Society for Medical Oncology has published known what effect vasoconstrictors in the local anes-
guidelines for diagnosis, treatment, and follow-up of thetic regimen will have in patients with a known history
cancer during pregnancy. The guidelines recommend of congenital prolonged QT interval or in patients taking
referral to a facility with expertise in cancer during any medication that prolongs the QT interval. Until more
pregnancy and encourage a multidisciplinary team information is obtained, it is suggested that the clinician
(obstetrician, neonatologist, oncology team). In general, consult with the physician prior to the use of a vaso-
if chemotherapy is indicated, it should be avoided constrictor in suspected patients, and that the vaso-
during in the first trimester, there should be a 3-week constrictor (epinephrine, mepivacaine and
time period between the last chemotherapy dose and levonordefrin [Carbocaine 2% with Neo-Cobefrin]) be
anticipated delivery, and chemotherapy should not be used with caution.
administered beyond week 33 of gestation (Pecca- Effects on Dental Treatment Key adverse event(s)
tori 2013). related to dental treatment: Xerostomia (normal salivary
flow resumes upon discontinuation) and taste perver-
Fertility (male and female) may be impaired during sion. Problems with SSRI-induced bruxism have been
fluorouracil treatment. reported and may preclude their use. Clinicians
attempting to evaluate any patient with bruxism or
FLUoxetine (floo OKS e teen) involuntary muscle movement, who is simultaneously
being treated with an SSRI drug, should be aware of
Related Information this potential association (see Effects on Bleeding and
Clinical Risk Related to Drugs Prolonging QT Interval Dental Health Professional Considerations)
on page 1462 Effects on Bleeding Selective serotonin reuptake
Management of the Patient With Anxiety or Depression inhibitors such as fluoxetine may impair platelet aggre-
on page 1564 gation due to platelet serotonin depletion, possibly
Vasoconstrictor Interactions With Antidepressants on increasing the risk of a bleeding complication. The risk
page 1606 of a bleeding complication can be increased by coad-
Brand Names: US PROzac; PROzac Weekly [DSC]; ministration of other antiplatelet agents such as NSAIDs
Sarafem and aspirin.
Brand Names: Canada Prozac Adverse Reactions As reported in adults, unless
Pharmacologic Category Antidepressant, Selective otherwise noted.
Serotonin Reuptake Inhibitor >10%:
Use Central nervous system: Insomnia (10% to 33%),
Bipolar major depression (excluding Sarafem): headache (21%), drowsiness (5% to 17%), anxiety
Acute treatment of major depressive episodes (in (6% to 15%), nervousness (8% to 14%), yawn-
combination with olanzapine or other antipsychotics) ing (≤11%)
(WFSBP [Grunze 2010]) associated with bipolar I Endocrine & metabolic: Decreased libido (4% to 11%)
disorder Gastrointestinal: Nausea (12% to 29%), diarrhea (8%
Bulimia nervosa (excluding Sarafem): Acute and to 18%), anorexia (4% to 17%), xerostomia (9%
maintenance treatment of binge eating and vomiting to 12%)
behaviors in patients with moderate to severe bulimia Neuromuscular & skeletal: Weakness (9% to 21%),
nervosa tremor (3% to 13%)
Major depressive disorder (unipolar) (excluding Respiratory: Pharyngitis (10% to 11%)
Sarafem): Acute and maintenance treatment of uni- 1% to 10%:
polar major depressive disorder (MDD) Cardiovascular: Vasodilation (1% to 5%), palpitations
Obsessive-compulsive disorder (excluding Sara- (≥1%), prolonged Q-T interval on ECG (≥1%; QTcF
fem): Acute and maintenance treatment of obsessions ≥450 msec3), chest pain, hypertension
and compulsions in patients with obsessive-compul- Central nervous system: Dizziness (9%), abnormal
sive disorder dreams (5%), agitation (children and adolescents:
Panic disorder (excluding Sarafem): Acute treatment ≥2%), personality disorder (children and adoles-
of panic disorder with or without agoraphobia cents: ≥2%), abnormality in thinking (2%), chills
Premenstrual dysphoric disorder (Sarafem only): (≥1%), emotional lability (≥1%), amnesia, confusion,
Treatment of premenstrual dysphoric disorder sleep disorder
Treatment-resistant depression (excluding Sara- Dermatologic: Diaphoresis (7% to 8%), skin rash (4%
fem): Acute treatment of treatment-resistant to 6%), pruritus (3%)
613
FLUOXETINE
Endocrine & metabolic: Hypermenorrhea (children Pregnancy Considerations

and adolescents: ≥2%), increased thirst (children Adverse events have been observed in animal repro-
an d ad ole sc ents : ≥2 %), weig ht los s (2 %), duction studies. Fluoxetine and its metabolite cross the
weight gain human placenta. Available studies evaluating terato-
Gastrointestinal: Dyspepsia (6% to 10%), constipation genic effects following maternal use of fluoxetine in
(5%), flatulence (3%), vomiting (3%), dysgeusia the first trimester have shown inconsistent results. An
(≥1%), increased appetite increased risk of cardiovascular events was observed in
Genitourinary: Ejaculatory disorder (≤7%), impotence one study; however, no specific pattern was observed
(≤7%), urinary frequency (children and adolescents: and a causal relationship has not been established.
≥2%), urination disorder (≥1%) Nonteratogenic effects in the newborn following SSRI/
Neuromuscular & skeletal: Hyperkinesia (children and SNRI exposure late in the third trimester include respi-
adolescents: ≥2%) ratory distress, cyanosis, apnea, seizures, temperature
Ophthalmic: Visual disturbance (2%) instability, feeding difficulty, vomiting, hypoglycemia,
Otic: Otalgia, tinnitus hypo- or hypertonia, hyper-reflexia, jitteriness, irritabil-
Respiratory: Flu-like symptoms (8% to 10%), sinusitis ity, constant crying, and tremor. Symptoms may be due
(5% to 6%), epistaxis (children and adoles- to the toxicity of the SSRIs/SNRIs or a discontinuation
cents: ≥2%) syndrome and may be consistent with serotonin syn-
<1%, postmarketing, and/or case reports: Abnormal drome associated with SSRI treatment. Persistent pul-
hepatic function tests, acne vulgaris, acute abdominal monary hypertension of the newborn (PPHN) has also
condition, akathisia, albuminuria, alopecia, amenor- been reported with SSRI exposure. The long-term
rhea, anaphylactoid reaction, anemia, angina pectoris, effects of in utero SSRI exposure on infant development
angle-closure glaucoma, aphthous stomatitis, aplastic and behavior are not known.
anemia, arthritis, asthma, ataxia, atrial fibrillation, Due to pregnancy-induced physiologic changes,
bruise, bruxism, bursitis, cardiac arrhythmia, cardiac women who are pregnant may require dose adjust-
failure, cataract, cerebrovascular accident, cholelithia- ments of fluoxetine to achieve euthymia. The ACOG
sis, cholestatic jaundice, colitis, dehydration, delu- recommends that therapy with SSRIs or SNRIs during
sions, depersonalization, dyskinesia, dysphagia, pregnancy be individualized; treatment of depression
dysuria, ecchymoses, edema, eosinophilic pneumo- during pregnancy should incorporate the clinical exper-
nitis, equilibrium disturbance, erythema multiforme, tise of the mental health clinician, obstetrician, primary
erythema nodosum, esophagitis, euphoria, exfoliative health care provider, and pediatrician. According to the
dermatitis, extrapyramidal reaction (rare), gastritis, American Psychiatric Association (APA), the risks of
gastroenteritis, gastrointestinal ulcer, glossitis, gout, medication treatment should be weighed against other
gynecological bleeding, gynecomastia, hallucination, treatment options and untreated depression. For
hemolytic anemia (immune-related), hepatic failure, women who discontinue antidepressant medications
hepatic necrosis, hepatitis, hiccups, hostility, hyper- during pregnancy and who may be at high risk for
cholesteremia, hyperprolactinemia, hypersensitivity postpartum depression, the medications can be
reaction, hypertonia, hyperventilation, hypoglycemia, restarted following delivery. Treatment algorithms have
hypokalemia, hyponatremia (possibly in association been developed by the ACOG and the APA for the
with SIADH), hypotension, hypothyroidism, immune management of depression in women prior to concep-
thrombocytopenia, laryngeal edema, laryngospasm, tion and during pregnancy.
leg cramps, lupus-like syndrome, malaise, melena, Pregnant women exposed to antidepressants during
memory impairment, migraine, mydriasis, myocardial pregnancy are encouraged to enroll in the National
infarction, myoclonus, neuroleptic malignant syn- Pregnancy Registry for Antidepressants (NPRAD).
drome (Stevens 2008), optic neuritis, orthostatic hypo- Women 18 to 45 years of age or their health care
tension, ostealgia, pancreatitis, pancytopenia, providers may contact the registry by calling
paranoia, petechia, priapism, pulmonary embolism, 844-405-6185. Enrollment should be done as early in
pulmonary fibrosis, pulmonary hypertension, purpuric pregnancy as possible.
rash, renal failure, serotonin syndrome, sexual disor- Dental Health Professional Considerations Prob-
der (may persist after discontinuation), skin photo- lems with SSRI-induced bruxism have been reported
sensitivity, Stevens-Johnson syndrome, suicidal and may preclude their use; clinicians attempting to
ideation, syncope, tachycardia, thrombocytopenia, evaluate any patient with bruxism or involuntary muscle
toxic epidermal necrolysis, vasculitis, ventricular movement, who is simultaneously being treated with an
tachycardia (including torsades de pointes), violent SSRI drug, should be aware of the potential association
behavior (see Local Anesthetic/Vasoconstrictor Precautions)
Mechanism of Action Inhibits CNS neuron serotonin
reuptake; minimal or no effect on reuptake of norepi-
nephrine or dopamine; does not significantly bind to
Fluoxymesterone (floo oks i MES te rone)
alpha-adrenergic, histamine, or cholinergic receptors Brand Names: US Androxy [DSC]

Pharmacodynamics/Kinetics Pharmacologic Category Androgen
Onset of Action Depression: The onset of action is Use
within a week; however, individual response varies Breast cancer, metastatic (females): Salvage treat-
greatly and full response may not be seen until 8 to ment of inoperable metastatic breast cancer in post-
12 weeks after initiation of treatment. menopausal females
Half-life Elimination Adults: Parent drug: 1 to 3 days Delayed puberty (males): Replacement therapy in the
(acute), 4 to 6 days (chronic), 7.6 days (cirrhosis); treatment of delayed male puberty
Metabolite (norfluoxetine): 9.3 days (range: 4 to 16 Hypogonadism (males): Treatment of male hypogo-
days), 12 days (cirrhosis) nadism (primary or hypogonadotropic)
Time to Peak Serum: 6 to 8 hours Local Anesthetic/Vasoconstrictor Precautions
Pregnancy Risk Factor C No information available to require special precautions
614
FLUPHENAZINE
Effects on Dental Treatment No significant effects or the TMJ are a possibility. Patients may experience
complications reported orthostatic hypotension as they stand up after treat-
Effects on Bleeding No information available to ment; especially if lying in dental chair for extended
require special precautions periods of time. Use caution with sudden changes in
Adverse Reactions Frequency not defined. position during and after dental treatment.
Cardiovascular: Edema Effects on Bleeding No information available to
Central nervous system: Anxiety, depression, head- require special precautions
ache, paresthesia Adverse Reactions Frequency not defined.
Dermatologic: Acne vulgaris, androgenetic alopecia Cardiovascular: Cardiac arrhythmia, edema, hyperten-
Endocrine & metabolic: Change in libido (decreased sion, hypotension, tachycardia, variable blood
libido or increased libido), electrolyte disturbance (cal- pressure
cium, chloride, inorganic phosphate, potassium, and Central nervous system: Akathisia, bizarre dream, cer-
sodium retention), fluid retention, gynecomastia ebral edema, depression, disruption of body temper-
(males), hirsutism, hypercholesterolemia, menstrual ature regulation, dizziness, drowsiness, dystonia,
disease (females; including amenorrhea) EEG pattern changes, excitement, headache, hyper-
Gastrointestinal: Gastrointestinal irritation, nausea, reflexia, lethargy, neuroleptic malignant syndrome,
vomiting Parkinsonian-like syndrome, restlessness, seizure,
Genitourinary: Benign prostatic hypertrophy (males), tardive dyskinesia
oligospermia (males; at higher doses), priapism Dermatologic: Dermatitis, eczema, erythema, pruritus,
(males), testicular atrophy (males), virilization seborrhea, skin photosensitivity, skin pigmentation,
(females; including clitoromegaly, deepening of the skin rash, urticaria
voice in females) Endocrine & metabolic: Amenorrhea, change in libido,
Hematologic & oncologic: Clotting factors suppression, galactorrhea, gynecomastia, increased serum prolac-
polycythemia, prostate carcinoma (males) tin, menstrual disease, SIADH (syndrome of inappro-
Hepatic: Abnormal hepatic function tests, cholestatic priate antidiuretic hormone secretion), weight gain
jaundice, hepatic insufficiency Gastrointestinal: Anorexia, constipation, paralytic ileus,
Hypersensitivity: Anaphylactoid reaction (non-immuno- salivation, xerostomia
logic anaphylaxis), hypersensitivity reaction Genitourinary: Bladder paralysis, ejaculatory disorder,
<1%, postmarketing, and/or case reports: Hepatic impotence, mastalgia, urinary incontinence
coma, hepatocellular neoplasm, hepatotoxicity (idio- Hematologic & oncologic: Agranulocytosis, eosino-
syncratic; Chalasani 2014), peliosis hepatitis philia, leukopenia, nonthrombocytopenic purpura,
Mechanism of Action Synthetic derivative of testos- pancytopenia, thrombocytopenia
terone; responsible for the normal growth and develop- Hepatic: Cholestatic jaundice, hepatotoxicity
ment of male sex hormones, male sex organs, and Neuromuscular & skeletal: Muscle spasm (neck), sys-
maintenance of secondary sex characteristics; large temic lupus erythematosus, tremor (fingers)
doses suppress endogenous testosterone release Ophthalmic: Blurred vision, corneal changes, glau-
Pharmacodynamics/Kinetics coma, lens disease, retinitis pigmentosa
Half-life Elimination 10 hours (range: 10-100 Renal: Polyuria
minutes) Respiratory: Asthma, laryngeal edema, nasal con-
Pregnancy Risk Factor X gestion
Pregnancy Considerations Use is contraindicated in Mechanism of Action Fluphenazine is a piperazine
phenothiazine antipsychotic which blocks nonselec-
women who are or may become pregnant. May cause
tively postsynaptic mesolimbic dopaminergic D2 recep-
androgenic effects to the female fetus; clitoral hyper-
tors in the brain (Risch 1996); fluphenazine has limited
trophy, labial fusion, urogenital sinus defect, vaginal
activity on histaminergic, muscarinic and alpha recep-
atresia, and ambiguous genitalia have been reported.
tors (Richelson 1999)
Product Availability Androxy has been discontinued Pharmacodynamics/Kinetics
in the US for more than 1 year.
Onset of Action Decanoate: 24 to 72 hours; Peak
Controlled Substance C-III effect: Decanoate: 48 to 96 hours
Duration of Action Decanoate: ~4 to 6 weeks
FluPHENAZine (floo FEN a zeen) Half-life Elimination Derivative dependent: Hydro-
chloride: Oral: 14.4 to 16.4 hours (Dysken 1981;
Brand Names: Canada Modecate Concentrate Koytchev 1996); Decanoate: ~14 days (Altamura
Pharmacologic Category First Generation (Typical) 2003)
Antipsychotic; Phenothiazine Derivative Time to Peak Serum: Hydrochloride: Oral: 2.8 hours
Use (Koytchev 1996); Decanoate: 8 to 10 hours (Altamura
Psychotic disorders: For the management of mani- 2003)
festations of psychotic disorders; decanoate injection Pregnancy Considerations Antipsychotic use during
is intended for use in the management of patients the third trimester of pregnancy has a risk for abnormal
requiring prolonged therapy. muscle movements (extrapyramidal symptoms [EPS])
Limitations of use: Fluphenazine has not been shown to and withdrawal symptoms in newborns following deliv-
be effective in the management of behavioral compli- ery. Symptoms in the newborn may include agitation,
cations in patients with mental retardation. feeding disorder, hypertonia, hypotonia, respiratory dis-
Local Anesthetic/Vasoconstrictor Precautions tress, somnolence, and tremor; these effects may be
No information available to require special precautions self-limiting or require hospitalization. The ACOG rec-
Effects on Dental Treatment Key adverse event(s) ommends that therapy during pregnancy be individu-
related to dental treatment: Xerostomia and increased alized; treatment with psychiatric medications during
salivation (normal salivary flow resumes upon discon- pregnancy should incorporate the clinical expertise of
tinuation); nasal congestion is possible; since the drug the mental health clinician, obstetrician, primary health-
is a dopamine antagonist, extrapyramidal symptoms of care provider, and pediatrician (ACOG 2008).
615
FLURANDRENOLIDE
confusion, depression, dizziness, drowsiness, drug

Flurandrenolide (flure an DREN oh lide) dependence, dysarthria, euphoria, falling, hallucina-
tion, hangover effect, headache, irritability, memory
Brand Names: US Cordran; Nolix impairment, nervousness, paradoxical reaction, rest-
Pharmacologic Category Corticosteroid, Topical lessness, slurred speech, staggering, talkativeness
Use Corticosteroid-responsive dermatoses: Relief of Dermatologic: Diaphoresis, pruritus, skin rash
inflammatory and pruritic manifestations of corticoste- Endocrine & metabolic: Weight gain, weight loss
roid-responsive dermatoses Gastrointestinal: Constipation, decreased appetite,
Local Anesthetic/Vasoconstrictor Precautions diarrhea, gastric distress, gastrointestinal pain, heart-
No information available to require special precautions burn, increased appetite, nausea, sialorrhea, vomiting,
Effects on Dental Treatment No significant effects or xerostomia
complications reported Hematologic & oncologic: Granulocytopenia, leuko-
Effects on Bleeding No information available to penia
require special precautions Hepatic: Abnormal bilirubin levels (total bilirubin
Adverse Reactions Frequency not defined. increased), cholestatic jaundice, increased serum
Central nervous system: Burning sensation alkaline phosphatase, increased serum ALT,
Dermatologic: Acne vulgaris, acneiform eruptions, aller- increased serum AST
gic contact dermatitis, atrophic striae, folliculitis, hypo- Neuromuscular & skeletal: Arthralgia, weakness
pigmentation, hypertrichosis, maceration of the skin, Ophthalmic: Accommodation disturbance, blurred
miliaria, perioral dermatitis, pruritus, skin atrophy, vision, burning sensation of eyes
xeroderma Respiratory: Apnea, dyspnea
Local: Local irritation <1%, postmarketing, and/or case reports: Anaphylaxis,
Infection: Secondary infection angioedema, parasomnias (cooking while sleeping,
Postmarketing and/or case reports: Hypersensitivity, making phone calls while sleeping, sleep driving,
skin discoloration sleep eating)
Mechanism of Action Topical corticosteroids have Mechanism of Action Binds to stereospecific benzo-
anti-inflammatory, antipruritic, and vasoconstrictive diazepine receptors on the postsynaptic GABA neuron
properties. May depress the formation, release, and at several sites within the central nervous system,
activity of endogenous chemical mediators of inflam- including the limbic system, reticular formation.
mation (kinins, histamine, liposomal enzymes, prosta- Enhancement of the inhibitory effect of GABA on neuro-
glandins) through the induction of phospholipase A2 nal excitability results by increased neuronal membrane
inhibitory proteins (lipocortins) and sequential inhibition permeability to chloride ions. This shift in chloride ions
of the release of arachidonic acid. Flurandrenolide has results in hyperpolarization (a less excitable state) and
intermediate range potency. stabilization. Benzodiazepine receptors and effects
Pregnancy Risk Factor C appear to be linked to the GABA-A receptors. Benzo-
Pregnancy Considerations Adverse events have diazepines do not bind to GABA-B receptors (Vinkers,
been observed with corticosteroids in animal reproduc- 2012).
tion studies. When topical corticosteroids are needed Pharmacodynamics/Kinetics
during pregnancy, low- to mid-potency preparations are Half-life Elimination
preferred; higher-potency preparations should be used Flurazepam: 2.3 hours
for the shortest time possible and fetal growth should be N-desalkylflurazepam:
monitored (Chi 2011; Chi 2013). Topical products are Adults: Single dose: 74 to 90 hours; Multiple doses:
not recommended for extensive use, in large quantities, 111 to 113 hours
or for long periods of time in pregnant women (Leach- Elderly (61 to 85 years): Single dose: 120 to 160
man 2006). hours; Multiple doses: 126 to 158 hours
Time to Peak Flurazepam: 30 to 60 minutes; N-
Flurazepam (flure AZ e pam) desalkylflurazepam: 10.6 hours (range: 7.6 to 13.6
hours); N-hydroxyethylflurazepam: ~1 hour (Green-
Related Information blatt, 1989)
Dentin Hypersensitivity, Acid Erosion, High Caries Pregnancy Risk Factor C
Index, Management of Alveolar Osteitis, and Xerosto- Pregnancy Considerations
mia on page 1548 Adverse events have been observed in animal repro-
Pharmacologic Category Hypnotic, Benzodiazepine duction studies for benzodiazepines. All benzodiaze-
Use Insomnia: For the treatment of insomnia charac- pines are assumed to cross the placenta. Teratogenic
terized by difficulty in falling asleep, frequent nocturnal effects have been observed with some benzodiaze-
awakenings, and/or early-morning awakenings. pines; however, additional studies are needed. The
Local Anesthetic/Vasoconstrictor Precautions incidence of premature birth and low birth weights
No information available to require special precautions may be increased following maternal use of benzodia-
Effects on Dental Treatment Key adverse event(s) zepines; hypoglycemia and respiratory problems in the
related to dental treatment: Xerostomia and changes in neonate may occur following exposure late in preg-
salivation (normal salivary flow resumes upon discon- nancy. Neonatal withdrawal symptoms may occur within
tinuation), and bitter taste. days to weeks after birth and "floppy infant syndrome"
Effects on Bleeding No information available to (which also includes withdrawal symptoms) has been
require special precautions reported with some benzodiazepines (Bergman 1992;
Adverse Reactions Frequency not defined. Iqbal 2002; Wikner 2007). Neonatal depression has
Cardiovascular: Chest pain, flushing, hypotension, pal- been observed, specifically following exposure to flur-
pitations, syncope azepam when used maternally for 10 consecutive days
Central nervous system: Abnormal reflexes (slowing), prior to delivery. Serum levels of N-desalkylflurazepam
apprehension, ataxia, bitter taste, body pain, were measurable in the infant during the first 4 days of
616
FLURBIPROFEN (SYSTEMIC)
life. Use of flurazepam during pregnancy is contra- hyperuricemia, interstitial nephritis, jaundice, leukope-
indicated. nia, paresthesia, peptic ulcer, pruritus, purpura, renal
failure, skin photosensitivity, stomatitis, thrombocyto-
Patients exposed to flurazepam during pregnancy are
penia, toxic epidermal necrolysis, urticaria, vasodila-
encouraged to enroll themselves into the North Amer-
tation
ican Antiepileptic Drug (NAAED) Pregnancy Registry by
calling 1-888-233-2334. Additional information is avail- Dental Usual Dosage Management of postoperative
able at http://www.aedpregnancyregistry.org. pain (off-label use): Adults: Oral: 100 mg every 12
Controlled Substance C-IV hours
Dosing
Adult Note: Use the lowest effective dose for the
Flurbiprofen (Systemic) (flure BI proe fen) shortest possible duration.
US labeling:
Related Information Rheumatoid arthritis and osteoarthritis: Oral: Ini-
Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis tial: 200 to 300 mg/day in 2 to 4 divided doses;
on page 1484 maximum single dose: 100 mg (in a multiple dose
Temporomandibular Dysfunction (TMD), Chronic Pain, daily regimen)
and Fibromyalgia on page 1559 Canadian labeling: Note: If a dose is missed, take as
Brand Names: Canada APO-Flurbiprofen FC; Teva- soon as remembered; if next dose is due within 2
Flurbiprofen hours, a single dose should be taken and the next
Generic Availability (US) Yes dose skipped.
Pharmacologic Category Analgesic, Nonopioid; Non- Ankylosing spondylitis, osteoarthritis, rheuma-
steroidal Anti-inflammatory Drug (NSAID), Oral toid arthritis: Oral: 200 mg/day in divided doses;
Dental Use Management of postoperative pain (off- some patients may require up to 300 mg/day during
label use) symptom exacerbations (maximum: 300 mg/day)
Use Dysmenorrhea: Oral: 50 mg 4 times daily
Rheumatoid arthritis, osteoarthritis: Relief of the Pain (mild to moderately severe): Oral: 50 mg
signs and symptoms of rheumatoid arthritis (RA) and every 4 to 6 hours as needed
osteoarthritis (OA) Geriatric Refer to adult dosing. Use with caution;
Canadian labeling: Additional use (not in US labeling): reduce the initial dose to the lower end of the dosing
Relief of signs and symptoms of ankylosing spondyli- range.
tis; relief of pain associated with dysmenorrhea; relief Renal Impairment: Adult
of mild to moderate pain accompanied by inflamma- US labeling:
tion (eg, bursitis, tendinitis, soft tissue trauma) Mild impairment: There are no dosage adjustments
Local Anesthetic/Vasoconstrictor Precautions provided in the manufacturer's labeling; use with
No information available to require special precautions caution.
Effects on Dental Treatment The dentist should be Moderate to severe impairment: There are no dos-
aware of the potential of abnormal coagulation. Caution age adjustments provided in the manufacturer's
should also be exercised in the use of NSAIDs in labeling; however dosage adjustment may be nec-
patients already on anticoagulant therapy with drugs essary due to possible metabolite accumulation.
such as warfarin (Coumadin®). See Effects on Bleed-
Avoid use in patients with advanced renal disease
ing.
unless benefits are expected to outweigh risk of
Effects on Bleeding Nonselective NSAIDs such as worsening renal function.
flurbiprofen inhibit platelet aggregation and prolong
Continuous ambulatory peritoneal dialysis: Not
bleeding time in some patients. Unlike aspirin, the
removed by dialysis.
NSAID effect on platelet function is quantitatively less,
Canadian labeling:
of shorter duration, and reversible.
CrCl ≥30 mL/minute or 0.5 mL/second: There are no
Adverse Reactions dosage adjustments provided in the manufacturer's
Frequency not defined.
labeling; use with extreme caution.
>1%:
CrCl <30 mL/minute or 0.5 mL/second: Use is con-
Cardiovascular: Edema
traindicated in severe renal impairment (CrCl <30
Central nervous system: Amnesia, anxiety, depres-
mL/minute or 0.5 mL/second) or deteriorating renal
sion, dizziness, drowsiness, headache, hyperre-
disease.
flexia, insomnia, malaise, nervousness, vertigo
Continuous ambulatory peritoneal dialysis: Not
Endocrine & metabolic: Weight changes removed by dialysis.
Gastrointestinal: Abdominal pain, constipation, diar- KDIGO 2012 guidelines provide the following recom-
rhea, dyspepsia, flatulence, gastrointestinal bleed- mendations for NSAIDs:
ing, nausea, vomiting eGFR 30 to <60 mL/minute/1.73 m2: Temporarily
Hepatic: Increased liver enzymes discontinue in patients with intercurrent disease
Neuromuscular & skeletal: Tremor, weakness that increases risk of acute kidney injury.
Ophthalmic: Visual disturbance eGFR <30 mL/minute/1.73 m2: Avoid use.
Otic: Tinnitus Hepatic Impairment: Adult
Respiratory: Rhinitis US labeling: There are no dosage adjustments pro-
<1%, postmarketing, and/or case reports: Altered sense vided in the manufacturer's labeling; reduced doses
of smell, anaphylaxis, anemia, angioedema, asthma, may be required due to extensive hepatic metabo-
bruise, cardiac failure, cerebral ischemia, confusion, lism.
decreased hematocrit, decreased hemoglobin, Canadian labeling: Use is contraindicated in severe
eczema, eosinophilia, epistaxis, exfoliative dermatitis, hepatic impairment or active hepatic disease.
fever, gastric ulcer, hematuria, hepatitis, hepatotoxicity Mechanism of Action Reversibly inhibits cyclooxyge-
(idiosyncratic; Chalasani 2014), hypertension, nase-1 and 2 (COX-1 and 2) enzymes, which results in
617
decreased formation of prostaglandin precursors; has renal toxicity. Rehydrate patient before starting therapy;
antipyretic, analgesic, and anti-inflammatory properties monitor renal function closely. Long-term NSAID use
may result in renal papillary necrosis and other renal
Other proposed mechanisms not fully elucidated (and
injury.
possibly contributing to the anti-inflammatory effect to
varying degrees), include inhibiting chemotaxis, altering Not recommended for use in patients with advanced
lymphocyte activity, inhibiting neutrophil aggregation/ renal disease; monitor closely if therapy must be ini-
activation, and decreasing proinflammatory cytokine tiated. The Canadian labeling contraindicates use in
levels. patients with severe renal impairment (CrCl <30 mL/
Contraindications minute or 0.5 mL/second) or deteriorating renal
Hypersensitivity to flurbiprofen or any component of the disease.
formulation; history of asthma, urticaria, or allergic-
[US Boxed Warning]: NSAIDs cause increased risk
type reactions after taking aspirin or other NSAIDs;
of serious GI inflammation, ulceration, bleeding,
use in the setting of coronary artery bypass (CABG)
surgery and perforation (may be fatal); elderly patients and
Canadian labeling: Additional contraindications (not in patients with history of peptic ulcer disease and/or
US labeling): Severe uncontrolled heart failure; active GI bleeding are at greater risk for serious GI events.
gastric/duodenal/peptic ulcer; active GI bleeding; his- These events may occur at any time during therapy
tory of recurrent ulceration or active inflammatory GI and without warning. Avoid use in patients with active
disease; inflammatory bowel disease; severe hepatic GI bleeding. In patients with a history of acute lower GI
impairment; active hepatic disease; severe renal bleeding, avoid use of non-aspirin NSAIDs, especially if
impairment (CrCl <30 mL/minute or 0.5 mL/second) due to angioectasia or diverticulosis (Strate 2016). Use
or deteriorating renal disease; cerebrovascular bleed- caution with a history of GI ulcers, concurrent therapy
ing or other bleeding disorders; known hyperkalemia; known to increase the risk of GI bleeding (eg, aspirin,
children and adolescents <18 years of age; breast- anticoagulants and/or corticosteroids, selective seroto-
feeding; pregnancy (third trimester) nin reuptake inhibitors), advanced hepatic disease,
Warnings/Precautions [US Boxed Warning]: coagulopathy, smoking, use of alcohol, or in the elderly,
NSAIDs cause an increased risk of serious (and or debilitated patients. Use the lowest effective dose for
potentially fatal) adverse cardiovascular thrombotic the shortest duration of time, consistent with individual
events, including MI and stroke. Risk may occur patient goals, to reduce risk of GI adverse events;
early during treatment and may increase with dura- alternate therapies should be considered for patients
tion of use. Relative risk appears to be similar in those at high risk. When used concomitantly with aspirin, a
with and without known cardiovascular disease or risk substantial increase in the risk of GI complications (eg,
factors for cardiovascular disease; however, absolute ulcer) occurs; concomitant gastroprotective therapy (eg,
incidence of serious cardiovascular thrombotic events proton pump inhibitors) is recommended (Bhatt 2008).
(which may occur early during treatment) was higher in Use the lowest effective dose for the shortest duration
patients with known cardiovascular disease or risk of time, consistent with individual patient goals, to
factors. New-onset hypertension or exacerbation of reduce risk of cardiovascular or GI adverse events.
hypertension may occur (NSAIDs may also impair Alternate therapies should be considered for patients
response to ACE inhibitors, thiazide diuretics, or loop at high risk.
diuretics); may contribute to cardiovascular events;
monitor blood pressure; use with caution in patients NSAIDs may cause potentially fatal serious skin
with hypertension. May cause sodium and fluid reten- adverse events including exfoliative dermatitis, Ste-
tion; use with caution in patients with edema. Avoid use vens-Johnson syndrome (SJS), and toxic epidermal
in heart failure (ACCF/AHA [Yancy 2013]). Avoid use in necrolysis (TEN); may occur without warning; discon-
patients with a recent MI unless benefits outweigh risk tinue use at first sign of skin rash (or any other hyper-
of cardiovascular thrombotic events. Use the lowest sensitivity). Anaphylactoid reactions may occur, even in
effective dose for the shortest duration of time, consis- patients without prior exposure; patients with "aspirin
tent with individual patient goals, to reduce risk of triad" (bronchial asthma, aspirin intolerance, rhinitis)
cardiovascular events; alternate therapies should be may be at increased risk. Contraindicated in patients
considered for patients at high risk. who experience bronchospasm, asthma, rhinitis, or
urticaria with NSAID or aspirin therapy. Severe, rarely
[US Boxed Warning]: Use is contraindicated in the fatal, anaphylactic-like reactions to NSAIDs have been
setting of coronary artery bypass graft (CABG) reported. Use caution in other forms of asthma. NSAIDs
surgery. Risk of MI and stroke may be increased with may increase the risk of aseptic meningitis (rare),
use following CABG surgery. especially in patients with autoimmune disorder (eg,
Platelet adhesion and aggregation may be decreased; systemic lupus erythematosus (SLE) mixed connective
may prolong bleeding time; patients with coagulation tissue disorders). NSAIDs may be associated with
disorders or who are receiving anticoagulants should be persistent urinary symptoms (bladder pain, dysuria,
monitored closely. Anemia may occur; patients on long- urinary frequency), hematuria or cystitis. The onset of
term NSAID therapy should be monitored for anemia. these symptoms may occur at any time after the
Rarely, NSAID use has been associated with potentially initiation of therapy. Some cases have become severe
severe blood dyscrasias (eg, agranulocytosis, thrombo- on continued treatment; discontinue therapy to ascer-
cytopenia, aplastic anemia). NSAID use may compro- tain if symptoms disappear. May cause drowsiness,
mise existing renal function; dose-dependent dizziness, blurred vision, and other neurologic effects
decreases in prostaglandin synthesis may result from which may impair physical or mental abilities; patients
NSAID use, reducing renal blood flow which may cause must be cautioned about performing tasks which
renal decompensation (usually reversible). Patients require mental alertness (eg, operating machinery or
with impaired renal function, dehydration, hypovolemia, driving). Transaminase elevations have been reported
heart failure, hepatic impairment, those taking diuretics, with use; closely monitor patients with any abnormal
and ACE inhibitors, and the elderly are at greater risk of LFT. Rare (sometimes fatal) severe hepatic reactions
618
(eg, fulminant hepatitis, liver necrosis, hepatic failure) The levels/effects of Flurbiprofen (Systemic) may be
have occurred with NSAID use; discontinue immedi- increased by: Acemetacin; Alcohol (Ethyl); Angioten-
ately if signs or symptoms of hepatic disease develop sin II Receptor Blockers; Angiotensin-Converting
or if systemic manifestations occur. Use with caution in Enzyme Inhibitors; Corticosteroids (Systemic); Cyclo-
patients with hepatic impairment; patients with hepatic SPORINE (Systemic); Dasatinib; Dexketoprofen;
impairment may require reduced doses due to exten- Diclofenac (Systemic); Fat Emulsion (Fish Oil Based);
sive hepatic metabolism. Patients with advanced hep- Felbinac; Floctafenine; Glucosamine; Herbs (Antico-
atic disease are at an increased risk of GI bleeding with agulant/Antiplatelet Properties); Ibrutinib; Inotersen;
NSAIDs. The Canadian labeling contraindicates use in Ketorolac (Nasal); Ketorolac (Systemic); Limaprost;
patients with severe hepatic impairment or active hep- Loop Diuretics; Morniflumate; Multivitamins/Fluoride
atic disease. Use with caution; dosage adjustment in (with ADE); Multivitamins/Minerals (with ADEK,
patients with moderate or severe impairment may be Folate, Iron); Multivitamins/Minerals (with AE, No
necessary due to possible metabolite accumulation. Iron); Naftazone; Omega-3 Fatty Acids; Pelubiprofen;
Avoid use in patients with advanced renal disease Pentosan Polysulfate Sodium; Pentoxifylline; Phenyl-
unless benefits are expected to outweigh risk of wor- butazone; Probenecid; Prostacyclin Analogues;
sening renal function; monitor closely if therapy must be Selective Serotonin Reuptake Inhibitors; Serotonin/
initiated. The Canadian labeling contraindicates use in Norepinephrine Reuptake Inhibitors; Sodium Phos-
patients with severe renal impairment (CrCl <30 mL/ phates; Talniflumate; Tenoxicam; Thiazide and Thia-
minute or 0.5 mL/second) or deteriorating renal dis- zide-Like Diuretics; Tipranavir; Tolperisone; Tricyclic
ease. NSAID use may increase the risk of hyperkale- Antidepressants (Tertiary Amine); Vitamin E (Sys-
mia, particularly in the elderly, diabetics, renal disease, temic); Zaltoprofen
and with concomitant use of other agents capable of Decreased Effect
inducing hyperkalemia (eg, ACE inhibitors). Monitor Flurbiprofen (Systemic) may decrease the levels/
potassium closely. The Canadian labeling contraindi- effects of: Aliskiren; Angiotensin II Receptor Blockers;
cates use in patients with known hyperkalemia. Blurred Angiotensin-Converting Enzyme Inhibitors; Beta-
and/or diminished vision has been reported; discon- Blockers; Eplerenone; HydrALAZINE; Loop Diuretics;
tinue use and refer for ophthalmologic evaluation if such Macimorelin; Mifamurtide; Potassium-Sparing Diu-
symptoms occur. retics; Prostaglandins (Ophthalmic); Salicylates;
Selective Serotonin Reuptake Inhibitors; Sincalide;
Elderly patients are at greater risk for serious GI, Thiazide and Thiazide-Like Diuretics
cardiovascular, and/or renal adverse events. Use with
caution; consider reducing the initial dose. The levels/effects of Flurbiprofen (Systemic) may be
decreased by: Bile Acid Sequestrants; Salicylates
Withhold for at least 4 to 6 half-lives prior to surgical or Food Interactions Food may decrease the rate but not
dental procedures. Potentially significant interactions the extent of absorption. Management: May administer
may exist, requiring dose or frequency adjustment, with food, milk, or antacid to decrease GI effects.
additional monitoring, and/or selection of alternative Pharmacodynamics/Kinetics
therapy. Half-life Elimination 4.7 to 5.7 hours
Drug Interactions Time to Peak ~2 hours
Metabolism/Transport Effects Substrate of Pregnancy Considerations Birth defects have been
CYP2C9 (minor); Note: Assignment of Major/Minor observed following in utero NSAID exposure in some
substrate status based on clinically relevant drug studies; however, data is conflicting (Bloor 2013). Non-
interaction potential teratogenic effects, including prenatal constriction of the
Avoid Concomitant Use ductus arteriosus, persistent pulmonary hypertension of
Avoid concomitant use of Flurbiprofen (Systemic) with the newborn (PPHN), oligohydramnios, necrotizing
any of the following: Acemetacin; Aminolevulinic Acid enterocolitis, renal dysfunction or failure, and intracra-
(Systemic); Dexibuprofen; Dexketoprofen; Floctafe- nial hemorrhage, have been observed in the fetus/neo-
nine; Ketorolac (Nasal); Ketorolac (Systemic); Maci- nate following in utero NSAID exposure. In addition,
morelin; Mifamurtide; Morniflumate; Nonsteroidal Anti- nonclosure of the ductus arteriosus postnatally may
Inflammatory Agents (COX-2 Selective); Omacetax- occur and be resistant to medical management (Ber-
ine; Pelubiprofen; Phenylbutazone; Talniflumate; mas 2014; Bloor 2013). Because NSAIDs may cause
Tenoxicam; Urokinase; Zaltoprofen premature closure of the ductus arteriosus, product
Increased Effect/Toxicity labeling for flurbiprofen specifically states use should
Flurbiprofen (Systemic) may increase the levels/ be avoided starting at 30 weeks' gestation.
effects of: 5-Aminosalicylic Acid Derivatives; Agents
with Antiplatelet Properties; Aliskiren; Aminoglyco- Use of NSAIDs can be considered for the treatment of
mild rheumatoid arthritis flares in pregnant women;
sides; Aminolevulinic Acid (Systemic); Aminolevulinic
however, use should be minimized or avoided early
Acid (Topical); Anticoagulants; Apixaban; Bisphosph-
and late in pregnancy (Bermas 2014; Saavedra Salinas
onate Derivatives; Cephalothin; Collagenase (Sys-
2015).
temic); CycloSPORINE (Systemic); Dabigatran
Etexilate; Deferasirox; Deoxycholic Acid; Desmopres- The chronic use of NSAIDs in women of reproductive
sin; Dexibuprofen; Digoxin; Drospirenone; Edoxaban; age may be associated with infertility that is reversible
Eplerenone; Haloperidol; Ibritumomab Tiuxetan; Lith- upon discontinuation of the medication. Consider dis-
ium; Methotrexate; Nonsteroidal Anti-Inflammatory continuing use in women having difficulty conceiving or
Agents (COX-2 Selective); Obinutuzumab; Omacetax- those undergoing investigation of fertility. The use of
ine; Porfimer; Potassium-Sparing Diuretics; PRALA- NSAIDs close to conception may be associated with an
trexate; Quinolones; Rivaroxaban; Salicylates; increased risk of miscarriage (Bermas 2014;
Tacrolimus (Systemic); Tenofovir Products; Thrombo- Bloor 2013).
lytic Agents; Tolperisone; Urokinase; Vancomycin; Breastfeeding Considerations Flurbiprofen is
Verteporfin; Vitamin K Antagonists present in breast milk.
619
The relative infant dose (RID) of flurbiprofen is 0.9% Gastrointestinal: Nausea (9%), proctitis (8%), gastric
when calculated using the highest breast milk concen- distress (4% to 6%), anorexia (4%), constipation,
tration located and compared to a weight-adjusted dyspepsia, increased appetite
maternal dose of 100 mg. In general, breastfeeding is Genitourinary: Hematuria (7%)
considered acceptable when the RID is <10% (Ander- Hematologic & oncologic: Anemia (6%), leukopenia
son 2016; Ito 2000). Using the highest milk concen- (3%), thrombocytopenia (1%)
tration (0.09 mcg/mL), the estimated daily infant dose Infection: Herpes zoster
via breast milk is 13.5 mcg/kg/day. This milk concen- Neuromuscular & skeletal: Weakness (1%)
tration was obtained following maternal administration <1%, postmarketing, and case reports: Cholestatic
of flurbiprofen 100 mg in a single dose. The maximum jaundice, hemolytic anemia, hepatic encephalopathy,
flurbiprofen concentration in breast milk occurred at 3 hepatic failure, hepatic necrosis, hepatitis, hypersen-
hours after the dose (Cox 1987). sitivity pneumonitis, increased blood urea nitrogen,
increased gamma-glutamyl transferase, increased
In general, NSAIDs may be used in postpartum women serum ALT, increased serum bilirubin, increased
who wish to breastfeed; however, agents other than serum creatinine, jaundice, macrocytic anemia, malig-
flurbiprofen are preferred (Montgomery 2012) and use nant neoplasm of breast (male), methemoglobinemia,
should be avoided in women breastfeeding infants with myocardial infarction, oligospermia, pulmonary embo-
platelet dysfunction or thrombocytopenia (Bloor 2013; lism, skin photosensitivity, sulfhemoglobinemia,
Sammaritano 2014). According to the manufacturer, the thrombophlebitis, urine discoloration (amber, yellow-
decision to breastfeed during therapy should consider green)
the risk of infant exposure, the benefits of breastfeeding Mechanism of Action Nonsteroidal antiandrogen that
to the infant, and benefits of treatment to the mother. inhibits androgen uptake and/or inhibits binding of
Dosage Forms: US androgen in target tissues.
Tablet, Oral: Pharmacodynamics/Kinetics
Generic: 50 mg, 100 mg Half-life Elimination ~6 hours (2-hydroxyflutamide)
Time to Peak ~2 hours (2-hydroxyflutamide)
Flutamide (FLOO ta mide) Pregnancy Risk Factor D
Brand Names: Canada Apo-Flutamide; Euflex; PMS- Adverse events have been observed in animal repro-
Flutamide; Teva-Flutamide duction studies. May cause fetal harm if administered in
Pharmacologic Category Antineoplastic Agent, Anti- pregnancy. Flutamide is not indicated for use in women.
androgen
Use Prostate cancer: Management of locally confined
Stage B2 to C and Stage D2 metastatic prostate cancer
Fluticasone (Nasal) (floo TIK a sone)
(in combination with a luteinizing hormone-releasing Brand Names: US Flonase Allergy Relief [OTC]; Flo-
hormone [LHRH] agonist). For Stage B2 to C prostate nase Sensimist [OTC]; GoodSense Nasoflow [OTC]
cancer, flutamide treatment (and goserelin) should start [DSC]; Ticaspray; Veramyst [DSC]; Xhance
8 weeks prior to initiating radiation therapy and continue Brand Names: Canada Avamys; Flonase
during radiation therapy. To achieve treatment benefit in Pharmacologic Category Corticosteroid, Nasal
Stage D2 metastatic prostate cancer, initiate flutamide Use
with the LHRH agonist and continue until disease Rx products:
progression. Allergic rhinitis (Veramyst, Avamys [Canadian
Local Anesthetic/Vasoconstrictor Precautions product], Flonase [Canadian product]): Manage-
No information available to require special precautions ment of seasonal and perennial allergic rhinitis in
Effects on Dental Treatment No significant effects or adults and children ≥2 years of age (Veramyst,
complications reported Avamys) and in patients 4 to 17 years of age
Effects on Bleeding Hemolytic anemia has been (Flonase)
reported. Nasal polyps (Xhance): Treatment of nasal polyps in
Adverse Reactions patients ≥18 years of age
>10%: Nonallergic rhinitis (Flonase): Management of the
Endocrine & metabolic: Hot flash (46% to 61%), nasal symptoms of perennial nonallergic rhinitis in
galactorrhea (9% to 42%), decreased libido (36%), adults and pediatric patients ≥4 years of age
increased lactate dehydrogenase (transient; mild) OTC products:
Gastrointestinal: Diarrhea (12% to 40%), vomiting Upper respiratory allergies: Relief of hay fever or
(11% to 12%) other upper respiratory allergies (eg, itchy and
Genitourinary: Impotence (33%), cystitis (16%), breast watery eyes, nasal congestion, runny nose, sneez-
tenderness ing, itchy nose) in adults and children ≥4 years of age
Hematologic & oncologic: Rectal hemorrhage (14%), (Clarispray, Flonase Allergy Relief, Good Sense
tumor flare Nasoflow) or children ≥2 years of age (Flonase
Hepatic: Increased serum AST (transient; mild) Sensimist)
Cardiovascular: Edema (4%), hypertension (1%) No information available to require special precautions
Central nervous system: Anxiety, confusion, depres- Effects on Dental Treatment No significant effects or
sion, dizziness, drowsiness, headache, insomnia, complications reported
nervousness Effects on Bleeding No information available to
Dermatologic: Skin rash (3% to 8%), ecchymoses, require special precautions
pruritus Adverse Reactions
Endocrine & metabolic: Gynecomastia (9%) >10%: Central nervous system: Headache (4% to 16%)
620
FLUTICASONE (ORAL INHALATION)
1% to 10%: Use
Central nervous system: Body pain (1% to 3%), dizzi- Asthma:
ness (1% to 3%), generalized ache (1% to 3%) ArmonAir RespiClick and Arnuity Ellipta: Maintenance
Endocrine & metabolic: Weight gain (1% to <3%) treatment of asthma as prophylactic therapy in
Gastrointestinal: Nausea and vomiting (3% to 5%), patients ≥5 years (Arnuity Ellipta) or ≥12 years
abdominal pain (1% to 3%), diarrhea (1% to 3%), (ArmonAir RespiClick).
abdominal distress (1% to <3%), toothache (1% Flovent Diskus and Flovent HFA: Maintenance treat-
to <3%) ment of asthma as prophylactic therapy in patients
Local: Local irritation (nose: 4% to 6%) ≥4 years.
Ophthalmic: Increased intraocular pressure (1% Limitations of use: Not indicated for relief of acute
to <3%) bronchospasm.
Respiratory: Epistaxis (6% to 12%), nasal mucosa Guideline recommendations: A low-dose inhaled cor-
ulcer (3% to 8%; includes nasal septal ulceration), ticosteroid (in addition to an as-needed short acting
pharyngitis (3% to 8%), nasopharyngitis (8%), acute beta2-agonist) is the initial preferred long-term control
asthma (7%), nasal congestion (6%), acute sinusitis medication for children, adolescents, and adult
(5%), cough (4%), blood in nasal mucosa (1% to patients with persistent asthma who are candidates
3%), bronchitis (1% to 3%), flu-like symptoms (1% to for treatment according to a step-wise treatment
3%), rhinorrhea (1% to 3%), dry nose (1% to <3%), approach (GINA 2018; NAEPP 2007).
oropharyngeal pain (1% to <3%), sinusitis (1% Local Anesthetic/Vasoconstrictor Precautions
to <3%) No information available to require special precautions
Miscellaneous: Fever (1% to 3%) Effects on Dental Treatment Key adverse event(s)
<1%, postmarketing, and/or case reports: Altered sense related to dental treatment: Localized infections with
of smell, anaphylactoid reaction, anaphylaxis, angioe- Candida albicans or Aspergillus niger have occurred
dema, blurred vision, bronchospasm, cataract, con- frequently in the mouth and pharynx with repetitive use
junctivitis, contact dermatitis, dry eye syndrome, dry of oral inhaler of corticosteroids. These infections may
throat, dysgeusia, dyspnea, esophageal candidiasis, require treatment with appropriate antifungal therapy or
eye irritation, facial edema, glaucoma, growth sup- discontinuance of treatment with corticosteroid inhaler.
pression, hoarseness, hypersensitivity reaction, intes- Effects on Bleeding No information available to
tinal candidiasis, nasal candidiasis, nasal septum require special precautions
perforation, pharyngeal candidiasis, pruritus, skin Adverse Reactions
rash, sore throat, throat irritation, tongue edema, >10%:
urticaria, voice disorder, wheezing Central nervous system: Fatigue (≤16%), malaise
Mechanism of Action Fluticasone belongs to a group (≤16%), headache (2% to 14%)
of corticosteroids which utilizes a fluorocarbothioate Gastrointestinal: Oral candidiasis (≤31%)
ester linkage at the 17 carbon position; extremely Neuromuscular & skeletal: Arthralgia (≤17%), muscu-
potent vasoconstrictive and anti-inflammatory activity loskeletal pain (2% to 12%)
Pharmacodynamics/Kinetics Respiratory: Sinus infection (≤33%), sinusitis (≤33%),
Onset of Action Maximal benefit may take several upper respiratory tract infection (2% to 31%), throat
days or several months (Xhance) irritation (<1% to 22%), nasal congestion (≥3% to
Half-life Elimination IV: Fluticasone propionate: ~8 16%), nasopharyngitis (8% to 13%), rhinitis (<1% to
hours (~7.8 hours [Xhance]); Fluticasone furoate: ~15 13%), bronchitis (≤8%)
hours 1% to 10%:
Pregnancy Considerations Cardiovascular: Hypertension (≤1%), subarachnoid
Fluticasone can be detected in cord blood following hemorrhage (≤1%)
maternal use via oral inhalation during pregnancy; one Central nervous system: Pain (10%), voice disorder
woman in the study was also using intranasal flutica- (≤9%), procedural pain (≤3%)
sone (Battista 2016). Hypoadrenalism may occur in Dermatologic: Skin rash (8%), pruritus (6%)
newborns following maternal use of corticosteroids in Gastrointestinal: Nausea and vomiting (1% to 9%),
pregnancy; monitor. viral gastrointestinal infection (3% to 5%), gastro-
intestinal distress (≤4%), gastrointestinal pain
Intranasal corticosteroids, including fluticasone, may be
(≤4%), oropharyngeal candidiasis (3%), toothache
acceptable for the treatment of rhinitis during pregnancy
(3%), viral gastroenteritis (3%), abdominal
when used at recommended doses (Lal 2016; Wallace
pain (≤3%)
2008). Pregnant females adequately controlled on fluti-
Hematologic & oncologic: Malignant neoplasm of
casone may continue therapy; if initiating treatment
breast (≤1%)
during pregnancy, use of an agent with more data
Infection: Influenza (4% to 7%), viral infection (≤5%),
during pregnancy may be preferred (Namazy 2016;
abscess (≤1%)
Wallace 2008).
Neuromuscular & skeletal: Muscle injury (≤5%), back
pain (3%), herniated disk (≤1%)
Fluticasone (Oral Inhalation) (floo TIK a sone) Respiratory: Viral respiratory infection (1% to 9%),
cough (≤9%), hoarseness (≤9%), pharyngitis (3% to
Related Information 6%), upper respiratory tract inflammation (≤5%),
Respiratory Diseases on page 1467 oropharyngeal pain (3% to 4%), allergic rhini-
Brand Names: US ArmonAir RespiClick 113 [DSC]; tis (≥3%)
ArmonAir RespiClick 232 [DSC]; ArmonAir RespiClick Miscellaneous: Fever (1% to 7%), accidental injury
55 [DSC]; Arnuity Ellipta; Flovent Diskus; Flovent HFA (≤5%), amputation (≤1%)
Brand Names: Canada Arnuity Ellipta; Flovent Dis- <1%, postmarketing, and/or case reports: Aggressive
kus; Flovent HFA behavior, agitation, allergic skin reaction, anaphylaxis,
Pharmacologic Category Corticosteroid, Inhalant anxiety, aphonia, arthritis, behavioral changes, blurred
(Oral) vision, bronchospasm, bruise, burn, cataract, chest
621
FLUTICASONE (ORAL INHALATION)
symptoms, chest tightness, Cushingoid appearance, COPD because an efficacy advantage of the higher
decreased linear skeletal growth rate, dental caries, strength fluticasone 500 mcg/salmeterol 50 mcg
dental discoloration, dental discomfort, depression, Diskus over fluticasone 250 mcg/salmeterol 50 mcg
diarrhea, dizziness, dyspepsia, dyspnea, ecchymo- Diskus has not been demonstrated.
ses, epistaxis, esophageal candidiasis, exacerbation Limitations of use: Fluticasone/salmeterol is not indi-
of asthma, facial edema, gastrointestinal disease, cated for the relief of acute bronchospasm.
hyperglycemia, hypersensitivity reaction (musculoske- Local Anesthetic/Vasoconstrictor Precautions
letal), laryngitis, migraine, mood disorder, mouth dis- No information available to require special precautions
ease, oropharyngeal edema, osteoporosis, Effects on Dental Treatment Key adverse event(s)
paradoxical bronchospasm, pneumonia, restlessness, related to dental treatment: Localized infections with
retinopathy (central serous), rhinorrhea, soft tissue Candida albicans or Aspergillus niger have occurred
injury, sore throat, urinary tract infection, weight gain, frequently in the mouth and pharynx with repetitive use
wheezing of oral inhaler of corticosteroids. These infections may
Mechanism of Action Fluticasone belongs to a group require treatment with appropriate antifungal therapy or
of corticosteroids which utilizes a fluorocarbothioate discontinuance of treatment with corticosteroid inhaler.
ester linkage at the 17 carbon position; extremely Effects on Bleeding No information available to
potent vasoconstrictive and anti-inflammatory activity. require special precautions
The effectiveness of inhaled fluticasone is due to its Adverse Reactions Adverse reactions occur in adults
direct local effect. and adolescents unless otherwise specified.
Onset of Action Maximal benefit may take 1 to 2 Central nervous system: Headache (5% to 21%)
weeks or longer Respiratory: Upper respiratory tract infection (16% to
Half-life Elimination IV: ~8 hours; Oral inhalation 27%), pneumonia (4% to 18%; higher incidence is
(plasma elimination phase following repeat dosing): associated with older adults), pharyngitis (≤13%)
24 hours (ArmonAir RespiClick: ~11.2 hours) 1% to 10%:
Time to Peak 0.5 to 1 hour Cardiovascular: Cardiac arrhythmia (1% to 3%), myo-
Pregnancy Considerations cardial infarction (1% to 3%), tachycardia (1% to
Fluticasone can be detected in cord blood following 3%), palpitations (<3%)
maternal use via oral inhalation during pregnancy (Bat- Central nervous system: Voice disorder (≤5%), dizzi-
tista 2016). Uncontrolled asthma is associated with ness (≤4%), migraine (1% to 3%), sleep disorder (1%
adverse events on pregnancy (increased risk of peri- to 3%)
natal mortality, preeclampsia, preterm birth, low birth Dermatologic: Dermatitis (1% to 3%), dermatologic
weight infants). Poorly controlled asthma or asthma disease (1% to 3%; includes dermatosis and disor-
exacerbations may have a greater fetal/maternal risk der of sweat and sebum), eczema (1% to 3%),
than what is associated with appropriately used asthma contact dermatitis (<3%), pruritus (1%)
medications (ACOG 2008; GINA 2018). Endocrine & metabolic: Weight gain (1% to 3%)
Gastrointestinal: Oral candidiasis (1% to 10%; includ-
Inhaled corticosteroids are recommended for the treat-
ing mouth and throat infections), nausea and vomit-
ment of asthma during pregnancy (ACOG 2008; GINA
ing (4% to 6%), nausea (>5%), gastrointestinal
2018; Namazy 2016). Pregnant females adequately
distress (≤4%), viral gastrointestinal infection (3%
controlled on fluticasone for asthma may continue
to 4%), diarrhea (2% to 4%), abdominal distress
therapy; if initiating treatment during pregnancy, use of
(1% to 3%), abdominal pain (1% to 3%), dental
an agent with more data in pregnant females may be
discomfort (1% to 3%), dental disease (disorder of
preferred (Namazy 2016).
hard tissue of teeth: 1% to 3%), gastrointestinal
infection (1% to 3%), infection of mouth (unspecified
Fluticasone and Salmeterol oropharyngeal plaque: 1% to 3%), toothache (1% to
(floo TIK a sone & sal ME te role) 3%), xerostomia (1% to 3%), dyspepsia (<3%),
upper abdominal pain (<3%)
Related Information Genitourinary: Genitourinary infection (1% to 3%),
Fluticasone (Oral Inhalation) on page 621 urinary tract infection (1% to 3%)
Salmeterol on page 1187 Hypersensitivity: Hypersensitivity reaction (1% to 3%;
Brand Names: US Advair Diskus; Advair HFA; AirDuo can be immediate or delayed), local ocular hyper-
RespiClick sensitivity (1% to 3%)
Brand Names: Canada Advair; Advair Diskus Infection: Candidiasis (3%), bacterial infection (1% to
Pharmacologic Category Beta2 Agonist; Beta2-Adre- 3%), viral infection (1% to 3%), influenza (<3%)
nergic Agonist, Long-Acting; Corticosteroid, Inhalant Neuromuscular & skeletal: Musculoskeletal pain (4%
(Oral) to 7%), myalgia (≤4%), back pain (3%), arthralgia
Use (1% to 3%), arthritis (1% to 3%), muscle injury (1% to
Asthma: Treatment of asthma in patients 4 years and 3%), muscle spasm (1% to 3%), ostealgia (1% to
older (Advair Diskus) and in patients 12 years and 3%), skeletal muscle disease (inflammation: 1% to
older (Advair HFA, AirDuo RespiClick). 3%), skeletal pain (1% to 3%), limb pain (<3%),
Chronic obstructive pulmonary disease (Advair Dis- muscle cramps (≤3%)
kus only): Maintenance treatment of airflow obstruc- Ophthalmic: Ocular edema (1% to 3%)
tion in patients with chronic obstructive pulmonary Otic: Ear sign or symptom (1% to 3%)
disease (COPD), including chronic bronchitis and/or Respiratory: Throat irritation (8% to 9%; children:
emphysema. Fluticasone 250 mcg/salmeterol 50 mcg ≥3%), nasopharyngitis (5% to 9%), bronchitis (8%),
Diskus is also indicated to reduce exacerbations of upper respiratory tract inflammation (4% to 7%;
COPD in patients with a history of exacerbations. includes upper respiratory tract irritation), cough
Fluticasone 250 mcg/salmeterol 50 mcg Diskus twice (4% to 6%), viral respiratory tract infection (4% to
daily is the only approved dosage for the treatment of 6%), hoarseness (≤5%), sinusitis (≤5%), ENT
622
FLUTICASONE AND VILANTEROL
infection (children: ≥3%), dry nose (1% to 3%), Pregnancy Considerations Adverse events were
epistaxis (1% to 3%), laryngitis (1% to 3%), lower observed in animal reproduction studies using this
respiratory signs and symptoms (1% to 3%), lower combination. Refer to individual agents.
respiratory tract infection (1% to 3%), postnasal drip
(1% to 3%), respiratory tract hemorrhage (lower
respiratory tract: 1% to 3%), nasal congestion
Fluticasone and Vilanterol
(floo TIK a sone & VYE lan ter ol)
(≤3%), allergic rhinitis (<3%), oropharyngeal pain
(<3%), respiratory tract infection (<3%), rhinitis Brand Names: US Breo Ellipta
(<3%), rhinorrhea (1% to 3%) Brand Names: Canada Breo Ellipta
Miscellaneous: Fever (4%), inflammation (1% to 3%), Pharmacologic Category Beta2 Agonist; Beta2-Adre-
laceration (1% to 3%), postoperative complication nergic Agonist, Long-Acting; Corticosteroid, Inhalant
(1% to 3%), soft tissue injury (1% to 3%), wound (Oral)
(1% to 3%) Use
Frequency not defined: Asthma: Treatment of asthma in patients ≥18 years.
Cardiovascular: Edema Chronic obstructive pulmonary disease: Mainte-
Central nervous system: Hypertonia, mouth pain, pain nance treatment of airflow obstruction in patients with
Dermatologic: Acquired ichthyosis, exfoliation of skin, chronic obstructive pulmonary disease (COPD),
viral skin infection including chronic bronchitis and/or emphysema; to
Endocrine & metabolic: Fluid retention, hyperglyce- reduce exacerbations of COPD in patients with a
mia, hypothyroidism history of exacerbations
Fluticasone 100 mcg/vilanterol 25 mcg is the only
Gastrointestinal: Dysgeusia, oral discomfort, oral
strength indicated for the treatment of COPD.
lesion, oral mucosa ulcer
Limitations of use: Not indicated for the relief of acute
Hematologic & oncologic: Hematoma, lymphaden-
bronchospasm.
opathy
Hepatic: Increased liver enzymes (incidence may be
No information available to require special precautions.
higher in children but were transient)
Neuromuscular & skeletal: Bone fracture, connective related to dental treatment: Infections with Candida
tissue disease (cartilage disorder), muscle rigidity albicans in the mouth and throat (thrush).
Ophthalmic: Conjunctivitis, eye infection, keratitis, Effects on Bleeding No information available to
xerophthalmia require special precautions.
Respiratory: Nasal signs and symptoms, paranasal Adverse Reactions Also see fluticasone (oral inhala-
sinus disease tion) monograph.
<1%, postmarketing, and/or case reports: Abnormal 1% to 10%:
hepatic function tests, aggressive behavior, agitation, Cardiovascular: Hypertension (≥3%), extrasystoles
anaphylaxis, angioedema, anxiety, aphonia, asthma, (≥2%), supraventricular extrasystole (≥2%), ventric-
atrial fibrillation, behavioral changes, blurred vision, ular premature contractions (≥2%)
bronchospasm (may be immediate), bruise, cataract, Central nervous system: Headache (5% to 8%), voice
chest congestion, chest tightness, choking sensation, disorder (2%)
cushingoid appearance, Cushing syndrome, Gastrointestinal: Oropharyngeal candidiasis (2% to
decreased linear skeletal growth rate, depression, 5%), upper abdominal pain (≥2%)
dysmenorrhea, dyspnea, ecchymoses, esophageal Infection: Influenza (≥3%)
candidiasis, exacerbation of asthma (can be serious), Neuromuscular & skeletal: Arthralgia (≥2%), back pain
extrasystoles, facial edema, glaucoma, hyperactivity, (≥2%), bone fracture (2%)
hypercorticoidism, hypertension, irregular menses, Respiratory: Nasopharyngitis (6% to 10%), pneumo-
irritability, laryngeal edema, laryngospasm, myositis, nia (2% to 7%), upper respiratory tract infection (2%
oropharyngeal edema, osteoporosis, otalgia, pallor, to 7%), acute sinusitis (≥2%), allergic rhinitis (≥2%),
paradoxical bronchospasm, paresthesia, pelvic oropharyngeal pain (≥2%), pharyngitis (≥2%), rhinitis
inflammatory disease, photodermatitis, restlessness, (≥2%), viral respiratory tract infection (≥2%), cough
retinopathy (central serous), sinus pain, skin rash, (≥1%), sinusitis (≥1%), bronchitis
sore throat, stridor, supraventricular tachycardia, syn- Miscellaneous: Fever (≥2%)
cope, tonsillitis, tracheitis, upper airway swelling, vag- <1%, postmarketing, and/or case reports: Anaphylaxis,
angioedema, hyperglycemia, hypersensitivity reac-
initis, ventricular tachycardia, vulvovaginal
tion, muscle spasm, nervousness, palpitations, para-
candidiasis, vulvovaginitis, wheezing
doxical bronchospasm, skin rash, tachycardia, tremor,
Mechanism of Action Combination of fluticasone urticaria
(corticosteroid) and salmeterol (long-acting beta2-ago-
Mechanism of Action
nist) designed to improve pulmonary function and con- Fluticasone: A corticosteroid with anti-inflammatory
trol over what is produced by either agent when used activity, immunosuppressive properties, and antiproli-
alone. Because fluticasone and salmeterol act locally in ferative actions.
the lung, plasma levels do not predict therapeutic effect. Vilanterol: A long-acting beta2-agonist, relaxes bron-
Fluticasone: The mechanism of action for all topical chial smooth muscle by selective action on beta2-
corticosteroids is believed to be a combination of three receptors with little effect on heart rate.
important properties: Anti-inflammatory activity, immu- Pregnancy Considerations Adverse events have not
nosuppressive properties, and antiproliferative been observed in animal reproduction studies. Hypoa-
actions. Fluticasone has extremely potent vasocon- drenalism may occur in infants born to mothers receiv-
strictive and anti-inflammatory activity. ing corticosteroids during pregnancy (refer to the
Salmeterol: Relaxes bronchial smooth muscle by selec- fluticasone, oral inhalation monograph for additional
tive action on beta2-receptors with little effect on details). Beta-agonists have the potential to affect ute-
heart rate rine contractility if administered during labor.
623
FLUTICASONE AND VILANTEROL
Uncontrolled asthma is associated with adverse events <1%, postmarketing, and/or case reports: Alopecia,
in pregnancy (increased risk of perinatal mortality, pre- amnesia (reversible), anaphylaxis, angioedema, ano-
eclampsia, preterm birth, low birth weight infants). rexia, anxiety, arthralgia, arthritis, blurred vision, cata-
ract, changes in nails, chills, cholestatic jaundice,
cognitive dysfunction (reversible), cystitis (interstitial;
Fluvastatin (FLOO va sta tin)
Huang 2015), decreased libido, depression, dermato-
Related Information myositis, dizziness, dry mucous membranes, dysgeu-
Cardiovascular Diseases on page 1442 sia, dyspnea, elevated glycosylated hemoglobin
(HbA1c), eosinophilia, erectile dysfunction, erythema
Brand Names: US Lescol XL; Lescol [DSC]
multiforme, facial paresis, fever, flushing, fulminant
Brand Names: Canada Lescol; Lescol XL
hepatic necrosis, gynecomastia, hemolytic anemia,
Pharmacologic Category Antilipemic Agent, HMG- hepatic cirrhosis, hepatic neoplasm, hepatitis, hyper-
CoA Reductase Inhibitor bilirubinemia, hypersensitivity reaction, immune-medi-
Use ated necrotizing myopathy (IMNM), impairment of
Dyslipidemias: extraocular movement, impotence, increased creatine
Heterozygous familial and nonfamilial hypercholester- phosphokinase (>10x normal), increased erythrocyte
olemia and mixed dyslipidemia: Adjunct to diet to sedimentation rate, increased gamma-glutamyl trans-
reduce elevated total cholesterol (total-C), low-den- ferase, increased serum alkaline phosphatase,
sity lipoprotein-cholesterol (LDL-C), triglyceride, and increased serum glucose, increased serum transami-
apolipoprotein B (apo-B) levels and to increase HDL- nases, interstitial pulmonary disease, leukopenia, liver
C in adults with primary hypercholesterolemia and steatosis, lupus-like syndrome, malaise, memory
mixed dyslipidemia (Fredrickson types IIa and IIb) impairment (reversible), muscle cramps, myopathy,
Heterozygous familial hypercholesterolemia: As an nodule, ophthalmoplegia, pancreatitis, paresthesia,
adjunct to diet to reduce total-C, LDL-C, and apo B peripheral nerve palsy, peripheral neuropathy, poly-
levels in children ≥10 years and adolescents ≤16 myalgia rheumatica, positive ANA titer, pruritus, psy-
years of age (female patients must be at least 1 year chic disorder, purpura, reversible confusional state,
postmenarche) with heterozygous familial hypercho- rhabdomyolysis, skin discoloration, skin photosensitiv-
lesterolemia and an LDL-C that remains ≥190 mg/dL ity, skin rash, Stevens-Johnson syndrome, thrombo-
or ≥160 mg/dL (with ≥2 cardiovascular risk factors or cytopenia, thyroid dysfunction, toxic epidermal
a positive family history of premature cardiovascular necrolysis, tremor, urticaria, vasculitis, vertigo, vomit-
disease). ing, xeroderma
Prevention of cardiovascular disease (CVD): Mechanism of Action Acts by competitively inhibiting
Secondary prevention of CVD: To slow the progres- 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA)
sion of coronary atherosclerosis in patients with reductase, the enzyme that catalyzes the reduction of
coronary heart disease; reduce risk of coronary HMG-CoA to mevalonate; this is an early rate-limiting
revascularization procedures in patients with coro- step in cholesterol biosynthesis. HDL is increased while
nary heart disease total, LDL, and VLDL cholesterols; apolipoprotein B;
Limitations of use: Has not been studied in conditions and plasma triglycerides are decreased. In addition to
where the major abnormality is elevation of chylomi- the ability of HMG-CoA reductase inhibitors to decrease
crons, very low-density lipoprotein (VLDL), or inter- levels of high-sensitivity C-reactive protein (hsCRP),
mediate density lipoprotein (IDL) (ie, they also possess pleiotropic properties including
hyperlipoproteinemia types I, III, IV, or V). improved endothelial function, reduced inflammation
Local Anesthetic/Vasoconstrictor Precautions at the site of the coronary plaque, inhibition of platelet
No information available to require special precautions aggregation, and anticoagulant effects (de Denus 2002;
Effects on Dental Treatment Key adverse event(s) Ray 2005).
related to dental treatment: Assess unusual presenta- Pharmacodynamics/Kinetics
tions of muscle weakness or myopathy resulting from Onset of Action Peak effect: Maximal LDL-C reduc-
lipid therapy such as patient having a difficult time tions achieved within 4 weeks
brushing teeth or weakness with chewing. Refer patient Half-life Elimination Immediate-release: ~3 hours;
back to their physician for evaluation and adjustment of Extended-release: 7.3 to 10.5 hours (due to prolonged
lipid therapy. absorption time) (Barilla 2004)
Effects on Bleeding No information available to Time to Peak
require special precautions Immediate-release: <1 hour (delayed more than 2-fold
Adverse Reactions Frequency not always defined. when administered with food as compared to admin-
The following adverse events were reported with flu- istering 4 hours after the evening meal)
vastatin capsules; in general, adverse reactions Extended-release: ~3 hours (minimally affected by
reported with fluvastatin extended release tablet were low-fat meals; however, with a high-fat meal, delayed
similar, but incidences were lower. <1%/Postmarketing by 2-fold)
adverse reactions include additional class-related Pregnancy Risk Factor X
events that were not necessarily reported with fluvas- Pregnancy Considerations
tatin therapy. Fluvastatin is contraindicated in pregnant females or
those who may become pregnant.
1% to 10%:
Central nervous system: Headache (9%), fatigue Studies in pregnant women have shown evidence of
(3%), insomnia (3%) fetal abnormalities and use is contraindicated in women
Gastrointestinal: Dyspepsia (8%), abdominal pain who are or may become pregnant. There are reports of
(5%), diarrhea (5%), nausea (3%) congenital anomalies following maternal use of HMG-
Genitourinary: Urinary tract infection (2%) CoA reductase inhibitors in pregnancy; however, mater-
Neuromuscular & skeletal: Myalgia (5%) nal disease, differences in specific agents used, and the
Respiratory: Sinusitis (3%), bronchitis (2%) low rates of exposure limit the interpretation of the
624
FLUVOXAMINE
available data (Godfrey 2012; Lecarpentier 2012). Cho- Central nervous system: Pain (10%), anxiety (5% to
lesterol biosynthesis may be important in fetal develop- 8%), anorgasmia (2% to 5%), yawning (2% to 5%),
ment; serum cholesterol and triglycerides increase abnormal dreams (3%), abnormality in thinking (3%),
normally during pregnancy. The discontinuation of lipid paresthesia (3%), agitation (2% to 3%), apathy (≥1%
lowering medications temporarily during pregnancy is to 3%), central nervous system stimulation (2%),
not expected to have significant impact on the long term chills (2%), depression (2%), hypertonia (2%), psy-
outcomes of primary hypercholesterolemia treatment. choneurosis (2%), twitching (2%), amnesia (≥1%),
manic reaction (≥1%), myoclonus (≥1%), psychotic
Fluvastatin should be discontinued immediately if an
reaction (≥1%), malaise (≤1%)
unplanned pregnancy occurs during treatment.
Dermatologic: Diaphoresis (6% to 7%), ecchymoses
Adequate contraception is recommended if an HMG- (4%), acne vulgaris (2%)
CoA reductase inhibitor is required in females of repro- Endocrine & metabolic: Decreased libido (2% to 10%;
ductive potential. Females planning a pregnancy should incidence higher in males), hypermenorrhea (3%),
discontinue the HMG-CoA reductase inhibitor 1 to 2 weight loss (≥1% to 2%), weight gain (≥1%)
months prior to attempting to conceive (AHA/ACC Gastrointestinal: Dyspepsia (8% to 10%), constipation
[Grundy 2018]). (4% to 10%), vomiting (5% to 6%), abdominal pain
(5%), flatulence (4%), dental caries (≤3%), tooth loss
(≤3%), toothache (≤3%), dysgeusia (2% to 3%),
FluvoxaMINE (floo VOKS a meen)
dysphagia (2%), gingivitis (2%)
Related Information Genitourinary: Urinary frequency (3%), sexual disor-
der (2% to 3%), impotence (2%), urinary tract infec-
Management of the Patient With Anxiety or Depression
tion (2%), urinary retention (1%)
on page 1564
Hepatic: Abnormal hepatic function tests (2%)
Vasoconstrictor Interactions With Antidepressants on
Infection: Tooth abscess (≤3%), viral infection (2%)
page 1606
Neuromuscular & skeletal: Tremor (5% to 8%), myal-
Brand Names: Canada Luvox gia (5%), hyperkinesia (≥1%), hypokinesia (≥1%)
Pharmacologic Category Antidepressant, Selective Ophthalmic: Amblyopia (2% to 3%)
Serotonin Reuptake Inhibitor Renal: Polyuria (2%)
Use Obsessive-compulsive disorder: Treatment of Respiratory: Upper respiratory tract infection (9%),
obsessive-compulsive disorder (OCD) in pediatric pharyngitis (6%), flu-like symptoms (3%), laryngitis
patients 8 to 17 years of age and adults. (3%), bronchitis (2%), dyspnea (2%), epistaxis (2%),
Local Anesthetic/Vasoconstrictor Precautions increased cough (≥1%), sinusitis (≥1%)
Although caution should be used in patients taking <1%, postmarketing, and/or case reports: Abnormal
tricyclic antidepressants, no interactions have been gait, activation syndrome, acute renal failure, aggres-
reported with vasoconstrictors and fluvoxamine, a non- sive behavior, agranulocytosis, akinesia, amenorrhea,
tricyclic antidepressant which acts to increase seroto- anaphylaxis, anemia, angina pectoris, angioedema,
nin; no precautions appear to be needed angle-closure glaucoma, anuria, aplastic anemia,
Effects on Dental Treatment Key adverse event(s) apnea, asthma, ataxia, blurred vision, bradycardia,
related to dental treatment: Xerostomia (normal salivary bruxism, bullous skin disease, cardiac conduction
flow resumes upon discontinuation) and abnormal delay, cardiomyopathy, cardiorespiratory arrest, cere-
taste. Problems with SSRI-induced bruxism have been brovascular accident, cholecystitis, cholelithiasis, col-
reported and may preclude their use; clinicians attempt- itis, crying, decreased white blood cell count, delirium,
ing to evaluate any patient with bruxism or involuntary diplopia, drowsiness (neonatal), dysarthria, dyskine-
muscle movement, who is simultaneously being treated sia, dystonia, extrapyramidal reaction, fatigue, fever,
with an SSRI drug, should be aware of the potential first degree atrioventricular block, gastroesophageal
association. See Effects on Bleeding and Dental Health reflux disease, gastrointestinal hemorrhage, glossal-
Professional Considerations. gia, goiter, hallucination, hematemesis, hematuria,
Effects on Bleeding Selective serotonin reuptake hemoptysis, hepatitis, homicidal ideation, hypercho-
inhibitors such as fluvoxamine may impair platelet lesterolemia, hyperglycemia, hypersensitivity reaction,
aggregation due to platelet serotonin depletion, possi- hypoglycemia, hypokalemia, hyponatremia, hypothyr-
bly increasing the risk of a bleeding complication. The oidism, IgA vasculitis, impulsivity, interstitial pulmo-
risk of a bleeding complication can be increased by nary disease, intestinal obstruction, intoxicated
coadministration of other antiplatelet agents such as feeling, irritability, jaundice, jitteriness, laryngismus,
NSAIDs and aspirin. lethargy, leukocytosis, leukopenia, loss of conscious-
Adverse Reactions Frequency varies by dosage form ness, lymphadenopathy, melena, myasthenia, myo-
and indication. Adverse reactions reported as a compo- cardial infarction, myopathy, neuroleptic malignant
site of all indications. syndrome (Stevens 2008), outbursts of anger, pan-
>10%: creatitis, paralysis, Parkinsonian-like syndrome, peri-
Central nervous system: Headache (22% to 35%), carditis, porphyria, priapism, prolonged Q-T interval on
insomnia (21% to 35%), drowsiness (22% to 27%), ECG, purpura, Raynaud's phenomenon (Khouri 2016;
dizziness (11% to 15%), nervousness (10% to 12%) Peiró 2007), renal insufficiency, rhabdomyolysis, seiz-
Gastrointestinal: Nausea (34% to 40%), diarrhea (11% ure, serotonin syndrome, shock, SIADH, ST segment
to 18%), xerostomia (10% to 14%), anorexia (6% changes on ECG, Stevens-Johnson syndrome, suici-
to 14%) dal tendencies, supraventricular extrasystole, tachy-
Genitourinary: Ejaculatory disorder (8% to 11%) cardia, tardive dyskinesia, thrombocytopenia,
Neuromuscular & skeletal: Weakness (14% to 26%) thromboembolism, toxic epidermal necrolysis, vascu-
1% to 10%: litis, ventricular arrhythmia, ventricular tachycardia
Cardiovascular: Chest pain (3%), palpitations (3%), (including torsades de pointes)
vasodilation (2% to 3%), hypertension (1% to 2%), Mechanism of Action Inhibits CNS neuron serotonin
edema (≥1%), hypotension (≥1%), syncope (≥1%) uptake; minimal or no effect on reuptake of
625
FLUVOXAMINE
norepinephrine or dopamine; does not significantly bind Use Megaloblastic and macrocytic anemias due to
to alpha-adrenergic, histamine or cholinergic receptors folate deficiency: Treatment of megaloblastic and
Pharmacodynamics/Kinetics macrocytic anemias due to folate deficiency
Onset of Action Individual responses may vary; Local Anesthetic/Vasoconstrictor Precautions
however, 8 to 12 weeks of treatment are needed for No information available to require special precautions
patients with obsessive-compulsive disorder and 4 to Effects on Dental Treatment No significant effects or
8 weeks of treatment are needed for patients with complications reported
depression before determining if a patient is partially Effects on Bleeding No information available to
or nonresponsive (APA, 2010; APA 2007). require special precautions
Half-life Elimination ~14 to 16 hours; ~17 to 26 Adverse Reactions Frequency not defined.
hours in the elderly Cardiovascular: Flushing (slight)
Time to Peak Plasma: 3 to 8 hours Central nervous system: Malaise (general)
Pregnancy Risk Factor C Dermatologic: Erythema, pruritus, skin rash
Pregnancy Considerations Adverse events have Hypersensitivity: Hypersensitivity reaction
been observed in animal reproduction studies. Fluvox- Respiratory: Bronchospasm
amine crosses the human placenta. An increased risk Mechanism of Action
of teratogenic effects, including cardiovascular defects, Folic acid is necessary for formation of a number of
may be associated with maternal use of fluvoxamine or coenzymes in many metabolic systems, particularly
other SSRIs; however, available information is conflict- for purine and pyrimidine synthesis; required for nucle-
ing. Nonteratogenic effects in the newborn following oprotein synthesis and maintenance in erythropoiesis;
SSRI/SNRI exposure late in the third trimester include stimulates WBC and platelet production in folate defi-
respiratory distress, cyanosis, apnea, seizures, temper- ciency anemia.
ature instability, feeding difficulty, vomiting, hypoglyce- In the treatment of methanol intoxication, folic acid
mia, hypo- or hypertonia, hyper-reflexia, jitteriness, enhances the metabolism of formic acid, the toxic
irritability, constant crying, and tremor. Symptoms may metabolite of methanol, to nontoxic metabolites (Bar-
be due to the toxicity of the SSRIs/SNRIs or a discontin- celoux 2002).
uation syndrome and may be consistent with serotonin Pharmacodynamics/Kinetics
syndrome associated with SSRI treatment. Persistent Onset of Action Peak effect: Oral: 0.5 to 1 hour
pulmonary hypertension of the newborn (PPHN) has Time to Peak Oral: 1 hour
also been reported with SSRI exposure. The long-term Pregnancy Considerations
effects of in utero SSRI exposure on infant development Water soluble vitamins cross the placenta (IOM 1998).
and behavior are not known.
Folate requirements increase during pregnancy (IOM
The ACOG recommends that therapy with SSRIs or 1998). Folate supplementation during the periconcep-
SNRIs during pregnancy be individualized; treatment of tual period decreases the risk of neural tube defects. All
depression during pregnancy should incorporate the females planning a pregnancy or who may potentially
clinical expertise of the mental health clinician, obste- become pregnant should begin folic acid supplementa-
trician, primary health care provider, and pediatrician. tion prior to conception. Higher doses are required in
According to the American Psychiatric Association females at high risk of neural tube defects (ACOG 2017;
(APA), the risks of medication treatment should be USPSTF 2017). Folic acid is also indicated for the
weighed against other treatment options and untreated treatment of anemias due to folate deficiency in preg-
depression. For women who discontinue antidepres- nant women.
sant medications during pregnancy and who may be
at high risk for postpartum depression, the medications
can be restarted following delivery. Treatment algo- Fomepizole (foe ME pi zole)
rithms have been developed by the ACOG and the
Brand Names: US Antizol
APA for the management of depression in women prior
to conception and during pregnancy. Brand Names: Canada Antizol
Pharmacologic Category Antidote
Pregnant women exposed to antidepressants during Use
pregnancy are encouraged to enroll in the National Ethylene glycol or methanol poisoning: Treatment of
Pregnancy Registry for Antidepressants (NPRAD). methanol or ethylene glycol poisoning alone or in
Women 18 to 45 years of age or their health care combination with hemodialysis
providers may contact the registry by calling Note: Fomepizole is the preferred antidote for known or
844-405-6185. Enrollment should be done as early in suspected ethylene glycol poisoning or methanol poi-
pregnancy as possible. soning. If fomepizole is unavailable or if the patient is
Dental Health Professional Considerations Prob- intolerant to fomepizole, ethanol therapy may be con-
lems with SSRI-induced bruxism have been reported sidered. Ethanol as an antidote is effective in the
and may preclude their use. Clinicians attempting to management of methanol and ethylene glycol poison-
evaluate any patient with bruxism or involuntary muscle ing (Thanacoody 2016; Zakharov 2015); however,
movement, who is simultaneously being treated with an ethanol is associated with a higher incidence of
SSRI drug, should be aware of the potential associa- adverse events and medication errors (Bestic 2009;
tion. Lepik 2009; Lepik 2011).
Folic Acid (FOE lik AS id) No information available to require special precautions
Brand Names: US FA-8 [OTC] related to dental treatment: Bad/metallic taste.
Brand Names: Canada Apo-Folic Effects on Bleeding No information available to
Pharmacologic Category Vitamin, Water Soluble require special precautions
626
FORMOTEROL
Adverse Reactions Local Anesthetic/Vasoconstrictor Precautions

>10%: No information available to require special precautions
Central nervous system: Headache (14%) Effects on Dental Treatment Key adverse event(s)
Gastrointestinal: Nausea (11%) related to dental treatment: Hemorrhage may occur at
1% to 10% (≤3% unless otherwise noted): any site. See Effects on Bleeding.
Cardiovascular: Bradycardia, facial flushing, hypoten- Effects on Bleeding Dose related bleeding is the most
sion, phlebitis, shock, tachycardia common adverse event. Bleeding from the gums is
Central nervous system: Dizziness (6%), drowsiness reported (3%). Moderate thrombocytopenia occurs in
(6%), metallic taste (≤6%), agitation, altered sense of 3% of patients and severe thrombocytopenia in 0.2%.
smell, anxiety, seizure, speech disturbance, vertigo Medical consult recommended.
Dermatologic: Skin rash Adverse Reactions As with all anticoagulants, bleed-
Gastrointestinal: Unpleasant taste (≤6%), abdominal ing is the major adverse effect. Hemorrhage may occur
pain, decreased appetite, diarrhea, heartburn, hic- at any site. Risk appears increased by a number of
cups, vomiting factors including renal dysfunction, age (>75 years),
Genitourinary: Anuria and weight (<50 kg).
Hematologic & oncologic: Anemia, disseminated intra- >10%: Hematologic & oncologic: Anemia (2% to 20%)
vascular coagulation (DIC), eosinophilia, lymphan- 1% to 10%:
gitis Cardiovascular: Hypotension (≤4%)
Hepatic: Increased liver enzymes Central nervous system: Insomnia (≤5%), dizziness
Local: Application site reaction, inflammation at injec- (≤4%), confusion (1% to 3%)
tion site, pain at injection site Dermatologic: Increased wound secretion (≤5%), skin
Neuromuscular & skeletal: Back pain blister (≤3%)
Ophthalmic: Nystagmus, transient blurred vision, vis- Endocrine & metabolic: Hypokalemia (≤4%)
ual disturbance Hematologic & oncologic: Purpura (≤4%), thrombocy-
Respiratory: Pharyngitis topenia (50,000 to 100,000/mm3: 3%), hematoma
Miscellaneous: Fever, multi-organ failure (2% to 3%), minor hemorrhage (2% to 3%), major
<1%, postmarketing and/or case reports: Hypersensi- hemorrhage (1% to 3%; risk of major hemorrhage
tivity reaction (mild; mild rash, eosinophilia) increased as high as 5% in patients receiving initial
Mechanism of Action Fomepizole competitively inhib- dose <6 hours following surgery), postoperative
its alcohol dehydrogenase, an enzyme which catalyzes hemorrhage (≤2%)
the metabolism of ethanol, ethylene glycol, and meth- Hepatic: Increased serum ALT (>3 × ULN: 1% to 3%),
anol to their toxic metabolites. Ethylene glycol is metab- increased serum AST (>3 × ULN: <1% to ≤2%)
Infection: postoperative wound infection (abdominal
olized to glycoaldehyde, then oxidized to glycolate,
surgery: 5%)
glyoxylate, and oxalate. Glycolate and oxalate are
Respiratory: Epistaxis (VTE: 1%)
responsible for metabolic acidosis and renal damage.
<1%, postmarketing, and/or case reports: Anaphylac-
Methanol is metabolized to formaldehyde, then oxidized
toid reaction, anaphylaxis, angioedema, catheter site
to formic acid. Formic acid is responsible for metabolic
thrombosis (during PCI; without heparin), elevated
acidosis and visual disturbances.
aPTT associated with bleeding, epidural hematoma,
hemorrhagic death, injection site reaction (bleeding at
Onset of Action Peak effect: Maximum: 1.5-2 hours injection site, skin rash, pruritus), intracranial hemor-
Half-life Elimination Has not been calculated; varies rhage, reoperation due to bleeding, severe thrombo-
with dose cytopenia (<50,000/mm 3 ), spinal hematoma,
Pregnancy Risk Factor C thrombocytopenia (with thrombosis)
Pregnancy Considerations Animal reproduction Mechanism of Action Fondaparinux is a synthetic
studies have not been conducted. In general, medica- pentasaccharide that causes an antithrombin III-medi-
tions used as antidotes should take into consideration ated selective inhibition of factor Xa. Neutralization of
the health and prognosis of the mother; antidotes factor Xa interrupts the blood coagulation cascade and
should be administered to pregnant women if there is inhibits thrombin formation and thrombus development.
a clear indication for use and should not be withheld Pharmacodynamics/Kinetics
because of fears of teratogenicity (Bailey, 2003). Half-life Elimination 17 to 21 hours; prolonged with
renal impairment and in the elderly
Fondaparinux (fon da PARE i nuks) Time to Peak SubQ: ~2 to 3 hours
Pregnancy Considerations Based on case reports,
Brand Names: US Arixtra small amounts of fondaparinux have been detected in
Brand Names: Canada Arixtra the umbilical cord following multiple doses during preg-
Pharmacologic Category Anticoagulant; Anticoagu- nancy (Dempfle 2004). Use of fondaparinux in preg-
lant, Factor Xa Inhibitor; Pentasaccharide, Synthetic nancy should be limited to those women who have
Use severe allergic reactions to heparin, including heparin-
Acute deep vein thrombosis: Treatment of acute DVT induced thrombocytopenia, and who cannot receive
in conjunction with warfarin. danaparoid (Guyatt 2012).
Acute pulmonary embolism: Treatment of acute PE in
conjunction with warfarin. Formoterol (for MOH te rol)
Venous thromboembolism prophylaxis in surgical
patients: Prophylaxis of VTE in patients undergoing Related Information
surgery for hip replacement, knee replacement, hip Respiratory Diseases on page 1467
fracture (including extended prophylaxis following hip Brand Names: US Foradil Aerolizer [DSC]; Perforo-
fracture surgery), or abdominal surgery (in patients at mist
risk for thromboembolic complications). Brand Names: Canada Foradil; Oxeze Turbuhaler
627
FORMOTEROL
Pharmacologic Category Beta2 Agonist; Beta2-Adre- Peak effect: Powder for inhalation: 80% of peak effect
nergic Agonist, Long-Acting within 15 minutes; Solution for nebulization: 2 hours
Use Duration of Action Improvement in FEV1 observed
US labeling: for 12 hours in most patients
Asthma: Treatment of asthma (only as concomitant Half-life Elimination Powder: ~10-14 hours; Nebu-
therapy with an inhaled corticosteroid) in patients lized solution: ~7 hours
with reversible obstructive airway disease, including Time to Peak Maximum improvement in FEV1 in 1-3
patients with symptoms of nocturnal asthma (Foradil hours
Aerolizer). Pregnancy Considerations Adverse events were
Chronic obstructive pulmonary disease (COPD): observed in some animal reproduction studies. Beta-
Maintenance treatment of bronchoconstriction in agonists may interfere with uterine contractility if admin-
patients with COPD (Foradil Aerolizer, Perforomist). istered during labor.
Exercise-induced bronchospasm: Prevention of Product Availability Foradil Aerolizer is no longer
exercise-induced bronchospasm when administered available in the US.
on an as-needed basis (monotherapy may be indi-
cated in patients without persistent asthma) (Foradil
Aerolizer). Fosamprenavir (FOS am pren a veer)
Canadian labeling:
Related Information
Asthma: Treatment of asthma (only as concomitant
therapy with an inhaled corticosteroid) in patients
with reversible obstructive airway disease, including Brand Names: US Lexiva
patients with symptoms of nocturnal asthma (Foradil, Brand Names: Canada Telzir
Oxeze Turbuhaler). Pharmacologic Category Antiretroviral, Protease
COPD: Maintenance treatment of COPD (Foradil). Inhibitor (Anti-HIV)
Exercise-induced bronchospasm: Prevention of Use HIV-1 infection, treatment: Treatment of HIV-1
exercise-induced bronchospasm when administered infection, in combination with other antiretroviral agents
on an as-needed basis (monotherapy may be indi- Local Anesthetic/Vasoconstrictor Precautions
cated in patients without persistent asthma) (Oxeze No information available to require special precautions
Turbuhaler). Effects on Dental Treatment No significant effects or
Local Anesthetic/Vasoconstrictor Precautions complications reported
No information available to require special precautions Effects on Bleeding No information available to
Effects on Dental Treatment Key adverse event(s) require special precautions
related to dental treatment: Xerostomia (normal salivary Adverse Reactions
flow resumes upon discontinuation). >10%:
Effects on Bleeding No information available to Dermatologic: Skin rash (≤19%; onset: ~11 days;
require special precautions duration: ~13 days)
Adverse Reactions Endocrine & metabolic: Hypertriglyceridemia
1% to 10%: (>750 mg/dL: ≤11%)
Cardiovascular: Chest pain (2% to 3%) Gastrointestinal: Diarrhea (5% to 13%; moderate-to-
Central nervous system: Anxiety (2%), dizziness (2%), severe)
insomnia (2%), voice disorder (1%), headache 1% to 10%:
Dermatologic: Pruritus (2%), skin rash (1%) Central nervous system: Fatigue (2% to 4%; moder-
Gastrointestinal: Diarrhea (5%), nausea (5%), xero- ate-to-severe), headache (2% to 4%; moderate-to-
stomia (1% to 3%), vomiting (2%), abdominal pain, severe)
dyspepsia, gastroenteritis Dermatologic: Pruritus (7% to 8%)
Neuromuscular & skeletal: Muscle cramps (2%), Endocrine & metabolic: Hyperglycemia
tremor (>251 mg/dL: ≤2%)
Respiratory: Respiratory tract infection (3% to 7%), Gastrointestinal: Increased serum lipase (>2x ULN:
exacerbation of asthma (ages 5 to 12 years: 5% to 5% to 8%), nausea (3% to 7%; moderate-to-severe),
6%; age >12 years: <4%; acute deterioration: <1%), vomiting (2% to 6%; moderate-to-severe), abdominal
bronchitis (5%), pharyngitis (3% to 4%), sinusitis pain (≤2%; moderate-to-severe)
(3%), dyspnea (2%), tonsillitis (1%) Hematologic & oncologic: Neutropenia (<750 cells/
Miscellaneous: Fever (2%) mm3: 3%)
<1%, postmarketing, and/or case reports: Agitation, Hepatic: Increased serum transaminases (>5x ULN:
anaphylaxis (including severe hypotension/angioe- 4% to 8%)
dema), angina pectoris, atrial fibrillation, behavioral <1%, postmarketing, and/or case reports: Angioedema,
changes, cardiac arrhythmia, cough, decreased glu- cerebrovascular accident, hypercholesterolemia, myo-
cose tolerance, dermatitis, disturbed sleep, dysgeusia, cardial infarction, nephrolithiasis, oral paresthesia,
fatigue, hyperglycemia, hypertension, hypokalemia, Stevens-Johnson syndrome
malaise, metabolic acidosis, muscle spasm, nervous- Mechanism of Action Fosamprenavir is rapidly and
ness, palpitations, paradoxical bronchospasm, pro- almost completely converted to amprenavir by cellular
l o ng e d Q - T in t e r v a l on EC G , r es t l e ss n e s s , phosphatases in vivo. Amprenavir binds to the site of
tachycardia, urticaria, variable blood pressure, ven- HIV-1 protease activity and inhibits cleavage of viral
tricular premature contractions Gag-Pol polyprotein precursors into individual func-
Mechanism of Action Relaxes bronchial smooth tional proteins required for infectious HIV. This results
muscle by selective action on beta2 receptors with little in the formation of immature, noninfectious viral par-
effect on heart rate. Formoterol has a long-acting effect. ticles.
Pharmacodynamics/Kinetics Pharmacodynamics/Kinetics
Onset of Action Powder for inhalation: Within 3 Half-life Elimination ~7.7 hours (amprenavir)
minutes Time to Peak 1.5 to 4 hours (median: 2.5 hours)
628
FOSCARNET
Pregnancy Considerations (initial and repeat courses; in combination with other

Fosamprenavir has a low level of transfer across the antiemetics) in patients ≥6 months of age
human placenta. Limitations of use: Fosaprepitant has not been studied
for the management of existing nausea and vomiting.
Data collected by the antiretroviral pregnancy registry
are insufficient to evaluate human teratogenic risk.
Maternal antiretroviral therapy (ART) may increase the
risk of preterm delivery, although available information
related to dental treatment: Stomatitis, taste disturban-
is conflicting possibly due to variability of maternal
factors (disease severity; gestational age at initiation ces, xerostomia (normal salivary flow resumes upon
of therapy). An increased risk of stillbirth, low birth discontinuation).
weight, and small for gestational age infants has been Effects on Bleeding No information available to
observed in some but not all studies. Because there is require special precautions
clear benefit to appropriate treatment, maternal ART Adverse Reactions Adverse reactions reported with
should not be withheld due to concerns for adverse fosaprepitant (as part of a combination chemotherapy
neonatal outcomes. Long-term follow-up is recom- regimen) occurring at a higher frequency than standard
mended for all infants exposed to antiretroviral medi- antiemetic therapy. Also see aprepitant monograph for
cations; children who develop significant organ system additional adverse reactions.
abnormalities of unknown etiology (particularly of the >10%:
CNS or heart) should be evaluated for potential mito- Central nervous system: Fatigue (15%)
chondrial dysfunction. Hyperglycemia, new onset of Gastrointestinal: Diarrhea (13%)
diabetes mellitus, or diabetic ketoacidosis have been 1% to 10%:
reported with protease inhibitors; it is not clear if preg- Central nervous system: Peripheral neuropathy (3%)
nancy increases this risk. Gastrointestinal: Dyspepsia (2%)
The Health and Human Services (HHS) Perinatal HIV Hematologic & oncologic: Neutropenia (8%), anemia
Guidelines do not recommend use of fosamprenavir in (3%), leukopenia (2%)
pregnancy and females who become pregnant on Local: Infusion-site reaction (2% to 3%; includes indu-
fosamprenavir should be switched to a recommended ration at injection site, infusion-site pain, local pruri-
regimen. If use is continued in pregnant females who tus, localized erythema)
are virologically suppressed on a stable fosamprenavir- Neuromuscular & skeletal: Weakness (4%), limb
containing regimen, fosamprenavir should only be given pain (2%)
with standard ritonavir-boosted twice-daily dosing and <1%, postmarketing, and/or case reports: Anaphylactic
close monitoring of viral load (lower exposure has been shock, anaphylaxis, dyspnea, erythema, flushing,
observed during pregnancy). Unboosted fosamprenavir hypersensitivity reaction, hypotension, pruritus, skin
and once-daily dosing with ritonavir are not recom- rash, Stevens-Johnson syndrome, syncope, toxic epi-
mended. dermal necrolysis, urticaria
In general, ART is recommended for all pregnant Mechanism of Action Fosaprepitant is a prodrug of
females with HIV to keep the viral load below the limit aprepitant, a substance P/neurokinin 1 (NK1) receptor
of detection and reduce the risk of perinatal trans- antagonist. Fosaprepitant is rapidly converted to apre-
mission. Monitoring during pregnancy is more frequent pitant, which prevents acute and delayed vomiting by
than in non-pregnant adults. ART should be continued inhibiting the substance P/neurokinin 1 (NK1) receptor;
postpartum for all females living with HIV and can be also augments the antiemetic activity of the 5-HT3
modified after delivery. receptor antagonist and corticosteroid activity and inhib-
its chemotherapy-induced emesis.
Half-life Elimination Aprepitant: ~9 to 13 hours
Pregnancy Registry (1-800-258-4263 or http://www.- Time to Peak Fosaprepitant is converted to aprepitant
APRegistry.com). Health care providers caring for within 30 minutes after the end of infusion
HIV-infected females and their infants may contact the Pregnancy Considerations Adverse events were not
National Perinatal HIV Hotline (888-448-8765) for clin- observed in animal reproduction studies for aprepitant.
ical consultation (HHS [perinatal] 2018). Efficacy of hormonal contraceptive may be reduced;
alternative or additional methods of contraception
should be used both during treatment with fosaprepitant
Fosaprepitant (fos a PRE pi tant) or aprepitant and for at least 1 month following the last
fosaprepitant/aprepitant dose.
Brand Names: US Emend
Brand Names: Canada Emend IV
Pharmacologic Category Antiemetic; Substance P/ Foscarnet (fos KAR net)
Neurokinin 1 Receptor Antagonist
Use Related Information
Prevention of chemotherapy-induced nausea and Systemic Viral Diseases on page 1496
vomiting: Brand Names: US Foscavir
Prevention of acute and delayed nausea and vomiting Brand Names: Canada Foscavir
associated with highly emetogenic chemotherapy, Pharmacologic Category Antiviral Agent
including high-dose cisplatin (initial and repeat Use
courses; in combination with other antiemetics) in Cytomegalovirus retinitis: Treatment of cytomegalo-
patients ≥6 months of age virus (CMV) retinitis in persons with AIDS
Prevention of delayed nausea and vomiting associ- Herpes simplex virus: Treatment of acyclovir-resistant
ated with moderately emetogenic chemotherapy mucocutaneous herpes simplex virus (HSV) infections
629
FOSCARNET
in immunocompromised persons (eg, with (1% to 5%), constipation (1% to 5%), dysgeusia
advanced AIDS) (1% to 5%), dyspepsia (1% to 5%), dysphagia (1%
Local Anesthetic/Vasoconstrictor Precautions to 5%), flatulence (1% to 5%), melena (1% to 5%),
Foscarnet is one of the drugs confirmed to prolong pancreatitis (1% to 5%), xerostomia (1% to 5%)
the QT interval and is accepted as having a risk of Genitourinary: Nephrotoxicity (8%), dysuria (1% to
causing torsade de pointes. In terms of epinephrine, it 5%), nocturia (1% to 5%), urinary retention (1% to
is not known what effect vasoconstrictors in the local 5%), urinary tract infection (1% to 5%)
anesthetic regimen will have in patients with a known Hematologic & oncologic: Bone marrow suppression
history of congenital prolonged QT interval or in patients (10%), leukopenia (≥5%), mineral abnormalities
taking any medication that prolongs the QT interval. (≥5%), neutropenia (≥5%), abnormal white cell differ-
Until more information is obtained, it is suggested that ential (1% to 5%), altered platelet function (1% to
the clinician consult with the physician prior to the use of 5%), lymphadenopathy (1% to 5%), pseudolym-
a vasoconstrictor in suspected patients, and that the phoma (1% to 5%), rectal hemorrhage (1% to 5%),
vasoconstrictor (epinephrine, mepivacaine and levonor- sarcoma (1% to 5%), thrombocytopenia (1% to 5%)
defrin [Carbocaine® 2% with Neo-Cobefrin®]) be used Hepatic: Abnormal hepatic function tests (1% to 5%),
with caution. increased lactate dehydrogenase (1% to 5%),
Effects on Dental Treatment Key adverse event(s) increased serum alkaline phosphatase (1% to 5%),
related to dental treatment: Xerostomia (normal salivary increased serum ALT (1% to 5%), increased serum
flow resumes upon discontinuation), taste perversion, AST (1% to 5%)
and ulcerative stomatitis. Infection: Infection (≥5%), sepsis (≥5%), abscess,
Effects on Bleeding No information available to bacterial infection (1% to 5%), fungal infection (1%
require special precautions to 5%)
Adverse Reactions Local: Inflammation at injection site (1% to 5%), pain
>10%: at injection site (1% to 5%)
Central nervous system: Headache (26%) Neuromuscular & skeletal: Muscle spasm (≥5%), neu-
Endocrine & metabolic: Hypokalemia (16% to 48%), ropathy (peripheral; ≥5%), weakness (≥5%), arthral-
hypocalcemia (15% to 30%), hypomagnesemia gia (1% to 5%), back pain (1% to 5%), leg cramps
(15% to 30%), hypophosphatemia (8% to 26%) (1% to 5%), myalgia (1% to 5%), tremor (1% to 5%)
Gastrointestinal: Nausea (47%), diarrhea (30%), vom- Ophthalmic: Visual disturbance (≥5%), conjunctivitis
iting (26%) (1% to 5%), eye pain (1% to 5%)
Hematologic & oncologic: Anemia (33%), granulocy- Renal: Decreased creatinine clearance (≥5%),
topenia (17%) increased serum creatinine (≥5%), acute renal failure
Renal: Renal insufficiency (27%) (1% to 5%), increased blood urea nitrogen (1% to
Miscellaneous: Fever (65%) 5%), polyuria (1% to 5%)
1% to 10%: Respiratory: Cough (≥5%), dyspnea (≥5%), broncho-
Cardiovascular: Chest pain (1% to 5%; including tran- spasm (1% to 5%), flu-like symptoms (1% to 5%),
sient chest pain as part of infusion reactions), edema hemoptysis (1% to 5%), pharyngitis (1% to 5%),
(1% to 5%), facial edema (1% to 5%), first degree pneumonia (1% to 5%), pneumothorax (1% to 5%),
atrioventricular block (1% to 5%), flushing (1% to pulmonary infiltrates (1% to 5%), respiratory failure
5%), hypertension (1% to 5%), hypotension (1% to
(1% to 5%), respiratory insufficiency (1% to 5%),
5%), palpitations (1% to 5%), sinus tachycardia (1%
rhinitis (1% to 5%), sinusitis (1% to 5%), stridor
to 5%), ST segment changes on ECG (1% to 5%),
(1% to 5%)
thrombosis (1% to 5%)
<1%, postmarketing, and/or case reports: Coma, dehy-
Central nervous system: Seizure (10%), anxiety
dration, diabetes insipidus (usually nephrogenic),
(≥5%), confusion (≥5%), depression (≥5%), dizzi-
erythema multiforme, esophageal ulcer, extravasation,
ness (≥5%), fatigue (≥5%), hypoesthesia (≥5%),
Fanconi syndrome, gastrointestinal hemorrhage, glo-
malaise (≥5%), neuropathy (≥5%), pain (≥5%), par-
esthesia (≥5%), rigors (≥5%), abnormal electroence- merulonephritis, hematuria, hypercalcemia, hypersen-
phalogram (1% to 5%), aggressive behavior (1% to sitivity reaction (including anaphylactic shock,
5%), agitation (1% to 5%), amnesia (1% to 5%), angioedema, urticaria), hypoproteinemia, increased
aphasia (1% to 5%), ataxia (1% to 5%), cerebrovas- amylase, increased creatine phosphokinase,
cular disease (1% to 5%), dementia (1% to 5%), increased gamma-glutamyl transferase, increased
hallucination (1% to 5%), insomnia (1% to 5%), serum lipase, local irritation (genitals), localized
meningitis (1% to 5%), nervousness (1% to 5%), edema, myasthenia, myopathy, myositis, nephrolithia-
sensory disturbance (1% to 5%), somnolence (1% sis, nephrotic syndrome, pancytopenia, penile ulcer-
to 5%), stupor (1% to 5%) ation, prolonged Q-T interval on ECG, proteinuria,
Dermatologic: Diaphoresis (≥5%), skin rash (≥5%), renal disease (crystal-induced), renal tubular acidosis,
dermal ulcer (1% to 5%), erythematous rash (1% to renal tubular necrosis, rhabdomyolysis, SIADH, status
5%), maculopapular rash (1% to 5%), pruritus (1% to epilepticus, Stevens-Johnson syndrome, torsades de
5%), seborrhea (1% to 5%), skin discoloration (1% pointes, toxic epidermal necrolysis, vaginal ulcer, ven-
to 5%) tricular arrhythmia
Endocrine & metabolic: Hyperphosphatemia (6%), Mechanism of Action Pyrophosphate analogue which
electrolyte disturbance (≥5%), abnormal albumin- acts as a noncompetitive inhibitor of many viral RNA
Globulin ratio (1% to 5%), acidosis (1% to 5%), and DNA polymerases as well as HIV reverse tran-
albuminuria (1% to 5%), cachexia (1% to 5%), hypo- scriptase. Similar to ganciclovir, foscarnet is a virostatic
natremia (1% to 5%), increased lactate dehydrogen- agent. Foscarnet does not require activation by thymi-
ase (1% to 5%), increased thirst (1% to 5%), weight dine kinase.
loss (1% to 5%) Pharmacodynamics/Kinetics
Gastrointestinal: Abdominal pain (≥5%), anorexia Half-life Elimination Elimination: ~3 to 4 hours; ter-
(≥5%), aphthous stomatitis (1% to 5%), cachexia minal: ~88 hours (due to bone deposition)
630
FOSINOPRIL
Pregnancy Considerations Information related to

use in pregnancy is limited (Alvarez-McLeod 1999). Fosinopril (foe SIN oh pril)
Monitoring of amniotic fluid volumes by ultrasound is
recommended weekly after 20 weeks of gestation to Related Information
detect oligohydramnios (HHS [OI adult 2015]). Cardiovascular Diseases on page 1442
Dental Health Professional Considerations See Pharmacologic Category Angiotensin-Converting
Local Anesthetic/Vasoconstrictor Precautions Enzyme (ACE) Inhibitor; Antihypertensive
Use
Heart failure: Adjunctive treatment of heart failure (HF)
Fosfomycin (fos foe MYE sin) Guideline recommendations: The American College
of Cardiology/American Heart Association (ACC/
Brand Names: US Monurol AHA) 2013 Heart Failure Guidelines recommend
Brand Names: Canada Monurol the use of ACE inhibitors, along with other guide-
Pharmacologic Category Antibiotic, Miscellaneous line-directed medical therapies, to prevent progres-
Use sion of HF and reduced ejection fraction in
Cystitis, acute uncomplicated: Treatment of uncom- asymptomatic patients with or without a history of
plicated urinary tract infections (acute cystitis) in myocardial infarction (Stage B HF), or to treat those
women due to susceptible strains of Escherichia coli with symptomatic heart failure and reduced ejection
and Enterococcus faecalis. fraction to reduce morbidity and mortality (Stage C
Limitations of use: Not indicated for the treatment of HFrEF).
pyelonephritis or perinephric abscess. If persistence Hypertension: Management of hypertension
or reappearance of bacteriuria occurs after treatment Guideline recommendations: The 2017 Guideline
with fosfomycin, other therapeutic agents should be for the Prevention, Detection, Evaluation, and Man-
selected. agement of High Blood Pressure in Adults recom-
Local Anesthetic/Vasoconstrictor Precautions mends if monotherapy is warranted, in the absence
No information available to require special precautions of comorbidities (eg, cerebrovascular disease,
Effects on Dental Treatment No significant effects or chronic kidney disease, diabetes, heart failure, ische-
complications reported mic heart disease, etc.), that thiazide-like diuretics or
Effects on Bleeding No information available to dihydropyridine calcium channel blockers may be
require special precautions preferred options due to improved cardiovascular
Adverse Reactions endpoints (eg, prevention of heart failure and stroke).
1% to 10%: ACE inhibitors and ARBs are also acceptable for
Central nervous system: Headache (4% to 10%), pain monotherapy. Combination therapy may be required
to achieve blood pressure goals and is initially pre-
(2%), dizziness (1% to 2%)
ferred in patients at high risk (stage 2 hypertension or
atherosclerotic cardiovascular disease [ASCVD] risk
Gastrointestinal: Diarrhea (9% to 10%), nausea (4% to
≥10%) (ACC/AHA [Whelton 2017]).
5%), abdominal pain (2%), dyspepsia (1% to 2%)
Genitourinary: Vaginitis (6% to 8%), dysmenor-
rhea (3%)
Neuromuscular & skeletal: Back pain (3%), weakness Effects on Dental Treatment Key adverse event(s)
(1% to 2%)
Respiratory: Rhinitis (5%), pharyngitis (3%)
ment; especially if lying in dental chair for extended
stools, anaphylaxis, angioedema, anorexia, aplastic
anemia, cholestatic jaundice, constipation, dermato-
logical disease, drowsiness, dysuria, ear disease, An angiotensin-converting enzyme (ACE) Inhibitor
exacerbation of asthma, fatigue, fever, flatulence, flu- cough is a dry, hacking, nonproductive cough that can
like symptoms, hearing loss, hematuria, hepatic potentially interfere with longer dental procedures if
necrosis, increased serum ALT, insomnia, lymphaden- patient has this side effect.
opathy, menstrual disease, migraine, myalgia, nerv- Effects on Bleeding No information available to
ousness, optic neuritis, paresthesia, pruritus, toxic require special precautions
megacolon, vomiting, xerostomia Adverse Reactions Frequency not always defined.
Mechanism of Action As a phosphonic acid deriva- Frequency ranges include data from hypertension and
tive, fosfomycin inhibits bacterial wall synthesis (bacter- heart failure trials. Higher rates of adverse reactions
icidal) by inactivating the enzyme, pyruvyl transferase, have generally been noted in patients with CHF. How-
which is critical in the synthesis of cell walls by bacteria ever, the frequency of adverse effects associated with
Pharmacodynamics/Kinetics placebo is also increased in this population.
Half-life Elimination 3 to 8 hours; CrCl <54 mL/ >10%: Central nervous system: Dizziness (1% to 2%;
minute: 50 hours cardiac failure patients: ≤12%)
Time to Peak Serum: 2 hours; within 4 hours with 1% to 10%:
high-fat meal Cardiovascular: Orthostatic hypotension (1% to 2%),
Pregnancy Considerations palpitations (1%)
Fosfomycin crosses the placenta. Central nervous system: Headache (3%), noncardiac
chest pain (≤2%), fatigue (1% to 2%)
Several studies have used a single dose therapy with Endocrine & metabolic: Hyperkalemia (3%)
fosfomycin for the treatment of asymptomatic bacter- Gastrointestinal: Diarrhea (2%), nausea and vomiting
iuria in pregnant women (Reeves 1992). However, (1% to 2%)
when treatment is needed in pregnant women, an Hepatic: Increased serum transaminases
appropriate antibiotic with a 3- to 7-day regimen is Neuromuscular & skeletal: Musculoskeletal pain
currently recommended (Nicolle 2005). (≤3%), weakness (1%)
631
FOSINOPRIL
Renal: Increased serum creatinine, renal function Chronic maternal hypertension itself is also associated
decompensation (patients with bilateral renal artery with adverse events in the fetus/infant and mother. ACE
stenosis or hypovolemia) inhibitors are not recommended for the treatment of
Respiratory: Cough (2% to 10%), upper respiratory uncomplicated hypertension in pregnancy (ACOG
infection (2%) 2013) and they are specifically contraindicated for the
<1%, postmarketing, and/or case reports: Abdominal treatment of hypertension and chronic heart failure
distention, anaphylactoid reaction, angina pectoris, during pregnancy by some guidelines (Regitz-Zagrosek
angioedema, arthralgia, behavioral changes, brady- 2011). In addition, ACE inhibitors should generally be
cardia, bronchospasm, cerebral infarction, cerebro- avoided in women of reproductive age (ACOG 2013). If
vascular accident, claudication, confusion, treatment for hypertension or chronic heart failure in
constipation, decreased libido, drowsiness, dysgeu- pregnancy is needed, other agents should be used
sia, dysphagia, edema, eosinophilia, epistaxis, eye (ACOG 2013; Regitz-Zagrosek 2011).
irritation, flatulence, flushing, gout, heartburn, hepati-
tis, hepatomegaly, hyperhidrosis, hypertension, hyper-
tensive crisis, hypotension, insomnia, laryngitis, lower
Fosnetupitant and Palonosetron
(fos net UE pi tant & pal oh NOE se tron)
extremity edema, lymphadenopathy, memory impair-
ment, mood changes, myalgia, myocardial infarction, Brand Names: US Akynzeo
numbness, pancreatitis, paranasal sinus disease Pharmacologic Category Antiemetic; Selective
(abnormality), paresthesia, pharyngitis, pleuritic chest 5-HT3 Receptor Antagonist; Substance P/Neurokinin 1
pain, pruritus, renal insufficiency, shock, skin photo- Receptor Antagonist
sensitivity, skin rash, sleep disorder, syncope, tachy- Use
cardia, tinnitus, tracheobronchitis, transient ischemic Chemotherapy-induced nausea and vomiting: Pre-
attacks, tremor, urinary frequency, urticaria, vertigo, vention of acute and delayed nausea and vomiting
visual disturbance, weight gain, xerostomia associated with initial and repeat courses of highly
Mechanism of Action Competitive inhibitor of angio- emetogenic chemotherapy (in combination with dex-
tensin-converting enzyme (ACE); prevents conversion amethasone).
of angiotensin I to angiotensin II, a potent vasoconstric- Limitations of use: Has not been studied for the pre-
tor; results in lower levels of angiotensin II which causes vention of nausea and vomiting associated with
an increase in plasma renin activity and a reduction in anthracycline plus cyclophosphamide (AC) chemo-
aldosterone secretion; a CNS mechanism may also be therapy.
involved in hypotensive effect as angiotensin II Local Anesthetic/Vasoconstrictor Precautions
increases adrenergic outflow from CNS; vasoactive No information available to require special precautions
kallikreins may be decreased in conversion to active Effects on Dental Treatment No significant effects or
hormones by ACE inhibitors, thus reducing blood pres- complications reported
sure Effects on Bleeding No information available to
Onset of Action 1 hour
Adverse Reactions See Palonosetron monograph.
Duration of Action 24 hours
Mechanism of Action Fosnetupitant is a prodrug of
Half-life Elimination Serum (fosinoprilat): netupitant, a selective substance P/neurokinin (NK1)
Children and Adolescents 6-16 years: 11-13 hours
receptor antagonist, which augments the antiemetic
Adults: 12 hours
activity of 5-HT3 receptor antagonists and corticoste-
Adults with CHF: 14 hours
roids to inhibit acute and delayed chemotherapy-
Time to Peak Serum: ~3 hours induced emesis. Palonosetron is a selective 5-HT3
Pregnancy Risk Factor D receptor antagonist, which blocks serotonin, both on
Pregnancy Considerations [US Boxed Warning]: vagal nerve terminals in the periphery and centrally in
Drugs that act on the renin-angiotensin system the chemoreceptor trigger zone. Palonosetron inhibits
can cause injury and death to the developing fetus. the cross-talk between the 5-HT3 and NK1 receptors.
Discontinue as soon as possible once pregnancy is The combination of palonosetron and netupitant works
detected. Fosinopril crosses the placenta. Drugs that synergistically to inhibit substance P response to a
act on the renin-angiotensin system are associated with greater extent than either agent alone (Aapro 2014).
oligohydramnios. Oligohydramnios, due to decreased Pharmacodynamics/Kinetics
fetal renal function, may lead to fetal lung hypoplasia Half-life Elimination Fosnetupitant: 0.75 ± 0.4 hours;
and skeletal malformations. The use of these drugs in Netupitant: 144 ± 73 hours; Palonosetron: 58 ± 27
pregnancy is also associated with anuria, hypotension, hours
renal failure, skull hypoplasia, and death in the fetus/ Time to Peak
neonate. Teratogenic effects may occur following At end of the 30-minute infusion
maternal use of an ACE inhibitor during the first trimes-
ter, although this finding may be confounded by mater-
observed in some animal reproduction studies using
nal disease. Because adverse fetal events are well
the components of this combination product.
documented with exposure later in pregnancy, ACE
inhibitor use in pregnant women is not recommended
(Seely 2014; Weber 2014). Infants exposed to an ACE Fosphenytoin (FOS fen i toyn)
hypotension, and oliguria. Oligohydramnios may not Related Information
appear until after irreversible fetal injury has occurred. Phenytoin on page 1079
Exchange transfusions or dialysis may be required to Brand Names: US Cerebyx
reverse hypotension or improve renal function, although Brand Names: Canada Cerebyx
data related to the effectiveness in neonates is limited. Pharmacologic Category Anticonvulsant, Hydantoin
632
FOSPHENYTOIN
Use pustular rash (≤1%), skin discoloration (≤1%), skin

Seizures: Control of generalized tonic-clonic status photosensitivity (≤1%), urticaria (≤1%)
epilepticus and the prevention and treatment of seiz- Endocrine & metabolic: Hypokalemia (>1%), acidosis
ures occurring during neurosurgery; short-term paren- (≤1%), albuminuria (≤1%), alkalosis (≤1%), cachexia
teral administration when oral phenytoin is not (≤1%), dehydration (≤1%), diabetes insipidus (≤1%),
possible hyperglycemia (≤1%), hyperkalemia (≤1%), hypo-
Guideline recommendations: Status epilepticus: A ben- phosphatemia (≤1%), ketosis (≤1%)
zodiazepine (eg, lorazepam, diazepam, midazolam) is Gastrointestinal: Nausea (IV: 9%; IM: 5%), tongue
the preferred initial treatment of status epilepticus disease (IV: 4%), xerostomia (IV: 4%), dysgeusia
according to clinical practice guidelines; IV fospheny- (3%), vomiting (IM: 3%; IV: 2%), constipation
toin among other antiepileptics (eg, IV valproic acid or (>1%), ageusia (≤1%), anorexia (≤1%), diarrhea
IV levetiracetam) is an option in patients failing first- (≤1%), dyspepsia (≤1%), dysphagia (≤1%), flatu-
line treatment (AES [Glauser 2016]; NCS lence (≤1%), gastritis (≤1%), gastrointestinal hemor-
[Glauser 2016]). rhage (≤1%), intestinal obstruction (≤1%), oral
Local Anesthetic/Vasoconstrictor Precautions paresthesia (≤1%), sialorrhea (≤1%), tenes-
No information available to require special precautions mus (≤1%)
Effects on Dental Treatment Key adverse event(s) Genitourinary: Pelvic pain (IV: 4%), dysuria (≤1%),
related to dental treatment: Tongue disorder and dry genital edema (≤1%), oliguria (≤1%), urethral pain
mouth. (≤1%), urinary incontinence (≤1%), urinary retention
Effects on Bleeding No information available to (≤1%), vaginitis (≤1%), vulvovaginal candidia-
require special precautions sis (≤1%)
Adverse Reactions Also refer to the phenytoin mono- Hematologic & oncologic: Anemia (≤1%), hypochro-
graph for additional adverse reactions. mic anemia (≤1%), leukocytosis (≤1%), leukopenia
>10%: (≤1%), lymphadenopathy (≤1%), petechia (≤1%),
Central nervous system: Burning sensation (≤44%), thrombocytopenia (≤1%)
paresthesia (≤44%), dizziness (IV: 31%; IM: 5%), Hepatic: Abnormal hepatic function tests (≤1%)
drowsiness (IV: 20%; IM: 7%), ataxia (IV: 4% to Hypersensitivity: Tongue edema (≤1%)
11%; IM: 8%) Infection: Infection (>1%), cryptococcosis (≤1%), sep-
Dermatologic: Pruritus (IV: 49%; IM: 3%; generally sis (≤1%)
transient; often reported in groin area) Local: Injection site reaction (>1%), pain at injection
Ophthalmic: Nystagmus disorder (IV: 44%; IM: 15%) site (>1%), bleeding at injection site (≤1%), inflam-
1% to 10%: mation at injection site (≤1%), swelling at injection
Cardiovascular: Hypotension (IV: 8%), vasodilatation site (≤1%)
(IV: 6%), tachycardia (IV: 2%), facial edema (>1%), Neuromuscular & skeletal: Tremor (IM: 10%; IV: 3%),
hypertension (>1%), atrial flutter (≤1%), bundle asthenia (IM: 9%; IV: 2%), back pain (IV: 2%),
branch block (≤1%), cardiac failure (≤1%), cardiome- arthralgia (≤1%), hyperkinetic muscle activity
galy (≤1%), cerebral infarction (≤1%), edema (≤1%), (≤1%), hypokinesia (≤1%), lower limb cramp (≤1%),
orthostatic hypotension (≤1%), palpitations (≤1%), myalgia (≤1%), myopathy (≤1%)
prolonged QT interval on ECG (≤1%), pulmonary Ophthalmic: Diplopia (IV: 3%), amblyopia (IV: 2%),
embolism (≤1%), shock (≤1%), sinus bradycardia conjunctivitis (≤1%), eye pain (≤1%), mydriasis
(≤1%), subdural hematoma (≤1%), syncope (≤1%), (≤1%), photophobia (≤1%), visual field defect (≤1%)
thrombophlebitis (≤1%), ventricular premature con- Otic: Tinnitus (IV: 9%), deafness (≤2%; more common
tractions (≤1%) with IV), otalgia (≤1%)
Central nervous system: Headache (IM: 9%; IV: 2%), Renal: Polyuria (≤1%), renal failure syndrome (≤1%)
stupor (IV: 8%), paresthesia (4%; generally transient; Respiratory: Pneumonia (>1%), apnea (≤1%), aspira-
often reported in groin area; may be more common tion pneumonia (≤1%), asthma (≤1%), atelectasis
with IV), extrapyramidal reaction (≤4%; more com- (≤1%), bronchitis (≤1%), cyanosis (≤1%), dyspnea
mon with IV), absent reflexes (IM: 3%), agitation (IV: (≤1%), epistaxis (≤1%), flu-like symptoms (≤1%),
3%), vertigo (IV: 2%), cerebral edema (≤2%; more hemoptysis (≤1%), hyperventilation (≤1%), hypoxia
common with IV), dysarthria (≤2%), hypoesthesia (≤1%), increased bronchial secretions (≤1%),
(≤2%; more common with IV), abnormality in thinking increased cough (≤1%), pharyngitis (≤1%), pneumo-
(>1%), chills (>1%), hyperreflexia (>1%), intracranial thorax (≤1%), rhinitis (≤1%), sinusitis (≤1%)
hypertension (>1%), myasthenia (>1%), nervous- Miscellaneous: Fever (>1%)
ness (>1%), speech disturbance (>1%), akathisia Frequency not defined: Cardiovascular: Cardiac
(≤1%), altered sense of smell (≤1%), amnesia arrhythmia, severe hypotension
(≤1%), aphasia (≤1%), brain disease (≤1%), central <1%, postmarketing, and/or case reports: Acute gener-
nervous system depression (≤1%), cerebral hemor- alized exanthematous pustulosis, anaphylaxis,
rhage (≤1%), coma (≤1%), confusion (≤1%), delirium angioedema, drug reaction with eosinophilia and sys-
(≤1%), depersonalization (≤1%), depression (≤1%), temic symptoms, dyskinesia, severe dermatological
emotional lability (≤1%), encephalitis (≤1%), hemi- reaction, signs and symptoms of injection site (purple
plegia (≤1%), hostility (≤1%), hyperacusis (≤1%), glove syndrome), Stevens-Johnson syndrome, toxic
hyperesthesia (≤1%), hypotonia (≤1%), insomnia epidermal necrolysis
(≤1%), malaise (≤1%), meningitis (≤1%), migraine Mechanism of Action Diphosphate ester salt of phe-
(≤1%), myoclonus (≤1%), paralysis (≤1%), person- nytoin that acts as a water soluble prodrug of phenytoin;
ality disorder (≤1%), positive Babinski sign (≤1%), after administration, plasma esterases convert fosphe-
psychoneurosis (≤1%), psychosis (≤1%), seizure nytoin to phosphate, formaldehyde (not expected to be
(≤1%), twitching (≤1%) clinically consequential [Fierro 1996]), and phenytoin as
Dermatologic: Ecchymoses (IM: 7%), skin rash (>1%), the active moiety. Phenytoin works by stabilizing neuro-
contact dermatitis (≤1%), cutaneous nodule (≤1%), nal membranes and decreasing seizure activity by
diaphoresis (≤1%), maculopapular rash (≤1%), increasing efflux or decreasing influx of sodium ions
633
FOSPHENYTOIN
across cell membranes in the motor cortex during Hepatic: Increased serum ALT (11%)
generation of nerve impulses Respiratory: Respiratory tract infection (11%)
Half-life Elimination Cardiovascular: Chest pain (6%), hypertensive crisis
Pediatric patients (ages: 1 day to 16.7 years): 8.3 (1%), syncope (1%, serious)
minutes (range: 2.5 to 18.5 minutes) (Fischer 2003) Central nervous system: Fatigue (6%)
Adults: Dermatologic: Skin rash (9%)
Fosphenytoin: IV: ~15 minutes; IM: ~30 minutes. Gastrointestinal: Abdominal pain (6%), toothache (1%,
Phenytoin: Variable (mean: 12 to 29 hours); pharma- serious)
cokinetics of phenytoin are saturable Hematologic & oncologic: Neutropenia (6%), febrile
Time to Peak Conversion to phenytoin: neutropenia (1%)
IV: Adults: Following IV administration (maximum rate Hepatic: Increased serum AST (9%)
of administration): ~15 minutes Neuromuscular & skeletal: Arthralgia (1%, serious),
IM: limb pain (1%, serious)
Neonates and Infants ≤6 months: 1-3 hours was Renal: Nephrolithiasis (1%, serious)
reported in a case series (n=3; PNA: 15 to 47 days) Respiratory: Dyspnea (2%, serious), hypoxia (1%,
(Fischer 2003) serious)
Pediatric patients >7 months: Therapeutic concen- Mechanism of Action Fostamatinib is a small mole-
trations within 30 minutes; time to maximum serum cule spleen tyrosine kinase (Syk) inhibitor. Syk affects
concentration not reported (Fischer 2003) cellular proliferation, differentiation, survival and
Adults: ~3 hours; Therapeutic phenytoin concentra- immune regulation via IgG Fc-receptor signaling and
tions may be achieved as early as 5 to 20 minutes is also linked to B-cell receptor signaling and autoanti-
following IM (gluteal) administration (Pryor 2001) body production (Bussel 2018). The major active
Pregnancy Considerations metabolite of fostamatinib, R406, inhibits signal trans-
Fosphenytoin is the prodrug of phenytoin. An increased duction of Fc-activating receptors and B-cell receptor
risk of congenital malformations and adverse outcomes and reduces antibody-mediated destruction of platelets.
may occur following in utero phenytoin exposure.
Reported malformations include orofacial clefts, cardiac
Onset of Action Median time to response (platelets
≥50,000/mm3): 15 days (Bussel 2018)
defects, dysmorphic facial features, nail/digit hypopla-
sia, growth abnormalities including microcephaly, and Half-life Elimination R406: 15 (± 4.3) hours
mental deficiency. Isolated cases of malignancies Time to Peak R406: ~1.5 hours (range: 1 to 4 hours)
(including neuroblastoma) and coagulation defects in Pregnancy Considerations
the neonate (may be life threatening) following delivery Based on the mechanism of action and information from
have also been reported. Potentially life-threatening animal reproduction studies, fostamatinib may cause
bleeding disorders in the newborn may also occur due fetal harm if exposure occurs during pregnancy.
to decreased concentrations of vitamin K-dependent In females of reproductive potential, pregnancy status
clotting factors following phenytoin exposure in utero; should be evaluated prior to therapy; effective contra-
vitamin K administration to the mother prior to delivery ception should be used during treatment and for at least
and the newborn after birth is recommended. 1 month after the last fostamatinib dose.
Also refer to the Phenytoin monograph for additional
information. Frovatriptan (froe va TRIP tan)
Patients exposed to fosphenytoin during pregnancy are Related Information
encouraged to enroll themselves into the North Amer- Temporomandibular Dysfunction (TMD), Chronic Pain,
ican Antiepileptic Drug (NAAED) Pregnancy Registry by and Fibromyalgia on page 1559
calling 1-888-233-2334. Additional information is avail-
Brand Names: US Frova
able at http://www.aedpregnancyregistry.org/.
Brand Names: Canada Frova
Pharmacologic Category Antimigraine Agent; Sero-
Fostamatinib (fos ta ma ti nib) tonin 5-HT1B, 1D Receptor Agonist
Use
Brand Names: US Tavalisse Migraines: Acute treatment of migraine with or without
Pharmacologic Category Spleen Tyrosine Kinase aura in adults
(Syk) Inhibitor; Tyrosine Kinase Inhibitor Limitations of use: For use only in patients with a clear
Use Immune thrombocytopenia (ITP) (chronic, diagnosis of migraine. Not indicated for prevention of
refractory): Treatment of thrombocytopenia in adults migraine attacks or the treatment of cluster headache.
with chronic immune thrombocytopenia (ITP) who have Local Anesthetic/Vasoconstrictor Precautions
had an insufficient response to a previous treatment. No information available to require special precautions
Local Anesthetic/Vasoconstrictor Precautions Effects on Dental Treatment No significant effects or
No information available to require special precautions complications reported
related to dental treatment: Tooth ache has been require special precautions
reported Adverse Reactions
Effects on Bleeding No information available to 1% to 10%:
require special precautions Cardiovascular: Flushing (4%), hot or cold flashes
Adverse Reactions (3%), chest pain (2%), palpitations (1%)
>10%: Central nervous system: Dizziness (8%), fatigue (5%),
Cardiovascular: Hypertension (28%) headache (4%), paresthesia (4%), drowsiness
Central nervous system: Dizziness (11%) (≥2%), anxiety (1%), dysesthesia (1%), hypoesthesia
Gastrointestinal: Diarrhea (31%), nausea (19%) (1%), insomnia (1%), pain (1%)
634
FULVESTRANT
Dermatologic: Diaphoresis (1%) Treatment of HR-positive, HER2-negative advanced

Gastrointestinal: Xerostomia (3%), nausea (≥2%), or metastatic breast cancer (in combination with
dyspepsia (2%), abdominal pain (1%), diarrhea palbociclib or abemaciclib) in women with disease
(1%), vomiting (1%) progression following endocrine therapy
Neuromuscular & skeletal: Musculoskeletal pain (3%) Local Anesthetic/Vasoconstrictor Precautions
Ophthalmic: Visual disturbance (1%) No information available to require special precautions
Otic: Tinnitus (1%) Effects on Dental Treatment No significant effects or
Respiratory: Rhinitis (1%), sinusitis (1%) complications reported
<1%, postmarketing, and/or case reports: Abnormal Effects on Bleeding No information available to
dreams, abnormal gait, abnormal lacrimation, abnor- require special precautions
mal reflexes, agitation, amnesia, anaphylactoid reac- Adverse Reactions
tion, anaphylaxis, anorexia, arthralgia, ataxia, back >10%:
pain, bradycardia, bullous rash, change in bowel hab- Central nervous system: Fatigue (8% to 32%), head-
its, cheilitis, chest tightness, confusion, conjunctivitis, ache (8% to 15%)
constipation, dehydration, depersonalization, depres- Endocrine & metabolic: Hot flash (7% to 11%)
sion, dysgeusia, dysphagia, dyspnea, ECG changes, Gastrointestinal: Nausea (10% to 28%), diarrhea (6%
emotional lability, epistaxis, eructation, esophageal to 25%), abdominal pain (16%), constipation (5% to
spasm, euphoria, eye pain, fever, flatulence, gastro- 16%), vomiting (6% to 15%), stomatitis (10% to
esophageal reflux disease, hiccups, hyperacusis, 13%), decreased appetite (8% to 12%)
hyperesthesia, hypersensitivity reaction (including Hematologic & oncologic: Anemia (4% to 40%; grade
angioedema), hypertonia, hyperventilation, hypocal- 3: ≤2%), lymphocytopenia (32%; grade 3: 2%)
cemia, hypoglycemia, hypotonia, increased thirst, Hepatic: Increased serum aspartate aminotransferase
involuntary muscle movements, jaw tightness, lack of (5% to 48%), increased serum alanine aminotrans-
concentration, laryngitis, leg pain, malaise, mouth ferase (5% to 34%), increased liver enzymes (>15%)
edema, myalgia, myasthenia, myocardial infarction, Infection: Infection (25% to 31%)
nervousness, nocturia, osteoarthritis, otalgia, peptic Local: Pain at injection site (12%; including neuralgia,
ulcer, personality disorder, pharyngitis, polyuria, pruri- peripheral neuropathy, sciatica)
tus, purpura, renal pain, rigors, salivary gland pain, Neuromuscular & skeletal: Arthralgia (8% to 17%)
seizure, sialorrhea, significant cardiovascular event, Renal: Increased serum creatinine (≤74%)
speech disturbance, stomatitis, syncope, tachycardia, Respiratory: Cough (5% to 11%)
tightness in chest and throat, tongue paralysis, tooth- 1% to 10%:
ache, tremor, urinary frequency, urine abnormality, Cardiovascular: Peripheral edema (7%)
vertigo, weakness Central nervous system: Dizziness (6%)
Mechanism of Action Selective agonist for serotonin Dermatologic: Pruritus (6%), skin rash (4% to 6%),
(5-HT1B and 5-HT1D receptors) in cranial arteries; alopecia (2% to 6%)
causes vasoconstriction and reduces sterile inflamma- Endocrine & metabolic: Weight loss (2%)
tion associated with antidromic neuronal transmission Gastrointestinal: Anorexia (6%), dysgeusia (3%)
correlating with relief of migraine. Hematologic & oncologic: Leukopenia (2% to 5%;
Pharmacodynamics/Kinetics grade 3: 1%; grade 4: 1%), neutropenia (4%; grade
Half-life Elimination ~26 hours 3: 1%; grade 4: <1%), thrombocytopenia (3%; grade
Time to Peak 2-4 hours 4: <1%)
Pregnancy Considerations Adverse events were Neuromuscular & skeletal: Ostealgia (9%), back pain
observed in animal reproduction studies. Information (8% to 9%), myalgia (7%), limb pain (6% to 7%),
related to the use of frovatriptan in pregnancy has not musculoskeletal pain (6%), asthenia (5% to 6%)
been located. Until additional information is available, Respiratory: Dyspnea (4%)
other agents are preferred for the initial treatment of Miscellaneous: Fever (5% to 6%)
migraine in pregnancy (Da Silva 2012; MacGregor <1%, postmarketing, and/or case reports: Hepatic fail-
2012; Williams 2012). ure, hepatitis, increased gamma-glutamyl transferase,
increased serum bilirubin, vaginal hemorrhage,
Fulvestrant (fool VES trant) venous thromboembolism
Mechanism of Action Fulvestrant is an estrogen
Brand Names: US Faslodex receptor antagonist; competitively binds to estrogen
Brand Names: Canada Faslodex receptors on tumors and other tissue targets, producing
Pharmacologic Category Antineoplastic Agent, a nuclear complex that causes a dose-related down-
Estrogen Receptor Antagonist regulation of estrogen receptors and inhibits tumor
Use growth.
Breast cancer (monotherapy): Pharmacodynamics/Kinetics
Treatment of hormone-receptor (HR)-positive Duration of Action IM: Steady state concentrations
advanced breast cancer in postmenopausal women reached within first month, when administered with
with disease progression following endocrine therapy additional dose given 2 weeks following the initial
Treatment of HR-positive, human epidermal growth dose; plasma levels maintained for at least 1 month
factor receptor 2 (HER2)-negative advanced breast Half-life Elimination
cancer in postmenopausal women not previously Children 1.7 to 8.5 years: 70.4 ± 8.1 days (Sims 2012)
treated with endocrine therapy Adults: 250 mg: ~40 days
Breast cancer (combination therapy): Pregnancy Considerations Based on findings from
Treatment of HR-positive, HER2-negative advanced animal reproduction studies and the mechanism of
or metastatic breast cancer (in combination with action, fulvestrant may cause fetal harm if administered
ribociclib) in postmenopausal women as initial endo- during pregnancy. For females of reproductive potential,
crine-based therapy or following disease progression pregnancy testing is recommended within 7 days prior
on endocrine therapy to initiation of fulvestrant and effective contraception
635
FULVESTRANT
should be used during treatment and for 1 year after the Pharmacodynamics/Kinetics
last fulvestrant dose. Animal data suggest that fulves- Onset of Action Diuresis: Oral, sublingual: 30 to 60
trant may affect female and male fertility (although not minutes; IM: 30 minutes; IV: ~5 minutes
approved for use in men). Symptomatic improvement with acute pulmonary
edema: Within 15 to 20 minutes; occurs prior to
diuretic effect
Furosemide (fyoor OH se mide)
Peak effect: Oral, SL: 1 to 2 hours; IV: 0.5 hours
Related Information Duration of Action Oral, sublingual: 6 to 8 hours; IV:
2 hours
Half-life Elimination Normal renal function: 0.5 to 2
Brand Names: US Lasix
hours; End-stage renal disease (ESRD): 9 hours
Brand Names: Canada Apo-Furosemide; Bio-Furose- Pregnancy Considerations Adverse events have
mide; Furosemide Injection Sandoz Standard; Furose- been observed in animal reproduction studies. Furose-
mide Injection, USP; Furosemide Special; Furosemide mide crosses the placenta (Riva 1978). Furosemide
Special Injection; Lasix; Lasix Special; PMS-Furose- has been used to treat heart failure in pregnant women
mide; Teva-Furosemide (ESC 2011; Johnson-Coyle 2012). Monitor fetal growth
Pharmacologic Category Antihypertensive; Diuretic, if used during pregnancy; may increase birth weight.
Loop
Use
Edema: Management of edema associated with heart
Gabapentin (GA ba pen tin)
failure and hepatic or renal disease; acute pulmonary Related Information

edema. Temporomandibular Dysfunction (TMD), Chronic Pain,
Hypertension: Management of hypertension. and Fibromyalgia on page 1559
Note: Not recommended for the initial treatment of Brand Names: US Gralise; Gralise Starter; Neurontin
hypertension (ACC/AHA [Whelton 2017]). Brand Names: Canada Neurontin
Local Anesthetic/Vasoconstrictor Precautions Generic Availability (US) May be product dependent
No information available to require special precautions Pharmacologic Category Anticonvulsant, Miscella-
Effects on Dental Treatment No significant effects or neous; GABA Analog
complications reported Dental Use Neuropathic pain (consult with physician)
require special precautions Postherpetic neuralgia: Management of postherpetic
Adverse Reactions neuralgia (PHN) in adults.
Frequency not defined: Seizures, focal (partial) onset (immediate release
Cardiovascular: Necrotizing angiitis, orthostatic hypo- only): As adjunctive therapy in the treatment of focal
tension, thrombophlebitis, vasculitis (partial) seizures with and without secondary general-
Central nervous system: Dizziness, headache, pares- ization in adults and pediatric patients 3 years of age
thesia, restlessness, vertigo and older with epilepsy.
Dermatologic: Acute generalized exanthematous pus- Local Anesthetic/Vasoconstrictor Precautions
tulosis, bullous pemphigoid, erythema multiforme, No information available to require special precautions
exfoliative dermatitis, pruritus, skin photosensitivity, Effects on Dental Treatment Key adverse event(s)
skin rash, Stevens-Johnson syndrome, toxic epider- related to dental treatment: Xerostomia (normal salivary
mal necrolysis, urticaria flow resumes upon discontinuation), dry throat, and
Endocrine & metabolic: Glycosuria, hyperglycemia, dental abnormalities.
hyperuricemia, increased serum cholesterol, Effects on Bleeding No information available to
increased serum triglycerides require special precautions
Gastrointestinal: Abdominal cramps, anorexia, consti- Adverse Reactions
pation, diarrhea, gastric irritation, mouth irritation, >10%:
nausea, pancreatitis, vomiting Central nervous system: Dizziness (immediate
Genitourinary: Bladder spasm release, adolescents and adults: 17% to 28%;
Hematologic & oncologic: Agranulocytosis, anemia, extended release, adults: 11%; immediate release,
aplastic anemia, eosinophilia, hemolytic anemia, leu- children: 3%), drowsiness (immediate release, ado-
kopenia, purpura, thrombocytopenia lescents and adults: 19% to 21%; immediate release,
Hepatic: Hepatic encephalopathy, intrahepatic choles- children: 8%; extended release, adults: 5%), ataxia
(immediate release, adolescents and adults: 1% to
tatic jaundice, liver enzymes increased
13%), fatigue (immediate release, adolescents and
Hypersensitivity: Anaphylaxis, anaphylactoid reaction,
adults: 11%; immediate release, children: 3%)
anaphylactic shock
Infection: Viral infection (immediate release, chil-
Immunologic: DRESS syndrome
dren: 11%)
Local: Pain at injection site (following IM injection) 1% to 10%:
Neuromuscular & skeletal: Muscle spasm, weakness Cardiovascular: Peripheral edema (adolescents and
Ophthalmic: Blurred vision, xanthopsia adults: 2% to 8%), hypertension (extended release,
Otic: Deafness, tinnitus adults: >1%), increased blood pressure (extended
Renal: Interstitial nephritis (allergic), renal disease release, adults: >1%), vasodilatation (immediate
Miscellaneous: Fever release, adolescents and adults: 1%)
Mechanism of Action Primarily inhibits reabsorption Central nervous system: Hostility (immediate release:
of sodium and chloride in the ascending loop of Henle 5% to 8%), emotional lability (immediate release: 4%
and proximal and distal renal tubules, interfering with to 6%), abnormality in thinking (immediate release:
the chloride-binding cotransport system, thus causing 2% to 3%), abnormal gait (immediate release, adults:
its natriuretic effect (Rose 1991). 2%), amnesia (immediate release, adolescents and
636
GABAPENTIN
adults: 2%), depression (immediate release, adoles- Postherpetic neuralgia or neuropathic pain: Adults:
cents and adults: 2%), status epilepticus (immediate Oral: Day 1: 300 mg, Day 2: 300 mg twice daily, Day
release, adolescents and adults: 2%), confusion 3: 300 mg 3 times/day; dose may be titrated as
(extended release, adults: >1%), memory impair- needed for pain relief (range: 1800-3600 mg/day, daily
ment (extended release, adults: >1%), lethargy doses >1800 mg do not generally show greater
(extended release, adults: 1%), pain (extended benefit)
release, adults: 1%), vertigo (extended release, Dosing
adults: 1%) Adult
Dermatologic: Skin rash (extended release, adults: Alcohol use disorder, moderate to severe (alter-
>1%), excoriation (immediate release, adolescents native agent) (off-label use): Immediate release:
and adults: 1%) Oral: Initial: 300 mg once daily; increase dose based
Endocrine & metabolic: Weight gain (2% to 3%), on response and tolerability in increments of 300 mg
hyperglycemia (immediate release, adults: 1%) every 1 to 2 days up to a target dose of 600 mg 3
Gastrointestinal: Nausea (immediate release: ≤8%; times daily (Brower 2008; Mason 2014; VA/DoD
extended release, adults: >1%), vomiting (immediate 2015). Note: Gabapentin is suggested by some
release: ≤8%), diarrhea (immediate release, adults: experts as an alternative when first-line agents can-
6%), xerostomia (adolescents and adults: ≤5%;), not be used (Johnson 2018; VA/DoD 2015). Gaba-
constipation (adolescents and adults: 1% to 4%), pentin may be misused by some patients with
dental disease (immediate release, adolescents substance use disorders; evaluate for risk and signs
and adults: 2%), dyspepsia (adolescents and adults: of addiction and dependence (Mersfelder 2016).
1% to 2%), viral gastroenteritis (extended release, Alcohol withdrawal, mild (alternative agent) (off-
adults: >1) label use): Note: Withdrawal will progress at differ-
Genitourinary: Impotence (immediate release, adoles- ent rates in some patients; flexibility in dosing and
cents and adults: 2%), urinary tract infection duration is warranted (Holt 2018; VA/DoD 2015). The
(extended release, adults: 2%) following is one suggested regimen based on a
Hypersensitivity: Seasonal allergy (extended release, single randomized, double-blind trial: Immediate
adults: >1%) release: Oral: Initial: 300 to 400 mg 3 times daily
Infection: Infection (immediate release, adults: 5%), on days 1 through 3, then 300 to 400 mg twice daily
herpes zoster infection (extended release, on day 4, then discontinue. For breakthrough symp-
adults: >1%) toms during days 1 through 4, consider providing
Neuromuscular & skeletal: Tremor (immediate single doses of 100 mg, which may be administered
release, adolescents and adults: 7%), asthenia up to 3 times daily, and a 300 mg dose reserved for
(immediate release, adults: 6%), hyperkinesia the evening (Myrick 2009).
Cough, chronic refractory (alternative agent) (off-
(immediate release: 3% to 5%), back pain (adoles-
label use): Immediate release: Oral: Initial: 300 mg
cents and adults: 2%), dysarthria (immediate
once daily; increase dose gradually based on
release, adolescents and adults: 2%), limb pain
response and tolerability in increments of 300 mg
(extended release, adults: 2%), joint swelling
to a maximum dose of 900 mg twice daily (ACCP
(extended release, adults: >1%)
[Gibson 2016]; Ryan 2012). Re-evaluate therapeutic
Ophthalmic: Nystagmus (immediate release, adoles-
need after 6 months (ACCP [Gibson 2016]).
cents and adults: 8%), diplopia (immediate release,
Fibromyalgia (alternative agent) (off-label use):
adolescents and adults: 1% to 6%), amblyopia
Note: For patients who do not respond to or tolerate
(immediate release: 3% to 4%), conjunctivitis (imme-
preferred agents (Goldenberg 2018): Immediate
diate release, adults: 1%) release: Oral: Initial: 100 to 300 mg once daily at
Otic: Otitis media (immediate release, adults: 1%) bedtime; increase dose gradually based on response
Respiratory: Bronchitis (immediate release, children: and tolerability every 1 to 2 weeks to a target dose of
3%), nasopharyngitis (extended release, adults: 3%), 1.2 to 2.4 g/day in divided doses (Arnold 2007; Gold-
respiratory tract infection (immediate release, chil- enberg 2018).
dren: 3%), pharyngitis (immediate release, adoles- Hiccups (singultus) (off-label use): Immediate
cents and adults: 1% to 3%), cough (immediate release: Oral: Usual dose range: 300 mg to 1.2 g/
release, adolescents and adults: 2%), dry throat day in 3 to 4 divided doses (Hernández 2004; Jatzko
(immediate release, adolescents and adults: ≤2%), 2007; Moretti 2004; Porzio 2010; Schuchmann
pneumonia (extended release, adults: >1%), upper 2007). Can be discontinued the day after hiccups
respiratory tract infection (extended release, subside; long-term therapy may be warranted for
adults: >1%) persistent or relapsing hiccups (eg, palliative care)
Miscellaneous: Fever (immediate release, children: (Lembo 2018). Note: In patients with refractory hic-
10%; extended release, adults: >1%), accidental cups, may use in combination with a proton pump
injury (immediate release, adults: 3%) inhibitor, baclofen, or metoclopramide (Kohse 2017).
<1%, postmarketing, and/or case reports: Agitation, Neuropathic pain:
altered serum glucose, anaphylaxis, angioedema, General dosing recommendations (for other than
anorgasmia, breast hypertrophy, change in libido, postherpetic neuralgia) (off-label use): Note: For
DRESS syndrome, ejaculatory disorder, erythema chronic use, an adequate trial with gabapentin may
multiforme, hyponatremia, increased creatine phos- require 2 months or more (Bone 2002; Rosenquist
phokinase, increased liver enzymes, jaundice, move- 2018). For critically ill patients with neuropathic
ment disorder, rhabdomyolysis, Stevens-Johnson pain, gabapentin may be a useful component of
syndrome, suicidal ideation, suicidal tendencies multimodal pain control (SCCM [Devlin 2018]).
Dental Usual Dosage Immediate release: Oral: Initial: 100 to 300 mg 1 to
Pain (off-label use): Children >12 years and Adults: 3 times daily (ADA [Pop-Busui 2017]; Dolgun
Oral: 300-1800 mg/day given in 3 divided doses has 2014; Mishra 2012); increase dose based on
been the most common dosage range response and tolerability to a target dose range
637
GABAPENTIN
of 300 mg to 1.2 g 3 times daily (AAN [Bril 2011]; Social anxiety disorder (alternative agent) (off-
ADA [Pop-Busui 2017]; EFNS [Attal 2010]; IASP label use): Note: Monotherapy or adjunctive therapy
[Finnerup 2015]) for patients who do not tolerate or respond to pre-
Extended release: Oral: Initial: 300 mg at bedtime; ferred agents (Stein 2018): Immediate release: Oral:
increase dose based on response and tolerability Initial: 300 mg twice daily; increase dose based on
to a target dose of 900 mg to 3.6 g once daily response and tolerability in increments of no more
(IASP [Finnerup 2015]; Sandercock 2012)
than 300 mg/day up to a maximum of 3.6 g/day in 3
Postherpetic neuralgia:
divided doses (Pande 1999).
Immediate release: Oral: 300 mg once on day 1,
300 mg twice daily on day 2, and 300 mg 3 times Vasomotor symptoms associated with menopause
daily on day 3, then increase as needed up to 1.8 to (off-label use):
3.6 g/day in divided doses. Additional benefit of Immediate release: Oral: Initial: 300 to 400 mg once
doses >1.8 g/day has not been established. daily at bedtime; some experts use an initial dose of
Extended release: Oral: Initial: 300 mg once daily; 100 mg once daily to avoid adverse effects (Santen
increase by 300 mg each day up to 900 mg once 2018); increase gradually (eg, over 3 to 12 days)
daily. Further increase as needed up to 1.8 g once based on response and tolerability up to 600 mg to
daily. Additional benefit of doses >1.8 g/day has not 2.4 g/day in 2 to 3 divided doses (ACOG 2014;
been established. NAMS 2015; Reddy 2006; Toulis 2009). Some
Postoperative pain (off-label use): Immediate experts suggest gabapentin for women whose
release: Oral: 300 mg to 1.2 g as a single dose,
symptoms occur primarily at night and favor a
given 1 to 2 hours prior to surgery or immediately
maximum dose of 900 mg to 1.2 g, given as one
following surgery as part of a multimodal analgesia
dose at bedtime (ES [Stuenkel 2015];
regimen (Chou 2016; Doleman 2015; Peng 2007; Yu
2013). Note: Some experts avoid use in patients with Santen 2018).
sleep-disordered breathing (eg, obstructive sleep Extended release: Oral: Initial: 600 mg once daily at
apnea) (Joshi 2018; Mariano 2018). bedtime; increase gradually (eg, 600 mg every 3
Pruritus, chronic (alternative agent) (off-label use): days) to target dose of 600 mg in the morning and
Note: For patients with pruritus resistant to preferred 1.2 g at bedtime (Pinkerton 2014)
therapies (Matsuda 2016; Weisshaar 2012):
Discontinuation of therapy: In patients receiving
Neuropathic (eg, brachioradial pruritus, notalgia par-
gabapentin chronically, unless safety concerns
esthetica) or malignancy-related pruritus: Immedi-
ate release: Oral: Initial: 300 mg/day in 1 to 3 require a more rapid withdrawal, gabapentin should
divided doses; increase dose based on response be withdrawn gradually over ≥1 week to minimize the
and tolerability up to 1.8 g/day in divided doses potential of increased seizure frequency (in patients
(Kanitakis 2006; Winhoven 2004; Yilmaz 2010). with epilepsy) or other withdrawal symptoms (eg,
Higher doses up to 3.6 g/day have been used in confusion, irritability, tachycardia, diaphoresis) (Nor-
oncology populations (Demierre 2006; Lee 2010). ton 2001; Tran 2005).
Uremic pruritus: Immediate release: Oral: Initial: Geriatric
100 mg after dialysis on hemodialysis days; may Restless legs syndrome (off-label use): Immediate
increase dose based on response and tolerability release: Oral: Initial: 100 mg once daily (IRLSSG/
up to 300 mg after dialysis on hemodialysis days
EURLSSG/RLS-F [Garcia-Borreguero 2016])
(Gunal 2004; Kobrin 2018; Nofal 2016; Raze-
Other indications: Refer to adult dosing. For post-
ghi 2009).
operative pain (off-label use), some experts avoid
Restless legs syndrome (off-label use): Immediate
release: Oral: Initial: 100 to 300 mg once daily 2 use in patients >65 years of age (Joshi 2018).
hours before bedtime; may increase dose every 1 Discontinuation of therapy: Refer to adult dosing.
to 2 weeks until symptom relief is achieved (range: Renal Impairment: Adult Note: Estimation of renal
300 mg to 2.4 g/day). Suggested maintenance dos- function for dosing adjustments should be done using
ing schedule for doses ≥600 mg/day: One-third of the Cockcroft-Gault formula.
total daily dose given midday, remaining two-thirds of Immediate release:
the total daily dose given in the evening (Garcia- CrCl ≥60 mL/minute: Oral: 300 mg to 1.2 g 3 times
Borreguero 2002; Happe 2003; IRLSSG/ daily
EURLSSG/RLS-F [Garcia-Borreguero 2016]; Saletu CrCl >30 to 59 mL/minute: Oral: 200 to 700 mg twice
2010; Silber 2018; Vignatelli 2006). daily
Seizures, focal (partial) onset: Immediate release:
CrCl >15 to 29 mL/minute: Oral: 200 to 700 mg once
Oral: Initial: 300 mg 3 times daily; increase dose
daily
based on response and tolerability. Usual dosage:
300 to 600 mg 3 times daily; doses up to 2.4 g/day CrCl 15 mL/minute: Oral: 100 to 300 mg once daily
and 3.6 g/day have been tolerated in long-term and CrCl <15 mL/minute: Oral: Reduce daily dose in
short-term clinical studies, respectively. Some proportion to creatinine clearance based on dose
experts recommend a lower starting dose (eg, for creatinine clearance of 15 mL/minute (eg,
100 mg 3 times daily) with titration as tolerated reduce dose by one-half [range: 50 to 150 mg/day]
(Schachter 2018). for CrCl 7.5 mL/minute)
638
GABAPENTIN
ESRD requiring hemodialysis: Oral: Dose based on

CrCl plus a single supplemental dose of 125 to
350 mg (given after each 4 hours of hemodialysis) Gabapentin Dosing Adjustments in Renal
or in patients with uremic pruritus (off-label use), Impairment
give 100 to 300 mg only after dialysis on hemodial- Total
ysis days (Gunal 2004; Kobrin 2018; Nofal 2016; Creatinine Daily Dosage Regimens
Clearance Dose (Maintenance Doses)
Razeghi 2009). (mL/min) Range (mg)
(mg/day)
Extended release: Note: Follow initial dose titration
≥60 900 to 300 400 600 800 1,200
schedule if treatment naive. 3,600 3 times/ 3 times/ 3 times/ 3 times/ 3 times/
CrCl ≥60 mL/minute: Oral: 1.8 g once daily day day day day day
CrCl >30 to 59 mL/minute: Oral: 600 mg to 1.8 g >30 to 59 400 to 200 300 400 500 700
1,400 twice twice twice twice twice
once daily; dependent on tolerability and clinical daily daily daily daily daily
response >15 to 29 200 to 200 300 400 500 700
CrCl <30 mL/minute: Use is not recommended. 700 daily daily daily daily daily
ESRD requiring hemodialysis: Use is not recom- 15A 100 to 100 125 150 200 300
300 daily daily daily daily daily
mended.
Hepatic Impairment: Adult There are no dosage B
Posthemodialysis Supplemental Dose
Hemodialysis
adjustments provided in the manufacturer's labeling; 125 mg 150 mg 200 mg 250 mg 350 mg
however, gabapentin is not hepatically metabolized. A
CrCl <15 mL/minute: Reduce daily dose in proportion to creatinine clearance.
Pediatric Note: Do not exceed 12 hours between B
Supplemental dose should be administered after each 4 hours of hemodialysis
(patients on hemodialysis should also receive maintenance doses based on renal
doses with 3 times daily dosing. Pediatric doses function as listed in the upper portion of the table).
presented as mg/kg/day and mg/kg/dose; use precau-
tion. Hepatic Impairment: Pediatric There are no dos-
Seizures, partial onset; adjunctive therapy: Oral: age adjustments provided in the manufacturer’s label-
Immediate release: Note: If gabapentin is discon- ing; however, adjustment not necessary since
tinued or if another anticonvulsant is added to gabapentin is not hepatically metabolized.
therapy, it should be done slowly over a minimum Mechanism of Action Gabapentin is structurally
of 1 week. related to GABA. However, it does not bind to GABAA
Children 3 to <12 years: or GABAB receptors, and it does not appear to influence
Initial: 10 to 15 mg/kg/day divided into 3 doses synthesis or uptake of GABA. High affinity gabapentin
daily; titrate dose upward over ~3 days binding sites have been located throughout the brain;
Maintenance usual dose: these sites correspond to the presence of voltage-gated
Children 3 to 4 years: 40 mg/kg/day divided into calcium channels specifically possessing the alpha-2-
3 doses daily; maximum daily dose: In one delta-1 subunit. This channel appears to be located
presynaptically, and may modulate the release of exci-
long-term study, doses up to 50 mg/kg/day
tatory neurotransmitters which participate in epilepto-
were well-tolerated
genesis and nociception.
Children 5 to <12 years: 25 to 35 mg/kg/day
Contraindications Hypersensitivity to gabapentin or
divided into 3 doses daily; maximum daily dose:
any component of the formulation
In one long-term study, doses up to 50 mg/kg/
Warnings/Precautions Antiepileptics are associated
day were well-tolerated with an increased risk of suicidal behavior/thoughts with
Children ≥12 years and Adolescents: Initial: 300 mg use (regardless of indication); patients should be moni-
3 times daily; titrate dose upward if needed; usual tored for signs/symptoms of depression, suicidal ten-
maintenance dose: 900 to 1,800 mg/day divided dencies, and other unusual behavior changes during
into 3 doses daily; doses up to 2,400 mg/day therapy and instructed to inform their healthcare pro-
divided into 3 doses daily are well tolerated long- vider immediately if symptoms occur. Avoid abrupt with-
term; maximum daily dose: Doses up to 3,600 mg/ drawal, may precipitate seizures or other withdrawal
day have been tolerated in short-term studies. symptoms; decrease dose slowly over ≥1 week (Norton
Neuropathic pain: Limited data available: Oral: 2001; Tran 2005). Use cautiously in patients with renal
Immediate release: Children and Adolescents: Ini- dysfunction; male rat studies demonstrated an associ-
tial: 5 mg/kg/dose up to 300 mg at bedtime; day 2: ation with pancreatic adenocarcinoma (clinical implica-
Increase to 5 mg/kg/dose twice daily (up to 300 mg tion unknown). May cause CNS depression including
twice daily); day 3: Increase to 5 mg/kg/dose 3 somnolence and dizziness, which may impair physical
times daily (up to 300 mg 3 times daily); further or mental abilities. Patients must be cautioned about
titrate with dosage increases (not frequency) to performing tasks which require mental alertness (eg,
effect; American Pain Society (APS) recommends operating machinery or driving). Pediatric patients have
a lower initial dose of 2 mg/kg/day which may be shown increased incidence of CNS-related adverse
effects, including emotional lability, hostility, changes
considered if concurrent analgesics are also sedat-
in behavior and thinking, and hyperkinesia. Immedi-
ing; usual dosage range: 8 to 35 mg/kg/day divided
ate-release and extended-release products are not
into 3 doses daily (APS, 2008; Galloway, 2000);
interchangeable with each other or with gabapentin
maximum daily dose: 3,600 mg/day enacarbil. The safety and efficacy of the extended-
Renal Impairment: Pediatric release formulation has not been studied in patients
Immediate release: with epilepsy. Potentially serious, sometimes fatal multi-
Children <12 years: There are no dosing adjust- organ hypersensitivity (also known as drug reaction
ments provided in the manufacturer’s labeling with eosinophilia and systemic symptoms [DRESS])
(has not been studied). has been reported with some antiepileptic drugs, includ-
Children ≥12 years and Adolescents: See table. ing gabapentin; may affect lymphatic, hepatic, renal,
639
GABAPENTIN
cardiac, and/or hematologic systems; fever, rash, and Pharmacodynamics/Kinetics

eosinophilia may also be present. Discontinue immedi- Half-life Elimination
ately if suspected. Anaphylaxis and/or angioedema may Infants 1 month to Children 12 years: 4.7 hours
occur after the first dose or at any time during treatment; Adults, normal: 5 to 7 hours; increased half-life with
discontinue therapy and seek immediate medical care if decreased renal function; anuric adult patients: 132
signs or symptoms of anaphylaxis or angioedema hours; adults during hemodialysis: 3.8 hours
occur. Use with caution in patients with a history of Time to Peak Immediate release: Infants 1 month to
substance abuse, including alcohol, benzodiazepines, Children 12 years: 2 to 3 hours; Adults: 2 to 4 hours;
cannabis, cocaine, and opioids; potential for drug Extended release: 8 hours
dependency exists. Tolerance, psychological and phys- Pregnancy Risk Factor C
ical dependence may occur (Evoy 2017; Mersfelder Pregnancy Considerations Adverse events have
2016). Potentially significant drug-drug interactions been observed in animal reproduction studies. Gaba-
may exist, requiring dose or frequency adjustment, pentin crosses the placenta. In a small study (n=6), the
additional monitoring, and/or selection of alternative umbilical/maternal plasma concentration ratio was
therapy. ~1.74. Neonatal concentrations declined quickly after
Warnings: Additional Pediatric Considerations delivery and at 24 hours of life were ~27% of the cord
Neuropsychiatric adverse events, such as emotional blood concentrations at birth (gabapentin neonatal half-
lability (eg, behavioral problems), hostility, aggressive life ~14 hours) (Ohman 2005). Pregnancy registry out-
behaviors, thought disorders (eg, problems with con- come data following maternal use of gabapentin during
pregnancy is limited (Holmes 2012). Folic acid supple-
centration and school performance), and hyperkinesia
mentation is recommended prior to and during preg-
(eg, hyperactivity and restlessness), have been
nancy in women using gabapentin (Borgelt 2016;
reported in clinical trials of pediatric patients ages 3 to
Picchietti 2015).
12 years. Most of these pediatric neuropsychiatric
adverse events are mild to moderate in terms of inten- Gabapentin is used off-label for the treatment of rest-
sity but discontinuation of gabapentin may be required; less leg syndrome; however, current guidelines note
children with mental retardation and attention-deficit there is insufficient evidence to recommend its use in
disorders may be at increased risk for behavioral side pregnant women for this indication (Picchietti 2015).
effects (Lee 1996). Pharmacological agents should not be used for the
Drug Interactions treatment of alcohol use disorder in pregnant women
Metabolism/Transport Effects None known. unless needed for the treatment of acute alcohol with-
Avoid Concomitant Use drawal or a coexisting disorder.
Avoid concomitant use of Gabapentin with any of the Patients exposed to gabapentin during pregnancy are
following: Azelastine (Nasal); Bromperidol; Orphena- encouraged to enroll in the North American Antiepileptic
drine; Oxomemazine; Paraldehyde; Thalidomide Drug (NAAED) Pregnancy Registry by calling
Increased Effect/Toxicity 1-888-233-2334. Additional information is available at
Gabapentin may increase the levels/effects of: Alcohol www.aedpregnancyregistry.org.
(Ethyl); Azelastine (Nasal); Blonanserin; Brexanolone; Breastfeeding Considerations Gabapentin is
Buprenorphine; CNS Depressants; Flunitrazepam; present in breast milk.
HYDROcodone; Methotrimeprazine; MetyroSINE; Mir-
The relative infant dose (RID) of gabapentin is 8.7% to
tazapine; Morphine (Systemic); Opioid Agonists;
13% when calculated using the highest breast milk
Orphenadrine; OxyCODONE; Paraldehyde; Piribedil;
concentration located and compared to an infant ther-
Pramipexole; ROPINIRole; Rotigotine; Selective Sero- apeutic dose of 10 to 15 mg/kg/day. In general, breast-
tonin Reuptake Inhibitors; Suvorexant; Thalidomide; feeding is considered acceptable when the RID is
Zolpidem <10%; when an RID is >25% breastfeeding should
The levels/effects of Gabapentin may be increased by: generally be avoided (Anderson 2016; Ito 2000).
Alizapride; Brimonidine (Topical); Bromopride; Brom- The RID of gabapentin was calculated using a milk
peridol; Cannabidiol; Cannabis; Chlormethiazole; concentration of 8.7 mcg/mL, providing an estimated
Chlorphenesin Carbamate; Dimethindene (Topical); daily infant dose via breast milk of 1.3 mg/kg/day. This
Doxylamine; Dronabinol; Droperidol; Esketamine; milk concentration was obtained following maternal
HydrOXYzine; Kava Kava; Lofexidine; Magnesium administration of oral gabapentin 2,100 mg/day. Gaba-
Salts; Methotrimeprazine; Minocycline; Morphine pentin was detected in the serum of two breastfeeding
(Systemic); Nabilone; Oxomemazine; Perampanel; infants 2 to 3 weeks after delivery and in one infant after
Rufinamide; Sodium Oxybate; Tapentadol; Tetrahy- 3 months of breastfeeding. Adverse events were not
drocannabinol; Tetrahydrocannabinol and Cannabi- reported in the breastfed infants (Ohman 2005).
diol; Trimeprazine
Manufacturer recommendations may vary; the decision
Decreased Effect to breastfeed during therapy should consider the risk of
The levels/effects of Gabapentin may be decreased infant exposure, the benefits of breastfeeding to the
by: Aluminum Hydroxide; Magnesium Salts; Meflo- infant, and benefits of treatment to the mother. Based
quine; Mianserin; Orlistat on limited information, gabapentin is considered rela-
Food Interactions Tablet, solution (immediate tively compatible with breastfeeding; infants should be
release): No significant effect on rate or extent of monitored for drowsiness, adequate weight gain, and
absorption; extended release tablet: Increases rate developmental milestones (Davanzo 2013; Veiby
and extent of absorption. Management: Administer 2015). Available guidelines state gabapentin may be
immediate release products without regard to food. considered for the treatment of refractory restless leg
Administer extended release with food. syndrome in breastfeeding women (Picchietti 2015).
Dietary Considerations Extended release tablet Pharmacological agents should not be used for the
should be taken with food. treatment of alcohol use disorder in breastfeeding
640
GANCICLOVIR (SYSTEMIC)
women unless needed for the treatment of acute alco- sites correspond to the presence of voltage-gated cal-
hol withdrawal or a coexisting disorder (APA cium channels specifically possessing the alpha-2-
[Reus 2018]). delta-1 subunit. This channel appears to be located
Dosage Forms Considerations presynaptically, and may modulate the release of exci-
Gralise is the extended release formulation. tatory neurotransmitters. These effects on RLS are
Fanatrex FusePaq is a compounding kit for the prepa- unknown.
ration of an oral suspension. Refer to manufacturer's Pharmacodynamics/Kinetics
labeling for compounding instructions. Half-life Elimination 5-6 hours
Neuraptine cream is compounded from a kit. Refer to Time to Peak Plasma: With food: 7.3 hours; Fasting: 5
manufacturer's labeling for compounding instructions. hours
Dosage Forms: US Pregnancy Risk Factor C
Capsule, Oral: Pregnancy Considerations Adverse events were
Neurontin: 100 mg, 300 mg, 400 mg observed in animal reproduction studies. Gabapentin
Generic: 100 mg, 300 mg, 400 mg enacarbil is the prodrug of gabapentin; bioavailability
Miscellaneous, Oral: following gabapentin enacarbil is increased in compar-
Gralise Starter: 300 & 600 mg (78 ea) ison to gabapentin (Backonja 2011). Current guidelines
Solution, Oral: note there is insufficient evidence to recommend gaba-
Neurontin: 250 mg/5 mL (470 mL) pentin encarbil in pregnant women for the treatment of
Generic: 250 mg/5 mL (470 mL, 473 mL); 300 mg/6 restless leg syndrome (Picchietti 2015).
mL (6 mL); 250 mg/5 mL (5 mL, 470 mL)
Tablet, Oral: Refer to Gabapentin monograph for information related
Gralise: 300 mg, 600 mg to gabapentin exposure during pregnancy.
Neurontin: 600 mg, 800 mg
Galcanezumab-gnlm (GAL ka NEZ ue mab gnlm)
Gabapentin Enacarbil (gab a PEN tin en a KAR bil) Brand Names: US Emgality
Pharmacologic Category Monoclonal Antibody, Cal-
Brand Names: US Horizant citonin Gene-Related Peptide (CGRP) Receptor Antag-
Pharmacologic Category Anticonvulsant, Miscella- onist
neous Use Migraine prophylaxis: Preventive treatment of
Use Treatment of moderate-to-severe restless leg syn- migraine in adults
drome (RLS); management of postherpetic neuralgia Local Anesthetic/Vasoconstrictor Precautions
(PHN) No information available to require special precautions
Local Anesthetic/Vasoconstrictor Precautions Effects on Dental Treatment No significant effects or
No information available to require special precautions complications reported
related to dental treatment: Xerostomia (normal salivary require special precautions
flow resumes upon discontinuation). Adverse Reactions
Effects on Bleeding No information available to >10%:
require special precautions Immunologic: Antibody development (5% to 13%;
Adverse Reactions Percentages reported are for rest- neutralizing: ≥50%)
less leg syndrome (RLS) 600 mg daily and postherpetic Local: Injection site reaction (18%)
neuralgia (PHN) 1200 mg daily. Frequency not defined: Hypersensitivity: Hypersensitiv-
>10%: Central nervous system: Drowsiness (RLS: ity reaction
≤20%; PHN: ≤10%), sedation (RLS: ≤20%; PHN: Mechanism of Action Galcanezumab-gnlm is a
≤10%), dizziness (13% to 17%), headache (10% humanized monoclonal antibody that binds to calcitonin
to 12%)
gene-related peptide (CGRP) ligand and blocks its
1% to 10%:
binding to the receptor.
Cardiovascular: Peripheral edema (PHN: 6%; Pharmacodynamics/Kinetics
RLS: <1%)
Half-life Elimination 27 days
Central nervous system: Fatigue (6%), irritability
(≤4%), insomnia (PHN: 3%), equilibrium disturbance
Time to Peak 5 days
(<2%), depression (<2%), disorientation (<2%), Pregnancy Considerations
intoxicated feeling (<2%), lethargy (<2%), ver- Adverse events were not observed in animal reproduc-
tigo (<2%) tion studies.
Endocrine & metabolic: Weight gain (2% to 3%) Galcanezumab-gnlm is a monoclonal antibody; con-
Gastrointestinal: Nausea (6% to 8%), flatulence sider the long half-life prior to use in females who are
(≤3%), xerostomia (≤3%), increased appetite (≤2%) or may become pregnant until information related to
Ophthalmic: Blurred vision (≤2%) pregnancy is available (Tepper 2018).
<1%, postmarketing, and/or case reports: Breast hyper-
trophy (gabapentin), decreased libido, feeling abnor-
mal, gynecomastia (gabapentin), increased creatine Ganciclovir (Systemic) (gan SYE kloe veer)
phosphokinase (gabapentin)
Mechanism of Action Gabapentin enacarbil is a pro- Related Information
drug of gabapentin. Gabapentin is structurally related to Systemic Viral Diseases on page 1496
GABA. However, it does not bind to GABAA or GABAB ValGANciclovir on page 1321
receptors, and it does not appear to influence synthesis Brand Names: US Cytovene
or uptake of GABA. High affinity gabapentin binding Brand Names: Canada Cytovene
sites have been located throughout the brain; these Pharmacologic Category Antiviral Agent
641
GANCICLOVIR (SYSTEMIC)
Use Otic: Deafness, otalgia, tinnitus

Cytomegalovirus disease, prophylaxis (transplant Renal: Decreased creatinine clearance, renal failure
patients): Prevention of cytomegalovirus (CMV) dis- syndrome, renal function abnormality
ease in adult transplant recipients at risk for CMV Respiratory: Cough, dyspnea, upper respiratory tract
disease. infection
Cytomegalovirus retinitis (immunocompromised Miscellaneous: Multiorgan failure
patients): Treatment of CMV retinitis in immunocom- <1%, postmarketing, and/or case reports: Acidosis,
promised adult patients, including patients with AIDS. agranulocytosis, amnesia, anaphylaxis, anosmia,
Local Anesthetic/Vasoconstrictor Precautions aphasia, arthritis, bronchospasm, cardiac conduction
No information available to require special precautions disturbance, cataract, cerebrovascular accident, chol-
Effects on Dental Treatment No significant effects or elithiasis, cholestasis, cranial nerve palsy (third), dys-
complications reported esthesia, dysphasia, encephalopathy, exfoliative
Effects on Bleeding Anemia (15% to 25%), thrombo- dermatitis, extrapyramidal reaction, facial nerve para-
cytopenia (57% in bone marrow transplant patients; lysis, granulocytopenia, hallucination, hemolytic ane-
less common in other populations [8%]), and unusual mia, hemolytic-uremic syndrome, hepatic failure,
bleeding are frequently reported. hepatitis, hypercalcemia, hypersensitivity reaction,
Adverse Reactions hyponatremia, increased serum triglycerides, infertil-
>10%: ity, intracranial hypertension, irritability, myelopathy,
Dermatologic: Hyperhidrosis (12%) oculomotor nerve paralysis, pancytopenia, peripheral
Gastrointestinal: Diarrhea (44%), anorexia (14%), ischemia, pulmonary fibrosis, renal tubular disease,
vomiting (13%) rhabdomyolysis, SIADH, Stevens-Johnson syndrome,
Hematologic & oncologic: Thrombocytopenia (6%; testicular hypotrophy, torsades de pointes, ulcerative
≤50,000/mcL: 8% to 57%; <25,000/mcL: 3% to bowel lesion, vasculitis, ventricular tachycardia,
32%), leukopenia (41%), neutropenia (ANC <500/ xerophthalmia
mcL: 4% to 25%; 500 to 1,000/mcL: 14% to 29%),
Mechanism of Action Ganciclovir is phosphorylated
anemia (25%; hemoglobin <6.5 g/dL: 5%)
to a substrate which competitively inhibits the binding of
Infection: Sepsis (15%), infection (13%)
deoxyguanosine triphosphate to DNA polymerase
Ophthalmic: Retinal detachment (11%; relationship to
resulting in inhibition of viral DNA synthesis
ganciclovir not established)
Renal: Increased serum creatinine (2% to 50%;
≥2.5 mg/dL: 2% to 20%)
Miscellaneous: Fever (48%) Neonates 2 to 49 days of age: 2.4 hours
1% to 10%: Children 9 months to 12 years: 2.4 ± 0.7 hours
Central nervous system: Chills (10%), peripheral neu- Adults: Mean: IV: 3.5 ± 0.9 hours; Oral: 4.8 ± 0.9
ropathy (9%) hours; CrCl <25 mL/minute: 10.7 ± 5.7 hours
Dermatologic: Pruritus (5%) Pregnancy Considerations
Infection: Catheter sepsis (8%) Ganciclovir crosses the placenta. [US Boxed Warn-
Local: Catheter infection (9%), catheter-site reac- ing]: Based on animal data, ganciclovir has the
tion (5%) potential to cause birth defects in humans.
[US Boxed Warning]: Based on animal data and
Cardiovascular: Cardiac arrhythmia, chest pain,
limited human data, ganciclovir may cause tempo-
edema, hypertension, hypotension, phlebitis, vaso-
rary or permanent inhibition of spermatogenesis in
dilatation
males and suppression of fertility in females.
Central nervous system: Abnormal dreams, abnormal-
ity in thinking, agitation, anxiety, confusion, depres- Female patients of reproductive potential should
sion, dizziness, drowsiness, fatigue, headache, undergo pregnancy testing prior to initiation and use
hypoesthesia, insomnia, malaise, myasthenia, pain, effective contraception during and for at least 30 days
paresthesia, psychosis, seizure after therapy. Male patients should use a barrier contra-
Dermatologic: Alopecia, cellulitis, dermatitis, skin rash, ceptive during and for at least 90 days after therapy.
urticaria, xeroderma
Endocrine & metabolic: Weight loss Gatifloxacin (gat i FLOKS a sin)
Gastrointestinal: Abdominal distention, abdominal
pain, aphthous stomatitis, constipation, dysgeusia, Related Information
dyspepsia, dysphagia, eructation, flatulence, gastro- Bacterial Infections on page 1525
intestinal perforation, nausea, oral candidiasis, oral Brand Names: US Zymaxid
mucosa ulcer, pancreatitis, xerostomia Brand Names: Canada Zymar
Genitourinary: Hematuria, urinary frequency, urinary Pharmacologic Category Antibiotic, Fluoroquinolone;
tract infection
Antibiotic, Ophthalmic
Hematologic & oncologic: Bone marrow failure
Hepatic: Abnormal hepatic function tests, increased
Use Conjunctivitis: Treatment of bacterial conjunctivitis
caused by Staphylococcus aureus, Staphylococcus
serum alanine aminotransferase, increased serum
aspartate aminotransferase, increased serum alka- epidermidis, Streptococcus mitis group, Streptococcus
line phosphatase oralis, Streptococcus pneumoniae, and Haemophilus
Infection: Candidiasis, influenza influenzae.
Local: Inflammation at injection site Local Anesthetic/Vasoconstrictor Precautions
Neuromuscular & skeletal: Arthralgia, asthenia, back No information available to require special precautions
pain, lower limb cramp, muscle spasm, myalgia, Effects on Dental Treatment Key adverse event(s)
tremor related to dental treatment: Taste disturbance.
Ophthalmic: Conjunctivitis, eye disease (vitreous dis- Effects on Bleeding No information available to
order), eye pain, macular edema, visual impairment require special precautions
642
GEFITINIB
Adverse Reactions decreased appetite (17%), vomiting (13% to 14%),

1% to 10%: stomatitis (7% to 13%), constipation (12%)
Central nervous system: Headache Genitourinary: Proteinuria (8% to 35%)
Endocrine & metabolic: Chemosis Hepatic: Increased serum AST (8% to 40%; grades
Gastrointestinal: Dysgeusia 3/4: 2% to 3%), increased serum ALT (11% to 38%;
Ophthalmic: Conjunctival hemorrhage, conjunctival
grades 3/4: 2% to 5%)
irritation, conjunctivitis (worsening), decreased visual
acuity, dry eye syndrome, eye discharge, eye irrita- Neuromuscular & skeletal: Weakness (18%)
tion, eye pain, eye redness, eyelid edema, increased 1% to 10%:
lacrimation, keratitis, papillary conjunctivitis Central nervous system: Hypoesthesia (4%), periph-
<1%, postmarketing, and/or case reports: Anaphylaxis, eral sensory neuropathy (4%), peripheral neuropa-
angioedema (including facial edema, oral edema, thy (2%)
pharyngeal edema), blepharitis, blurred vision, dysp- Dermatologic: Nail disease (5% to 8%), acneiform
nea, eye pruritus, hypersensitivity reaction (including
eruption (6%)
allergic dermatitis, eye allergy), nausea, pruritus
(including skin rash), Stevens-Johnson syndrome, Endocrine & metabolic: Dehydration (2%; secondary
swelling of eye (including corneal edema, conjunctival to diarrhea, nausea, vomiting, or anorexia)
edema), urticaria Gastrointestinal: Xerostomia (2%)
Mechanism of Action Gatifloxacin is a DNA gyrase Genitourinary: Cystitis (1%)
inhibitor, and also inhibits topoisomerase IV. DNA Hematologic & oncologic: Anemia (7%), pulmonary
gyrase (topoisomerase II) is an essential bacterial hemorrhage (4% to 5%), hemorrhage (4%; including
enzyme that maintains the superhelical structure of epistaxis, hematuria), neutropenia (3%), leukopenia
DNA. DNA gyrase is required for DNA replication and (2%), thrombocytopenia (1%)
transcription, DNA repair, recombination, and transpo-
Hepatic: Increased serum bilirubin (3%; grades
sition; inhibition is bactericidal.
Pregnancy Considerations Systemic concentrations 3/4: <1%)
of gatifloxacin following ophthalmic administration are Neuromuscular & skeletal: Myalgia (8%), arthral-
below the limit of quantification. If ophthalmic agents gia (6%)
are needed during pregnancy, the minimum effective Ophthalmic: Eye disease (6% to 7%; grades 3/4: <1%;
dose should be used in combination with punctual including conjunctivitis, blepharitis, and dry eye)
occlusion for 3 to 5 minutes after application to Renal: Increased serum creatinine (2%)
decrease potential exposure to the fetus (Samples Respiratory: Cough (9%), interstitial pulmonary dis-
1988).
ease (1%; grades 3/4: 3%)
Gefitinib (ge FI tye nib) <1%, postmarketing, and/or case reports: Angioedema,
Brand Names: US Iressa bullous skin disease, corneal erosion (reversible; may
Brand Names: Canada IRESSA be associated with aberrant eyelash growth),
Pharmacologic Category Antineoplastic Agent, Epi- decreased white blood cell count, erythema multi-
dermal Growth Factor Receptor (EGFR) Inhibitor; Anti- forme, fulminant hepatitis, gastrointestinal perforation,
neoplastic Agent, Tyrosine Kinase Inhibitor hemorrhagic cystitis, hepatic failure, hepatitis, hyper-
Use sensitivity angiitis, hypersensitivity reaction, keratitis,
Non-small cell lung cancer: First-line treatment of keratoconjunctivitis sicca, pancreatitis, renal failure,
metastatic non-small cell lung cancer (NSCLC) in skin fissure, Stevens-Johnson syndrome, toxic epider-
tumors with epidermal growth factor receptor (EGFR)
mal necrolysis, urticaria
exon 19 deletions or exon 21 (L858R) substitution
mutations as detected in tumor or plasma specimen Mechanism of Action Gefitinib is a tyrosine kinase
by an approved test. inhibitor (TKI) which reversibly inhibits kinase activity of
Limitation of use: Safety and efficacy have not been wild-type and select activation mutations of epidermal
established in patients with metastatic NSCLC growth factor receptor (EGFR). EGFR is expressed on
whose tumors have EGFR mutations other than cell surfaces of normal and cancer cells and has a role
exon 19 deletions or exon 21 (L858R) substitution in cell growth and proliferation. Gefitinib prevents auto-
mutations phosphorylation of tyrosine residues associated with
the EGFR receptor, which blocks downstream signaling
Effects on Dental Treatment Key adverse event(s) and EGFR-dependent proliferation. Gefitinib has a
related to dental treatment: Mouth ulceration. higher binding affinity for EGFR exon 19 deletion and
Effects on Bleeding Bleeding has been reported in exon 21 (L858R) substitution mutation than for wild-
<1% of patients, but can be serious. type EGFR.
>10%: Half-life Elimination Oral: 48 hours
Central nervous system: Insomnia (15%), Time to Peak Plasma: Oral: 3 to 7 hours
fatigue (14%) Pregnancy Considerations Adverse events have
Dermatologic: Dermatological reaction (47% to 58%),
been observed in animal reproduction studies. Gefitinib
skin rash (52%), xeroderma (24%), pruritus (18%),
paronychia (14%), acne vulgaris (11%), alopecia (5% may cause fetal harm when administered to a pregnant
to 11%) female. Females of reproductive potential should use
Gastrointestinal: Diarrhea (29% to 47%; grades 3/4: effective contraception during and for at least 2 weeks
3%), anorexia (19% to 20%), nausea (17% to 18%), following gefitinib treatment.
643
GELATIN (ABSORBABLE)
Gelatin (Absorbable) (JEL a tin, ab SORB a ble) Gemcitabine (jem SITE a been)
Related Information Brand Names: US Gemzar [DSC]; Infugem

Antiplatelet and Anticoagulation Considerations in Den- Brand Names: Canada Gemzar
tistry on page 1454 Pharmacologic Category Antineoplastic Agent, Anti-
Brand Names: US Gel-Flow NT; Gelfilm; Gelfoam; metabolite; Antineoplastic Agent, Antimetabolite (Pyri-
Gelfoam Dental; Surgifoam; Surgifoam Hermorrhoidec- midine Analog)
tomy Use
Pharmacologic Category Hemostatic Agent Breast cancer (metastatic): First-line treatment of
Use metastatic breast cancer (in combination with pacli-
Hemostasis (adjunct): Adjunct to provide hemostasis taxel) after failure of adjuvant chemotherapy that con-
in surgical procedures (except ophthalmic) when contained an anthracycline (unless anthracyclines are
trol of bleeding by pressure, ligature and other con- contraindicated)
ventional techniques are ineffective; adjunct in neuro, Non-small cell lung cancer (inoperable, locally
thoracic, or ocular surgeries to promote tissue repair advanced, or metastatic): First-line treatment (in
and/or prevent adhesions (Gelfilm). combination with cisplatin) of inoperable, locally
Note: May be moistened with sterile saline or sterile advanced (stage IIIA or IIIB) or metastatic (stage IV)
topical thrombin. non-small cell lung cancer (NSCLC)
Local Anesthetic/Vasoconstrictor Precautions Ovarian cancer (advanced): Treatment of advanced
No information available to require special precautions ovarian cancer (in combination with carboplatin) that
Effects on Dental Treatment Key adverse event(s) has relapsed at least 6 months following completion of
related to dental treatment: Local infection and abscess platinum-based chemotherapy
formation. Pancreatic cancer (locally advanced or metastatic):
First-line treatment of locally advanced (nonresectable
Effects on Bleeding Used as adjunct to enhance
stage II or III) or metastatic (stage IV) pancreatic
hemostasis.
adenocarcinoma. Gemcitabine is indicated for patients
Adverse Reactions Cardiopulmonary bypass surgery previously treated with fluorouracil.
(Gelfoam):
>10%: Cardiovascular: Atrial fibrillation (13%)
1% to 10%:
Cardiovascular: Cardiac failure (4%), atrial flutter
related to dental treatment: Stomatitis.
(2%), peripheral vascular disease (2%), ventricular
Effects on Bleeding Bleeding occurs in 2% to 17% of
tachycardia (2%), heart block (1%)
patients. Anemia (68% to 73%) and thrombocytopenia
Infection: Wound infection (6%)
(24% to 36%) frequently occur. Medical consult is
Respiratory: Pneumothorax (2%), respiratory fail-
recommended.
ure (2%)
Adverse Reactions Frequency of adverse reactions
reported for single-agent use of gemcitabine only.
Frequency not defined (Gelfoam was used in cited
>10%:
surgical procedures):
Cardiovascular: Peripheral edema (20%),
Central nervous system: Arachnoiditis (laminectomy
edema (≤13%)
operations), cauda equina syndrome (laminectomy
Central nervous system: Drowsiness (11%)
operations), headache (laminectomy operations),
Dermatologic: Skin rash (30%), alopecia (15%)
meningitis (laminectomy operations), pain (laminec-
Gastrointestinal: Nausea and vomiting (69%), diarrhea
tomy operations), paresthesia (laminectomy opera- (19%), stomatitis (11%; grade 3: <1%)
tions), spinal cord compression (brain implant surgery) Genitourinary: Proteinuria (45%), hematuria (35%)
Gastrointestinal: Gastrointestinal disease (laminectomy Hematologic & oncologic: Anemia (68%; grade 3: 7%;
operations) grade 4: 1%), neutropenia (63%; grade 3: 19%;
Genitourinary: Bladder dysfunction (laminectomy oper- grade 4: 6%), thrombocytopenia (24%; grade 3:
ations), impotence (laminectomy operations) 4%; grade 4: 1%), hemorrhage (17%; grade 3:
Hematologic & oncologic: Hematoma <1%; grade 4: <1%)
Infection: Abscess, localized infection, toxic shock syn- Hepatic: Increased serum alanine aminotransferase
drome (nasal surgery) (68%), increased serum aspartate aminotransferase
Local: Injection site granuloma (brain; brain implant (67%), increased serum alkaline phosphatase
surgery), localized edema (includes encapsulation of (55%), hyperbilirubinemia (13%)
fluid and fluid accumulation in the brain and spinal Infection: Infection (16%)
cord; brain implant surgery and laminectomy opera- Renal: Increased blood urea nitrogen (16%)
tions) Respiratory: Dyspnea (23%), flu-like symptoms (19%)
Neuromuscular & skeletal: Tendon disease (prolonged Miscellaneous: Fever (41%)
fixation of tendon post severed tendon repair) 1% to 10%:
Otic: Hearing loss (tympanoplasty) Central nervous system: Paresthesia (10%)
Miscellaneous: Fever, fibrosis (tendon repair), foreign Local: Injection site reaction (4%)
body reaction Renal: Increased serum creatinine (8%)
Mechanism of Action Arrests bleeding by forming Respiratory: Bronchospasm (<2%)
artificial clot and producing mechanical matrix which <1%, postmarketing, and/or case reports (reported with
facilitates clotting single-agent use or with combination therapy): Acute
Pregnancy Considerations When administered topi- respiratory distress syndrome, anaphylactoid shock,
cally, gelatin is completely absorbed; however, the bullous skin disease, capillary leak syndrome, cardiac
amount of gelatin available systemically following top- arrhythmia, cardiac failure, cellulitis (including pseu-
ical application is unknown. docellulitis), cerebrovascular accident (Kuenen 2002),
644
GEMIFLOXACIN
desquamation, gangrene of skin and/or subcutaneous Effects on Bleeding Anemia has been reported in
tissues, hemolytic-uremic syndrome, hepatic failure, <1% of patients.
hepatic sinusoidal obstruction syndrome, hepatotox- Adverse Reactions
icity, interstitial pneumonitis, myocardial infarction, >10%: Gastrointestinal: Dyspepsia (20%)
petechia (Nishijima 2013; Zupancic 2007), pruritus 1% to 10%:
(Curtis 2016), pulmonary edema, pulmonary fibrosis, Cardiovascular: Atrial fibrillation (1%)
radiation recall phenomenon, renal failure syndrome, Central nervous system: Fatigue (4%), vertigo (2%)
respiratory failure, reversible posterior leukoencephal- Dermatologic: Eczema (2%), skin rash (2%)
opathy syndrome, sepsis, supraventricular cardiac Gastrointestinal: Abdominal pain (10%), nausea and
arrhythmia, thrombotic microangiopathy, thrombotic vomiting (3%)
thrombocytopenic purpura (Nishijima 2013; Zupancic <1%, postmarketing and/or case reports (probable cau-
2007), vasculitis (peripheral) sation): Anemia, angioedema, arthralgia, blurred
Mechanism of Action Gemcitabine is a pyrimidine vision, bone marrow depression, cholecystitis, chole-
antimetabolite that inhibits DNA synthesis by inhibition lithiasis, cholestatic jaundice, decreased libido,
of DNA polymerase and ribonucleotide reductase, cell depression, dermatitis, dermatomyositis, dizziness,
cycle-specific for the S-phase of the cycle (also blocks drowsiness, dysgeusia, eosinophilia, exfoliative der-
cellular progression at G1/S-phase). Gemcitabine is matitis, headache, hypoesthesia, hypokalemia, impo-
phosphorylated intracellularly by deoxycytidine kinase tence, increased creatine phosphokinase, increased
to gemcitabine monophosphate, which is further phos- serum alkaline phosphatase, increased serum biliru-
phorylated to active metabolites gemcitabine diphos- bin, increased serum transaminases, laryngeal
edema, leukopenia, limb pain, myalgia, myasthenia,
phate and gemcitabine triphosphate. Gemcitabine
myopathy, nephrotoxicity, paresthesia, peripheral neu-
diphosphate inhibits DNA synthesis by inhibiting ribo-
ritis, polymyositis, pruritus, Raynaud phenomenon,
nucleotide reductase; gemcitabine triphosphate incor-
rhabdomyolysis, synovitis, urticaria
porates into DNA and inhibits DNA polymerase.
Pharmacodynamics/Kinetics Reports where causal relationship has not been estab-
Half-life Elimination lished: Alopecia, anaphylaxis, cataract, colitis, confu-
Gemcitabine: Infusion time ≤70 minutes: 42 to 94 sion, extrasystoles, hepatic neoplasm, intracranial
minutes; infusion time 3 to 4 hours: 4 to 10.5 hours hemorrhage, lupus-like syndrome, pancreatitis,
(affected by age and gender) peripheral vascular disease, positive ANA titer,
Metabolite (gemcitabine triphosphate), terminal reduced fertility (male), renal insufficiency, retinal
phase: 1.7 to 19.4 hours edema, seizure, skin photosensitivity, syncope, throm-
Time to Peak 30 minutes after completion of infusion bocytopenia, vasculitis, weight loss
Pregnancy Considerations Mechanism of Action The exact mechanism of action
Based on the mechanism of action and on findings from of gemfibrozil is unknown, however, several theories
animal reproduction studies, gemcitabine may cause exist regarding the VLDL effect; it can inhibit lipolysis
fetal harm if administered during pregnancy. and decrease subsequent hepatic fatty acid uptake as
well as inhibit hepatic secretion of VLDL; together these
Verify pregnancy status (with pregnancy test) prior to actions decrease serum VLDL levels; increases HDL-
treatment initiation in females of reproductive potential. cholesterol; the mechanism behind HDL elevation is
Females of reproductive potential should use effective currently unknown
contraception during treatment and for 6 months after Pharmacodynamics/Kinetics
the final gemcitabine dose. Males with female partners Onset of Action May require several days
of reproductive potential should use effective contra- Half-life Elimination 1.5 hours
ception during treatment and for 3 months after the final Time to Peak Serum: 1 to 2 hours
gemcitabine dose. Pregnancy Considerations
Gemcitabine may impair fertility in males of reproduc-
duction studies.
tive potential (based on animal studies).
Gemfibrozil crosses the placenta (Tsai 2004).
Gemfibrozil (jem FI broe zil) Triglyceride concentrations increase during pregnancy
as required for normal fetal development. When
Related Information increases are greater than expected, supervised dietary
Cardiovascular Diseases on page 1442 intervention should be initiated. In women who develop
Brand Names: US Lopid very severe hypertriglyceridemia and are at risk for
Pharmacologic Category Antilipemic Agent, Fibric pancreatitis, use of gemfibrozil beginning in the second
Acid trimester is one intervention that may be considered
Use Treatment of hypertriglyceridemia in Fredrickson ( Av is 20 0 9; B erg lu n d 2 01 2; Ja c ob so n 20 15 ;
types IV and V hyperlipidemia for patients who are at Wong 2015).
greater risk for pancreatitis and who have not
responded to dietary intervention; to reduce the risk of Gemifloxacin (je mi FLOKS a sin)
CHD development in Fredrickson type IIb patients with-
out a history or symptoms of existing CHD who have not Related Information
responded to dietary and other interventions (including Bacterial Infections on page 1525
pharmacologic treatment) and who have decreased Clinical Risk Related to Drugs Prolonging QT Interval
HDL, increased LDL, and increased triglycerides on page 1462
Local Anesthetic/Vasoconstrictor Precautions Brand Names: US Factive [DSC]
No information available to require special precautions Brand Names: Canada Factive
Effects on Dental Treatment No significant effects or Pharmacologic Category Antibiotic, Fluoroquinolone;
complications reported Antibiotic, Respiratory Fluoroquinolone
645
GEMIFLOXACIN
Use phosphokinase, increased gamma-glutamyl transfer-

Treatment of acute exacerbation of chronic bronchitis; ase, increased hematocrit, increased hemoglobin,
treatment of community-acquired pneumonia (CAP), increased INR, increased intracranial pressure,
including pneumonia caused by multidrug-resistant increased lactate dehydrogenase, increased neutro-
strains of S. pneumoniae (MDRSP) phils, increased nonprotein nitrogen, increased serum
Limitations of use: Because fluoroquinolones have alkaline phosphatase, increased serum bilirubin,
been associated with disabling and potentially irrever- increased serum calcium, increased serum creatinine,
sible serious adverse reactions (eg, tendinitis and increased serum potassium, increased serum sodium,
tendon rupture, peripheral neuropathy, CNS effects), insomnia, interstitial nephritis, jaundice, leukopenia,
reserve gemifloxacin for use in patients who have no lower limb cramp, myalgia, nervousness, pain, pan-
alternative treatment options for acute bacterial exac- cytopenia, paresthesia, peripheral edema, peripheral
erbation of chronic bronchitis. neuropathy, pharyngitis, pneumonia, prolonged QT
Local Anesthetic/Vasoconstrictor Precautions interval on ECG, pruritus, renal failure syndrome,
Gemifloxacin is one of the drugs confirmed to prolong retinal hemorrhage, rupture of tendon, serum sick-
the QT interval and is accepted as having a risk of ness, severe dermatological reaction, skin photosen-
causing torsade de pointes. The risk of drug-induced sitivity, Stevens-Johnson syndrome, supraventricular
torsade de pointes is extremely low when a single QT tachycardia, syncope, tendonitis, thrombocythemia,
interval prolonging drug is prescribed. In terms of epi- thrombocytopenia, thrombotic thrombocytopenic pur-
nephrine, it is not known what effect vasoconstrictors in pura, toxic epidermal necrolysis, transient ischemic
the local anesthetic regimen will have in patients with a attacks, tremor, urine abnormality, urticaria, vaginitis,
known history of congenital prolonged QT interval or in vertigo, visual disturbance, xerostomia
patients taking any medication that prolongs the QT Mechanism of Action Gemifloxacin is a DNA gyrase
interval. Until more information is obtained, it is sug- inhibitor and also inhibits topoisomerase IV. DNA
gested that the clinician consult with the physician prior gyrase (topoisomerase IV) is an essential bacterial
to the use of a vasoconstrictor in suspected patients, enzyme that maintains the superhelical structure of
and that the vasoconstrictor (epinephrine, mepivacaine DNA. DNA gyrase is required for DNA replication and
and levonordefrin [Carbocaine® 2% with Neo-Cobe- transcription, DNA repair, recombination, and transpo-
frin®]) be used with caution. sition; bactericidal
Effects on Dental Treatment No significant effects or Pharmacodynamics/Kinetics
complications reported Half-life Elimination 7 hours (range 4-12 hours)
Effects on Bleeding No information available to Time to Peak Plasma: 0.5-2 hours
require special precautions Pregnancy Considerations Adverse events have
Adverse Reactions been observed in some animal reproduction studies.
1% to 10%: Product Availability Factive is no longer available in
Central nervous system: Headache (4%), dizzi- the United States.
ness (≤2%) Dental Health Professional Considerations See
Dermatologic: Skin rash (≤4%) Local Anesthetic/Vasoconstrictor Precautions
Gastrointestinal: Diarrhea (5%), nausea (4%),
abdominal pain (≤2%), vomiting (≤2%)
Hematologic: Increased platelets (1%) Gemtuzumab Ozogamicin
Hepatic: Increased serum alanine aminotransferase (gem TOO zoo mab oh zog a MY sin)
(≤4%), increased serum aspartate aminotransferase Brand Names: US Mylotarg
(≤1%)
Frequency not defined: Central nervous system: Agi-
CD33; Antineoplastic Agent, Antibody Drug Conjugate;
tation, anxiety, confusion, delirium, depression, disori-
Antineoplastic Agent, Monoclonal Antibody
entation, disturbance in attention, hallucination,
Use
memory impairment, paranoia, pseudotumor cerebri,
Acute myeloid leukemia (newly diagnosed): Treat-
restlessness, seizure, suicidal ideation, suicidal ten-
ment of newly diagnosed CD33-positive acute myeloid
dencies, toxic psychosis
<1%, postmarketing and/or case reports: Acute renal leukemia (AML) in adults.
failure, agranulocytosis, anaphylaxis, anemia, angioe- Acute myeloid leukemia (relapsed/refractory): Treat-
dema, anorexia, antibiotic-associated colitis, aplastic ment of relapsed or refractory CD33-positive acute
anemia, arthralgia, asthenia, axonal peripheral poly- myeloid leukemia (AML) in adults and pediatric
neuropathy, back pain, candidiasis, Clostridioides dif- patients ≥2 years of age.
ficile associated diarrhea, Clostridioides difficile colitis, Local Anesthetic/Vasoconstrictor Precautions
constipation, decreased hematocrit, decreased hemo- No information available to require special precautions
globin, decreased neutrophils, decreased serum albu- Effects on Dental Treatment Key adverse event(s)
min, decreased serum calcium, decreased serum related to dental treatment: Mucositis and stomatitis
potassium, decreased serum sodium, decreased have been reported
serum total protein, dermatitis, drowsiness, dysesthe- Effects on Bleeding Bleeding reported in 13% of
sia, dysgeusia, dyspepsia, dyspnea, eczema, eosino- patients with gum hemorrhage reported in 9%. Bone
philia, eosinophilic pneumonitis, erythema multiforme, marrow suppression with anemia and thrombocytope-
exacerbation of myasthenia gravis, exfoliation of skin, nia are common. Recovery of platelets may be delayed.
facial edema, fatigue, fever, flatulence, flushing, fungal Medical consult recommended.
infection, gastritis, gastroenteritis, genital candidiasis, Adverse Reactions
genital pruritus, granulocytopenia, hemolytic anemia, >10%:
hemorrhage, hepatic necrosis, hepatitis, hepatotoxic- Cardiovascular: Cardiotoxicity (28%)
ity, hot flash, hyperbilirubinemia, hyperglycemia, Central nervous system: Fatigue (44%), head-
hypersensitivity reaction, hypoesthesia, increased ache (19%)
blood urea nitrogen, increased creatine Dermatologic: Skin rash (16%)
646
GENTAMICIN (SYSTEMIC)
Gastrointestinal: Constipation (21%), mucositis (21%), Effects on Bleeding No information available to

nausea and vomiting (21%) require special precautions
Hematologic & oncologic: Hemorrhage (23% to 25%; Adverse Reactions Frequency not defined.
≥ grade 3: 7% to 13%), febrile neutropenia (18%; Cardiovascular: Edema, hypertension, hypotension,
≥ grade 3: 18%) phlebitis, thrombophlebitis
Hepatic: Hepatotoxicity (51%), increased serum AST Central nervous system: Abnormal gait, ataxia, brain
(40%), increased serum ALT (16%) disease, confusion, depression, dizziness, drowsi-
Infection: Infection (42% to 44%) ness, headache, lethargy, myasthenia, numbness,
Miscellaneous: Fever (79%) paresthesia, peripheral neuropathy, pseudomotor cer-
1% to 10%: ebri, seizure, vertigo
Genitourinary: Nephrotoxicity (6%) Dermatologic: Alopecia, erythema, pruritus, skin rash,
Hepatic: Hyperbilirubinemia urticaria
<1%, postmarketing and/or case reports: Bacterial Endocrine & metabolic: Hypocalcemia, hypokalemia,
infection, hemorrhagic cystitis, hepatic veno-occlusive hypomagnesemia, hyponatremia, weight loss
disease, interstitial pneumonitis, neutropenic entero- Gastrointestinal: Anorexia, Clostridioides (formerly
colitis, pulmonary infection, pneumonia due to Pneu- Clostridium) difficile-associated diarrhea, decreased
mocystis carinii appetite, enterocolitis, nausea, sialorrhea, stomatitis,
Mechanism of Action Gemtuzumab ozogamicin is a vomiting
humanized CD-33 directed monoclonal antibody-drug Genitourinary: Casts in urine (hyaline, granular), Fan-
conjugate, which is composed of the IgG4 kappa anti- coni-like syndrome (infants and adults; high dose,
body gemtuzumab linked to a cytotoxic calicheamicin prolonged course), oliguria, proteinuria
derivative. CD33 is expressed on leukemic cells in over Hematologic & oncologic: Agranulocytosis, anemia,
80% of patients with AML (Castaigne 2012). Gemtuzu- eosinophilia, granulocytopenia, leukopenia, purpura,
mab ozogamicin binds to the CD33 antigen, resulting in reticulocytopenia, reticulocytosis, splenomegaly,
internalization of the antibody-antigen complex. Follow- thrombocytopenia
ing internalization, the calicheamicin derivative is Hepatic: Hepatomegaly, increased liver enzymes
released inside the myeloid cell. The calicheamicin Hypersensitivity: Anaphylaxis, anaphylactoid reaction,
derivative binds to DNA resulting in double strand hypersensitivity reaction
breaks, inducing cell cycle arrest and apoptosis. Local: Injection site reaction, pain at injection site
Pharmacodynamics/Kinetics Neuromuscular & skeletal: Arthralgia, muscle cramps,
Half-life Elimination Based on a 9 mg/m2 dose: muscle fatigue (myasthenia gravis-like syndrome),
Antibody portion: 62 hours (after first dose); 90 hours
muscle twitching, tremor, weakness
(after second dose)
Ophthalmic: Visual disturbance
Pregnancy Considerations Based on the mecha- Otic: Auditory impairment, hearing loss (associated with
nism of action and information from animal reproduction persistently increased serum concentrations; early
studies, gemtuzumab ozogamicin may cause adverse toxicity usually affects high-pitched sound), tinnitus
effects if used during pregnancy. Pregnancy status
Renal: Decreased creatinine clearance, decreased
should be evaluated prior to therapy. Women of repro-
urine specific gravity, increased blood urea nitrogen,
ductive potential should avoid becoming pregnant while
increased serum creatinine, polyuria, renal failure
receiving treatment and should use effective contra-
(high trough serum concentrations), renal tubular
ception during treatment and for at least 6 months after
necrosis
the last dose. Males with female partners of reproduc-
Respiratory: Dyspnea, laryngeal edema, pulmonary
tive potential should use effective contraception during
fibrosis, respiratory depression
therapy and for at least 3 months after the last dose.
Gemtuzumab ozogamicin may impair fertility in males
and females of reproductive potential. Mechanism of Action Interferes with bacterial protein
synthesis by binding to 30S ribosomal subunit resulting
Prescribing and Access Restrictions In Canada,
in a defective bacterial cell membrane
gemtuzumab is available through a special access
program (access information is available from Health
Canada). Half-life Elimination
Neonates: <1 week: 3 to 11.5 hours; 1 week to 1
month: 3 to 6 hours
Gentamicin (Systemic) (jen ta MYE sin) Infants: 4 ± 1 hour
Children: 2 ± 1 hour
Brand Names: Canada Gentamicin Injection, USP Adolescents: 1.5 ± 1 hour
Pharmacologic Category Antibiotic, Aminoglycoside Adults: ~2 hours (Regamey 1973); Renal failure:
Use Serious infections: Treatment of serious infections mean: 41 ± 24 hours; Range: 6 to 127 hours (Dager
(eg, sepsis, meningitis, urinary tract infections, respira- 2006)
tory tract infections, peritonitis, bone infections, skin Time to Peak Serum: IM: 30 to 90 minutes; IV: 30
and soft tissue infections) caused by susceptible strains minutes after 30-minute infusion (MacDougall 2011);
of the following microorganisms: P. aeruginosa, Proteus Note: Distribution may be prolonged after larger
species (indole-positive and indole-negative), Escher- doses. One study reported a 1.7-hour distribution
ichia coli, Klebsiella species, Enterobacter species, period after a 60-minute, high-dose aminoglycoside
Serratia species, Citrobacter species, and Staphylococ- infusion (Demczar 1997).
cus species (coagulase-positive and coagulase-nega- Pregnancy Risk Factor D
tive); treatment of infective endocarditis caused by
enterococci, in combination with other antibiotics.
Gentamicin crosses the placenta.
No information available to require special precautions [US Boxed Warning]: Aminoglycosides may cause
Effects on Dental Treatment No significant effects or fetal harm if administered to a pregnant woman.
complications reported There are several reports of total irreversible bilateral
647
GENTAMICIN (SYSTEMIC)
congenital deafness in children whose mothers Infection: Sepsis (13% to 15%)

received another aminoglycoside (streptomycin) during Neuromuscular & skeletal: Arthralgia (≤42%), myalgia
pregnancy. Although serious side effects to the fetus/ (≤42%), increased creatine phosphokinase (54%)
infant have not been reported following maternal use of Renal: Increased serum creatinine (94%), renal insuf-
all aminoglycosides, a potential for harm exists. ficiency (5% to 19%)
Respiratory: Dyspnea (7% to 34%), pneumonia (19%
to 30%), cough (25%)
pharmacokinetic parameters of gentamicin may be
Miscellaneous: Fever (13% to 35%)
altered (Popović 2007). Gentamicin use has been eval-
1% to 10%:
uated for various infections in pregnant women includ-
Cardiovascular: Prolonged QT interval on ECG (1% to
ing the treatment of acute pyelonephritis (Jolley 2010)
7%), cardiac failure (4%), pericardial effusion (3%),
and as an alternative antibiotic for prophylactic use prior
pericarditis (2%)
to cesarean delivery (Bratzler 2013).
Central nervous system: Reversible posterior leukoen-
cephalopathy syndrome (1%)
Gilteritinib (GIL te RI ti nib) Hematologic & oncologic: APL differentiation syn-
drome (1%)
Brand Names: US Xospata Hypersensitivity: Anaphylaxis (1%)
Pharmacologic Category Antineoplastic Agent, FLT3 Frequency not defined:
Inhibitor; Antineoplastic Agent, Tyrosine Kinase Inhib- Central nervous system: Altered mental status,
itor seizure
Use Acute myeloid leukemia, relapsed or refractory: Gastrointestinal: Pancreatitis
Treatment of relapsed or refractory acute myeloid leu- Mechanism of Action Gilteritinib is a tyrosine kinase
kemia (AML) in adult patients with an FMS-like tyrosine inhibitor which inhibits multiple tyrosine kinases, such
kinase 3 (FLT3) mutation as detected by an approved as FMS-like tyrosine kinase 3 (FLT3). Gilteritinib inhibits
test. FLT3 receptor signaling and proliferation in cells
Local Anesthetic/Vasoconstrictor Precautions expressing FLT3 (including FLT3-ITD), tyrosine kinase
Gilteritinib is one of the drugs confirmed to prolong domain mutations (TKD) FLT3-D835Y and FLT3-ITD-
the QT interval and is accepted as having a risk of D835Y; it induces apoptosis in FLT3-ITD-expressing
causing torsades de pointes. The risk of drug-induced leukemia cells.
torsades de pointes is extremely low when a single QT Pharmacodynamics/Kinetics
interval prolonging drug is prescribed. In terms of epi- Onset of Action Inhibition of FLT3 phosphorylation:
nephrine, it is not known what effect vasoconstrictors in Rapid (within 24 hours after the initial dose)
the local anesthetic regimen will have in patients with a Half-life Elimination 113 hours
known history of congenital prolonged QT interval or in Time to Peak ~4 to 6 hours
patients taking any medication that prolongs the QT Pregnancy Considerations
interval. Until more information is obtained, it is sug- Based on the mechanism of action and information from
gested that the clinician consult with the physician prior animal reproductions studies, gilteritinib may cause
to the use of a vasoconstrictor in suspected patients, fetal harm following maternal use during pregnancy.
and that the vasoconstrictor (epinephrine, mepivacaine,
and levonordefrin [Carbocaine 2% with Neo-Cobefrin]) Pregnancy status should be evaluated within 7 days
be used with caution. prior to starting therapy in females of reproductive
Effects on Dental Treatment Key adverse event(s) potential. Females of reproductive potential should
related to dental treatment: Frequent occurrence of use effective contraception during treatment and for at
stomatitis least 6 months after the last gilteritinib dose. Males with
Effects on Bleeding Chemotherapy with other anti- female partners of reproductive potential should use
neoplastic FLT3 inhibitor midostaurin has resulted in effective contraception during treatment and for at least
significant myelosuppression, potentially including sig- 4 months after the last gilteritinib dose.
nificant reduction in platelet counts and altered hemo-
stasis. So far there are no reports of the FLT3 inhibitor Glasdegib (glas DEG ib)
gilteritinib causing any effects on bleeding.
Adverse Reactions Brand Names: US Daurismo
>10%: Pharmacologic Category Antineoplastic Agent,
Cardiovascular: Edema (34%), hypotension (21%), Hedgehog Pathway Inhibitor
hypertension (10%) Use
Central nervous system: Fatigue (≤40%), malaise Acute myeloid leukemia: Treatment of newly-diag-
(≤40%), headache (21%), dizziness (20%), insomnia nosed acute myeloid leukemia (in combination with
(14%) low-dose cytarabine) in adult patients who are ≥75
Dermatologic: Skin rash (30%) years of age or who have comorbidities that preclude
Endocrine & metabolic: Hyperglycemia (86%), hyper- use of intensive induction chemotherapy.
triglyceridemia (81%), hypocalcemia (61%), hypoal- Limitation of use: Has not been studied in patients with
buminemia (58%), hypophosphatemia (48%), severe renal impairment or moderate-to-severe hep-
hypokalemia (35%) hyponatremia (32%) atic impairment.
Gastrointestinal: Diarrhea (34%), constipation (27%), Local Anesthetic/Vasoconstrictor Precautions
nausea (27%), stomatitis (26%; grades ≥3: 4%), Glasdegib is one of the drugs confirmed to prolong
vomiting (20%), abdominal pain (17%), decreased the QT interval and is accepted as having a risk of
appetite (15%), dysgeusia (11%) causing torsades de pointes. The risk of drug-induced
Hepatic: Increased serum alanine aminotransferase torsades de pointes is extremely low when a single QT
(78%), increased serum aspartate aminotransferase interval prolonging drug is prescribed. In terms of epi-
(78%), increased serum alkaline phosphatase nephrine, it is not known what effect vasoconstrictors in
(65%), increased serum transaminases (41%) the local anesthetic regimen will have in patients with a
648
GLECAPREVIR AND PIBRENTASVIR
known history of congenital prolonged QT interval or in administered to a pregnant female. Glasdegib is

patients taking any medication that prolongs the QT embryotoxic, fetotoxic, and teratogenic in animals.
interval. Until more information is obtained, it is sug- Glasdegib inhibits the Hedgehog pathway which is
gested that the clinician consult with the physician prior critical to fetal development (Walterhouse 1999).
and that the vasoconstrictor (epinephrine, mepivacaine, [US Boxed Warning] Conduct pregnancy testing in
and levonordefrin [Carbocaine 2% with Neo-Cobefrin]) females of reproductive potential prior to initiation
be used with caution. of glasdegib treatment. Pregnancy testing should be
Effects on Dental Treatment Key adverse event(s) conducted within 7 days prior to starting glasdegib
related to dental treatment: Frequent occurrence of treatment. Advise females of reproductive potential
mucositis to use effective contraception during glasdegib
Effects on Bleeding Bone marrow depression (eg, treatment and for at least 30 days after the last
anemia, neutropenia, thrombocytopenia, and hemor- glasdegib dose. Advise males of the potential risk
rhage) has been reported. In patients under active of glasdegib exposure through semen and to use
treatment with glasdegib, medical consult is suggested. condoms (even after vasectomy) with a pregnant
Adverse Reactions partner or a female partner of reproductive potential
>10%: during glasdegib treatment and for at least 30 days
Cardiovascular: Edema (30%), atrial arrhythmia after the last glasdegib dose to avoid potential drug
(13%), chest pain (12%) exposure. Semen should not be donated during treat-
Central nervous system: Fatigue (36%), dizziness ment and for at least 30 days after the last dose of
(18%), headache (12%) glasdegib. Based on animal data, males should con-
Dermatologic: Skin rash (20%) sider effective fertility preservation prior to therapy.
Endocrine & metabolic: Hyponatremia (11% to 54%),
Health care providers are encouraged to enroll females
hypomagnesemia (33%), hyperkalemia (16%), hypo-
inadvertently exposed to glasdegib during pregnancy to
kalemia (15%), weight loss (13%)
the Pfizer pregnancy registry (800-438-1985).
Gastrointestinal: Nausea (29%), decreased appetite
(21%), dysgeusia (21%), mucositis (21%; grade ≥3:
1%), constipation (20%), abdominal pain (19%), Glecaprevir and Pibrentasvir
diarrhea (18%), vomiting (18%) (glek A pre vir & pi BRENT as vir)
Hematologic & oncologic: Anemia (43%; grade ≥3:
41%), hemorrhage (36%; grade ≥3: 6%), febrile Brand Names: US Mavyret
neutropenia (31%; grade ≥3: 31%), thrombocytope- Brand Names: Canada Maviret
nia (30%; grade ≥3: 30%), decreased white blood Pharmacologic Category Antihepaciviral, NS3/4A
cell count (11%; grade ≥3: 11%) Protease Inhibitor (Anti-HCV); Antihepaciviral, NS5A
Hepatic: Increased serum aspartate aminotransferase Inhibitor; NS3/4A Inhibitor; NS5A Inhibitor
(28%), increased serum bilirubin (25%), increased Use Chronic hepatitis C: Treatment of chronic hepatitis
serum alanine aminotransferase (24%), increased C virus (HCV) genotype 1, 2, 3, 4, 5, or 6 infection in
serum alkaline phosphatase (23%) adults without cirrhosis or with compensated cirrhosis
Neuromuscular & skeletal: Musculoskeletal pain (Child-Pugh class A); HCV genotype 1 infection in
(30%), increased creatine phosphokinase in blood adults previously treated with a regimen containing an
specimen (16%), muscle spasm (15%) HCV NS5A inhibitor or an NS3/4A protease inhibitor,
Renal: Increased serum creatinine (96%), renal insuf- but not both
ficiency (19%) Local Anesthetic/Vasoconstrictor Precautions
Respiratory: Dyspnea (23%), pneumonia (19%), No information available to require special precautions
cough (18%) Effects on Dental Treatment No significant effects or
Miscellaneous: Fever (18%) complications reported
Cardiovascular: Prolonged QT interval on ECG (4%
to 5%)
Infection: Sepsis (7%)
Adverse Reactions
Frequency not defined: Endocrine & metabolic: Hypo- >10%:
phosphatemia Central nervous system: Headache (9% to 17%),
Mechanism of Action Glasdegib is a small molecule fatigue (11% to 16%)
inhibitor of the Hedgehog pathway. Glasdegib binds to Gastrointestinal: Nausea (6% to 12%)
and inhibits Smoothened (SMO), which is a transmem- 1% to 10%:
brane protein involved in hedgehog signal transduction. Dermatologic: Pruritus (7%)
Glasdegib blocks the translocation of SMO into cilia and Gastrointestinal: Diarrhea (3% to 7%)
prevents SMO-mediated activation of downstream Hepatic: Increased serum bilirubin (2x ULN: 4%)
Hedgehog targets (Cortes 2018). In an animal AML Mechanism of Action
model, glasdegib (in combination with low-dose cytar- Glecaprevir is an inhibitor of hepatitis C virus (HCV)
abine) reduced the percentage of CD45+/CD33+ blasts NS3/4A protease, necessary for the proteolytic cleav-
in the bone marrow and inhibited increases in tumor age of the HCV-encoded polyprotein (into mature
size to a greater extent than either agent alone. forms of the NS3, NS4A, NS4B, NS5A, and NS5B
Pharmacodynamics/Kinetics proteins) and is essential for viral replication.
Half-life Elimination 17.4 hours ± 3.7 hours Pibrentasvir is an inhibitor of HCV NS5A, essential for
Time to Peak 1.3 to 1.8 hours viral RNA replication and virion assembly.
Pregnancy Considerations Pharmacodynamics/Kinetics
Glasdegib use is not recommended in pregnant Half-life Elimination Glecaprevir: 6 hours; Pibrentas-
females. [US Boxed Warning] Glasdegib can cause vir: 13 hours
embryo-fetal death or severe birth defects when Time to Peak 5 hours
649
GLECAPREVIR AND PIBRENTASVIR
Pregnancy Considerations Otic: Otitis media (≤1%)

Adverse events were not observed in animal reproduc- Respiratory: Bronchitis (4% to 5%), rhinitis (4% to
tion studies with glecaprevir or pibrentasvir as individual 5%), pharyngitis (4%), upper respiratory tract infec-
agents. tion (3% to 4%), cough (2%), pneumonia (1% to 2%),
sinusitis (1% to 2%)
Treatment of hepatitis C is not currently recommended Frequency not defined:
to treat maternal infection or to decrease the risk of Endocrine & metabolic: Increased lactate dehydro-
mother-to-child transmission during pregnancy (Tran genase
2016). HCV-infected females of childbearing potential Renal: Increased serum creatinine
should consider postponing pregnancy until therapy is <1%, postmarketing, and/or case reports: Abnormal
complete to reduce the risk of HCV transmission lacrimation, acute pancreatitis, agranulocytosis, albu-
(AASLD/IDSA 2017). When HCV infection is detected minuria, anal fissure, anemia, angioedema, anxiety,
during pregnancy, treatment should be deferred until arteritis, asthma, auditory impairment, balanitis, bone
after delivery. Direct-acting antiviral medications should disease (spine malformation), breast neoplasm
not be used in pregnant females outside of clinical trials (female; benign), bullous rash, bursitis, cardiac failure,
until safety and efficacy information is available (SMFM carpal tunnel syndrome, cataract, cerebrovascular
[Hughes 2017]). disease, chest pain, cholestatic jaundice, colitis, con-
fusion, conjunctival hemorrhage, coronary artery dis-
Gliclazide (GLYE kla zide) ease, cystitis, dermal ulcer, diplopia, disulfiram-like
reaction, DRESS syndrome, duodenal ulcer, dyspep-
Brand Names: Canada ACT Gliclazide MR; Apo- sia, dyspnea, eczema, epigastric fullness, epistaxis,
Gliclazide; Apo-Gliclazide MR; Diamicron; Diamicron erythema, erythrocytopenia, esophagitis, fecal incon-
MR; Gliclazide-80; Mint-Gliclazide MR; Mylan-Glicla- tinence, fever, flatulence, fungal dermatitis, fungal
zide; Mylan-Gliclazide MR; PMS-Gliclazide; Teva-Gli- infection, gastroesophageal reflux disease, gastroin-
clazide testinal neoplasm (benign), glaucoma, glycosuria,
Pharmacologic Category Antidiabetic Agent, Sulfo- gout, hemolytic anemia, hemorrhoids, hepatitis, hep-
nylurea atomegaly, hernia (congenital), hypercholesterolemia,
Use Note: Not approved in the US hyperkeratosis, hypersensitivity angiitis, hypersensi-
Diabetes mellitus, type 2: Management of type 2 tivity reaction, hypertriglyceridemia, hypoglycemic
diabetes mellitus (noninsulin dependent, NIDDM) coma, hyponatremia, hypotension, hypothyroidism,
Local Anesthetic/Vasoconstrictor Precautions impotence, increased appetite, increased serum alka-
No information available to require special precautions line phosphatase, increased serum ALT, increased
Effects on Dental Treatment Key adverse event(s) serum AST, increased serum transaminases,
related to dental treatment: Patients with diabetes increased thirst, infection, leg pain, leukopenia,
should be questioned by the dental professional at each malaise, mastitis, melena, menstrual disease, myocar-
dental visit to assess their risk for stress-induced hypo- dial infarction, nail disease, nephrolithiasis, nervous-
glycemia. The dental professional should inquire about ness, neuropathy, nocturia, onychomycosis, pain,
the patient's routine (ie, work, sleep schedule, eating palpitations, pancytopenia, polyuria, prostatic disease,
patterns), history of hypoglycemia, time of last medica- renal cyst, retinopathy, sialorrhea, skeletal pain, Ste-
tion dose, last meal, and most recent blood sugar vens-Johnson syndrome, tachycardia, thrombocyto-
assessment. Keep a supply of glucose tablets and other penia, thrombophlebitis, tinnitus, toothache, toxic
carbohydrates in the office to prepare for a hypoglyce- epidermal necrolysis, tracheitis, urticaria, vaginitis,
mic event. Seek medical attention when necessary vascular disease (vein disorder), visual disturbance,
(American Diabetes Association 2018). vitreous disorder, vomiting, weight gain, xeroderma,
Effects on Bleeding No information available to xerophthalmia, xerostomia
require special precautions Mechanism of Action Stimulates insulin release from
Adverse Reactions the pancreatic beta cells; reduces insulin uptake and
>10%: Endocrine & metabolic: Hypoglycemia (11% to glucose output by the liver; insulin sensitivity is
12%) increased at peripheral target sites. Reduces micro-
1% to 10%: thrombosis by decreasing platelet aggregation and
Cardiovascular: Hypertension (3% to 4%), angina adhesion, and by restoring fibrinolysis with an increase
pectoris (2%), peripheral edema (1%) in tissue plasminogen activator (t-PA) activity. Antiox-
Central nervous system: Headache (4% to 5%), dizzi- idant effects include a decrease in plasma levels of
ness (2%), depression (1% to 2%), insomnia (1% to peroxidized lipids and increased erythrocyte superoxide
2%), neuralgia (≤1%) dismutase activity.
Dermatologic: Dermatological disease (2%), dermati- Pharmacodynamics/Kinetics
tis (1% to 2%), skin rash (1%; includes maculopap- Duration of Action Modified-release tablet: 24 hours
ular rash, morbilliform rash), pruritus (≤1%) Half-life Elimination Immediate-release tablet: 10.4
Endocrine & metabolic: Hyperglycemia (2%), hyper- hours; Modified-release tablet: 16 hours (range: 12 to
lipidemia (≤1%), lipid metabolism disorder (≤1%) 20 hours)
Gastrointestinal: Diarrhea (2% to 3%), constipation Time to Peak Immediate-release tablet: 4 to 6 hours;
(1% to 2%), gastroenteritis (1% to 2%), abdominal Modified-release tablet: ~6 hours
pain (1%), gastritis (1%), nausea (≤1%) Pregnancy Considerations Use during pregnancy is
Genitourinary: Urinary tract infection (3%) contraindicated. Maternal hyperglycemia can be asso-
Infection: Viral infection (6% to 8%) ciated with adverse effects in the fetus, including mac-
Neuromuscular & skeletal: Back pain (4% to 5%), rosomia, neonatal hyperglycemia, and
arthralgia (3% to 4%), weakness (2% to 3%), hyperbilirubinemia; the risk of congenital malformations
arthropathy (2%), myalgia (2%), arthritis (1% to is increased when the Hb A1c is above the normal
2%), tendonitis (1%) range. Diabetes can also be associated with adverse
Ophthalmic: Conjunctivitis (1%) effects in the mother. Poorly-treated diabetes may
650
GLIPIZIDE
cause end-organ damage that may in turn negatively Pregnancy Considerations

affect obstetric outcomes. Physiologic glucose levels Severe hypoglycemia lasting 4 to 10 days has been
should be maintained prior to and during pregnancy to noted in infants born to mothers taking a sulfonylurea at
decrease the risk of adverse events in the mother and the time of delivery. Information related to the use of
the fetus. Insulin is the drug of choice for the control of glimepiride during pregnancy is limited (Balaguer San-
diabetes mellitus during pregnancy. tamaria 2000; Kalyoncu 2005). If exposure during preg-
Product Availability Not available in the US nancy occurs, discontinue at least 2 weeks prior to
delivery.
Glimepiride (GLYE me pye ride) In women with diabetes, maternal hyperglycemia can
be associated with congenital malformations as well as
Related Information adverse effects in the fetus, neonate, and the mother
Endocrine Disorders and Pregnancy on page 1471 (ACOG 2005; ADA 2018c; Metzger 2007). To prevent
Brand Names: US Amaryl adverse outcomes prior to conception and throughout
Brand Names: Canada Amaryl pregnancy, maternal blood glucose and HbA1c should
Pharmacologic Category Antidiabetic Agent, Sulfo- be kept as close to target goals as possible but without
nylurea causing significant hypoglycemia (ADA 2018c; Blumer
Use Diabetes mellitus, type 2: As an adjunct to diet 2013). Agents other than glimepiride are currently rec-
and exercise to improve glycemic control in adults with ommended to treat diabetes in pregnant women (ADA
type 2 diabetes mellitus 2018c).
No information available to require special precautions GlipiZIDE (GLIP i zide)
related to dental treatment: Patients with diabetes Related Information
should be questioned by the dental professional at each Endocrine Disorders and Pregnancy on page 1471
dental visit to assess their risk for stress-induced hypo- Brand Names: US glipiZIDE XL; Glucotrol; Glucotrol
glycemia. The dental professional should inquire about XL
the patient's routine (ie, work, sleep schedule, eating Pharmacologic Category Antidiabetic Agent, Sulfo-
patterns), history of hypoglycemia, time of last medica- nylurea
tion dose, last meal, and most recent blood sugar Use Diabetes mellitus, type 2, treatment: Adjunct to
assessment. Keep a supply of glucose tablets and other diet and exercise to improve glycemic control in adults
carbohydrates in the office to prepare for a hypoglyce- with type 2 diabetes mellitus
mic event. Seek medical attention when necessary Local Anesthetic/Vasoconstrictor Precautions
(American Diabetes Association, 2018). No information available to require special precautions
require special precautions related to dental treatment: Patients with diabetes
Adverse Reactions should be questioned by the dental professional at each
>10%: Endocrine & metabolic: Hypoglycemia (4% to dental visit to assess their risk for stress-induced hypo-
20%) glycemia. The dental professional should inquire about
1% to 10%: the patient's routine (ie, work, sleep schedule, eating
Central nervous system: Dizziness (2%), headache patterns), history of hypoglycemia, time of last medica-
Gastrointestinal: Nausea (5%) tion dose, last meal, and most recent blood sugar
Hepatic: Increased serum ALT (2%) assessment. Keep a supply of glucose tablets and other
Respiratory: Flu-like symptoms (5%) carbohydrates in the office to prepare for a hypoglyce-
Miscellaneous: Accidental injury (6%) mic event. Seek medical attention when necessary
(American Diabetes Association, 2018).
hepatic function tests, accommodation disturbance Effects on Bleeding No information available to
(early treatment), agranulocytosis, alopecia, anaphy- require special precautions
laxis, angioedema, aplastic anemia, cholestatic jaun- Adverse Reactions Frequency not always defined.
dice, diarrhea, disulfiram-like reaction, dysgeusia, Cardiovascular: Syncope (<3%)
dyspnea, erythema, gastrointestinal pain, hemolytic Central nervous system: Dizziness (2% to 7%), nerv-
anemia, hepatic failure, hepatic insufficiency, hepatic ousness (4%), anxiety (<3%), depression (<3%),
hypoesthesia (<3%), insomnia (<3%), pain (<3%),
porphyria, hepatitis, hypersensitivity, hypersensitivity
paresthesia (<3%), drowsiness (2%), headache (2%)
angiitis, hyponatremia, hypotension, immune throm-
Dermatologic: Diaphoresis (<3%), pruritus (1% to <3%),
bocytopenia, leukopenia, maculopapular rash, morbil-
eczema (1%), erythema (1%), maculopapular rash
liform rash, pancytopenia, porphyria cutanea tarda,
(1%), morbilliform rash (1%), skin rash (1%), urticaria
pruritus, shock, SIADH, skin photosensitivity, Ste-
(1%)
vens-Johnson syndrome, thrombocytopenia, urticaria,
Endocrine & metabolic: Hypoglycemia (<3%),
vomiting, weight gain
increased lactate dehydrogenase
Mechanism of Action Stimulates insulin release from Gastrointestinal: Diarrhea (1% to 5%), flatulence (3%),
the pancreatic beta cells; reduces glucose output from dyspepsia (<3%), vomiting (<3%), constipation (1% to
the liver; insulin sensitivity is increased at peripheral <3%), nausea (1% to <3%), abdominal pain (1%)
target sites Hepatic: Increased serum alkaline phosphatase,
Pharmacodynamics/Kinetics increased serum AST
Onset of Action Peak effect: Blood glucose reduc- Neuromuscular & skeletal: Tremor (4%), arthralgia
tions: 2 to 3 hours (<3%), leg cramps (<3%), myalgia (<3%)
Duration of Action 24 hours Ophthalmic: Blurred vision (<3%)
Half-life Elimination 5 to 9 hours Renal: Increased blood urea nitrogen, increased serum
Time to Peak 2 to 3 hours creatinine
651
GLIPIZIDE
Respiratory: Rhinitis (<3%) Adverse Reactions

1%, postmarketing, and/or case reports: Agranulocyto- 1% to 10%:
sis, anorexia, aplastic anemia, bloody stools, cardiac Gastrointestinal: Epigastric fullness (≤2%), heartburn
arrhythmia, chills, cholestatic jaundice, confusion, (≤2%), nausea (≤2%)
conjunctivitis, decreased libido, disulfiram-like reac- Hypersensitivity: Hypersensitivity reaction (2%; includ-
tion, dyspnea, dysuria, edema, eye pain, flushing, ing erythema, maculopapular rash, morbilliform rash,
hemolytic anemia, hepatic injury, hypertension, hyper- pruritus, urticaria)
tonia, hyponatremia, jaundice, leukopenia, migraine, Frequency not defined:
pancytopenia, pharyngitis, porphyria, retinal hemor- Central nervous system: Disulfiram-like reaction
rhage, SIADH (syndrome of inappropriate antidiuretic Endocrine & metabolic: Hypoglycemia, hyponatremia,
hormone secretion), skin photosensitivity, thrombocy- weight gain
topenia, unsteady gait, vertigo Genitourinary: Diuresis (minor)
Mechanism of Action Stimulates insulin release from Hematologic & oncologic: Hemolytic anemia
the pancreatic beta cells; reduces glucose output from Hepatic: Cholestatic jaundice, hepatic failure, hepatitis
the liver; insulin sensitivity is increased at peripheral
<1%, postmarketing, and/or case reports: Accommoda-
target sites
tion disturbance, angioedema, arthralgia, blurred
vision, bullous rash, erythema multiforme, exfoliative
Duration of Action 12 to 24 hours
dermatitis, increased serum transaminases, myalgia,
Half-life Elimination 2 to 5 hours
vasculitis
Time to Peak 1 to 3 hours; extended release tablets: 6
Mechanism of Action Stimulates insulin release from
to 12 hours
the pancreatic beta cells; reduces glucose output from
Pregnancy Considerations Glipizide was found to
the liver; insulin sensitivity is increased at peripheral
cross the placenta in vitro (Elliott 1994). Severe hypo-
target sites
glycemia lasting 4 to 10 days has been noted in infants
born to mothers taking a sulfonylurea at the time of
delivery. Onset of Action Serum insulin levels begin to
increase 15-60 minutes after a single dose
In women with diabetes, maternal hyperglycemia can Duration of Action ≤24 hours
be associated with congenital malformations as well as Half-life Elimination DiaBeta: 10 hours; Glynase
adverse effects in the fetus, neonate, and the mother PresTab: ~4 hours; may be prolonged with renal or
(ACOG 201 2018; ADA 2019; Metzger 2007). To pre- hepatic impairment
vent adverse outcomes, prior to conception and Time to Peak Serum: Adults: 2-4 hours
throughout pregnancy, maternal blood glucose and
HbA1c should be kept as close to target goals as
Glyburide crosses the placenta. Some pharmacokinetic
possible but without causing significant hypoglycemia
(ADA 2019; Blumer 2013). Agents other than glipizide properties of glyburide may change during pregnancy
are currently recommended to treat diabetes in preg- (Hebert 2009).
nant women (ADA 2019). Severe hypoglycemia lasting 4 to 10 days has been
The manufacturer recommends if glipizide is used dur- noted in infants born to mothers taking a sulfonylurea at
ing pregnancy, it should be discontinued at least 1 the time of delivery. Additional adverse maternal and
month before the expected delivery date. fetal events have been noted in some studies and may
be influenced by maternal glycemic control and/or dif-
ferences in study design (Bertini 2005; Ekpebegh 2007;
GlyBURIDE (GLYE byoor ide) Joy 2012; Langer 2000; Langer 2005).
Related Information In women with diabetes, maternal hyperglycemia can
Endocrine Disorders and Pregnancy on page 1471 be associated with congenital malformations as well as
Brand Names: US Diabeta [DSC]; Glynase adverse effects in the fetus, neonate, and the mother
Brand Names: Canada DiaBeta; Euglucon (ACOG 201 2018; ADA 2019; Metzger 2007). To pre-
Pharmacologic Category Antidiabetic Agent, Sulfo- vent adverse outcomes, prior to conception and
nylurea throughout pregnancy, maternal blood glucose and
Use Diabetes mellitus, type 2: Adjunct to diet and HbA1c should be kept as close to target goals as
exercise to improve glycemic control in adults with type possible but without causing significant hypoglycemia
2 diabetes mellitus (ADA 2019; Blumer 2013).
Agents other than glyburide are currently recommended
to treat diabetes in pregnant women (ADA 2019).
According to the manufacturer, if glyburide is used
related to dental treatment: Patients with diabetes
during pregnancy, it should be discontinued at least 2
should be questioned by the dental professional at each
dental visit to assess their risk for stress-induced hypo- weeks before the expected delivery date.
glycemia. The dental professional should inquire about
the patient's routine (ie, work, sleep schedule, eating Glyburide and Metformin
patterns), history of hypoglycemia, time of last medica- (GLYE byoor ide & met FOR min)
tion dose, last meal, and most recent blood sugar
assessment. Keep a supply of glucose tablets and other Related Information
carbohydrates in the office to prepare for a hypoglyce- GlyBURIDE on page 652
mic event. Seek medical attention when necessary MetFORMIN on page 863
(American Diabetes Association, 2018). Brand Names: US Glucovance [DSC]
Effects on Bleeding No information available to Pharmacologic Category Antidiabetic Agent, Bigua-
require special precautions nide; Antidiabetic Agent, Sulfonylurea
652
GLYCOPYRROLATE (SYSTEMIC)
Use Diabetes mellitus, type 2: As an adjunct to diet secretions during induction of anesthesia and intu-
and exercise, to improve glycemic control in adults with bation
type 2 diabetes Reversal of bradycardia, vagal reflexes (injection
Local Anesthetic/Vasoconstrictor Precautions only): To block cardiac vagal inhibitory reflexes during
No information available to require special precautions induction of anesthesia and intubation; intraopera-
Effects on Dental Treatment Key adverse event(s) tively to counteract surgically or drug-induced or vagal
related to dental treatment: Patients with diabetes reflexes associated arrhythmias
should be questioned by the dental professional at each Reversal of muscarinic effects of cholinergic
dental visit to assess their risk for stress-induced hypo- agents (injection only): Protects against the periph-
glycemia. The dental professional should inquire about eral muscarinic effects (eg, bradycardia, excessive
the patient's routine (ie, work, sleep schedule, eating secretions) of cholinergic agents (eg, neostigmine,
patterns), history of hypoglycemia, time of last medica- pyridostigmine) given to reverse the neuromuscular
tion dose, last meal, and most recent blood sugar blockade due to non-depolarizing muscle relaxants
assessment. Keep a supply of glucose tablets and other Local Anesthetic/Vasoconstrictor Precautions
carbohydrates in the office to prepare for a hypoglyce- No information available to require special precautions
mic event. Seek medical attention when necessary Effects on Dental Treatment Key adverse event(s)
(American Diabetes Association, 2018). related to dental treatment: Significant xerostomia (nor-
Effects on Bleeding No information available to mal salivary flow resumes upon discontinuation).
require special precautions Effects on Bleeding No information available to
Adverse Reactions Also see individual agents. require special precautions
>10%: Adverse Reactions Frequency not always defined.
Endocrine & metabolic: Hypoglycemia (11% to 38%, Cardiovascular: Flushing (30%), pallor (≤2%), cardiac
effects higher when increased doses were used as arrhythmias, heart block, hypertension, hypotension,
initial therapy) palpitation, tachycardia
Gastrointestinal: Gastrointestinal symptoms (38%; Central nervous system: Headache (15%), aggressive-
ness (≤2%), agitation (≤2%), crying (abnormal; ≤2%),
combined GI effects increased to 38% in patients
irritability (≤2%), mood changes (≤2%), pain (≤2%),
taking high doses as initial therapy), diarrhea (17%)
restlessness (≤2%), confusion, dizziness, drowsiness,
Respiratory: Upper respiratory infection (17%)
excitement (higher incidence in older adults), insom-
1% to 10%:
nia, nervousness
Central nervous system: Headache (9%), dizzi-
Dermatologic: Dry skin (≤2%), pruritus (≤2%), rash
ness (6%)
(≤2%), hypohidrosis, urticaria
Gastrointestinal: Nausea (8%), vomiting (8%),
Endocrine & metabolic: Dehydration (≤2%)
abdominal pain (7%)
Gastrointestinal: Vomiting (40%), xerostomia (40%),
<1%, postmarketing, and/or case reports: Cholestatic
constipation (35%), abdominal distention (≤2%),
jaundice, hepatitis abdominal pain (≤2%), flatulence (≤2%), retching
Mechanism of Action The combination of glyburide (≤2%), intestinal obstruction, loss of taste, nausea,
and metformin is used to improve glycemic control in pseudo-obstruction
patients with type 2 diabetes mellitus by using two Genitourinary: Urinary retention (15%), urinary tract
different, but complementary, mechanisms of action: infection (≤2%), decreased lactation, impotence, uri-
Glyburide: Stimulates insulin release from the pancre- nary hesitancy
atic beta cells; reduces glucose output from the liver; Neuromuscular & skeletal: Weakness
insulin sensitivity is increased at peripheral target sites Ophthalmic: Nystagmus (≤2%), blurred vision, cyclo-
Metformin: Decreases hepatic glucose production, plegia, increased intraocular pressure, mydriasis
decreasing intestinal absorption of glucose and Respiratory: Nasal congestion (30%), sinusitis (15%),
improves insulin sensitivity (increases peripheral glu- upper respiratory tract infection (15%), bronchial
cose uptake and utilization) secretion (thickening; ≤2%), nasal dryness (≤2%),
Pharmacodynamics/Kinetics pneumonia (≤2%)
Time to Peak Glucovance: 2.75 hours when taken <1%, postmarketing, and/or case reports: Arrhythmias,
with food hypertension, hypotension, malignant hyperthermia,
Pregnancy Considerations If exposure during preg- seizure
nancy occurs, discontinue at least 2 weeks prior to Mechanism of Action Blocks the action of acetylcho-
expected delivery. Refer to individual monographs for line at parasympathetic sites in smooth muscle, secre-
additional information. tory glands, and the CNS; indirectly reduces the rate of
salivation by preventing the stimulation of acetylcholine
Glycopyrrolate (Systemic) receptors
(glye koe PYE roe late) Pharmacodynamics/Kinetics
Onset of Action IM: 15 to 30 minutes; IV: Within 1
Brand Names: US Cuvposa; Glycate; Glyrx-PF; Rob- minute; Peak effect: IM: Within ~30 to 45 minutes
inul [DSC]; Robinul-Forte [DSC] Duration of Action Vagal effect: 2 to 3 hours; Inhib-
Brand Names: Canada Cuvposa ition of salivation: Up to 7 hours; Parenteral: 7 hours
Pharmacologic Category Anticholinergic Agent Half-life Elimination IV: Infants: 21.6 to 130 minutes;
Use Children: 19.2 to 99.2 minutes; IM: Adults: 0.55 to 1.25
Chronic drooling (Cuvposa only): To reduce chronic, hours; IV: 0.83 ± 0.27 hour; Oral solution: Adults: 3
severe drooling in pediatric patients 3 to 16 years with hours
neurologic conditions (eg, cerebral palsy) associated Time to Peak 3.1 hours
with problem drooling Pregnancy Risk Factor B (injection)
Reduction of secretions (injection only): To reduce Pregnancy Considerations Glycopyrrolate does not
salivary, tracheobronchial, and pharyngeal secretions appear to penetrate through the placental barrier in
and to reduce the volume and acidity of gastric significant amounts. Glycopyrrolate in doses of
653
GLYCOPYRROLATE (SYSTEMIC)
0.004 mg/kg has not been found to affect fetal heart Local Anesthetic/Vasoconstrictor Precautions
rate or fetal heart rate variability to a significant degree. No information available to require special precautions
Product Availability Glyrx-PF (glycopyrrolate Effects on Dental Treatment No significant effects or
0.2 mg/mL injection): FDA approved July 2018; avail- complications reported
ability anticipated in the third quarter 2018. Effects on Bleeding No information available to
Glycopyrrolate (Oral Inhalation) Adverse Reactions See individual agents.
(glye koe PYE roe late) 1% to 10%:
Brand Names: US Lonhala Magnair Refill Kit; Lonhala Respiratory: Cough (4%)
Magnair Starter Kit; Seebri Neohaler Frequency not defined:
Brand Names: Canada Seebri Breezhaler Cardiovascular: Depression of ST segment on ECG,
Pharmacologic Category Anticholinergic Agent; Anti- ECG changes (prolongation of the QTc interval),
cholinergic Agent, Long-Acting flattened T wave on ECG
Use Chronic obstructive pulmonary disease: Main- Dermatologic: Skin rash, urticaria
tenance treatment of airflow obstruction in patients with Endocrine & metabolic: Exacerbation of diabetes mel-
chronic obstructive pulmonary disease (COPD), includ- litus, hypokalemia, ketoacidosis (exacerbation)
ing chronic bronchitis and/or emphysema. Genitourinary: Urinary retention (exacerbation)
Local Anesthetic/Vasoconstrictor Precautions Hypersensitivity: Angioedema, immediate hypersensi-
No information available to require special precautions tivity
Effects on Dental Treatment Key adverse event(s) Ophthalmic: Exacerbation of angle-closure glaucoma
related to dental treatment: Significant xerostomia (nor- (narrow angle)
mal salivary flow resumes upon discontinuation). Respiratory: Paradoxical bronchospasm
Effects on Bleeding No information available to Mechanism of Action
require special precautions Glycopyrrolate: In COPD, competitively and reversibly
Adverse Reactions inhibits the action of acetylcholine at muscarinic
1% to 10%: receptor subtypes 1-3 (greater affinity for subtypes 1
Cardiovascular: Peripheral edema (<2%) and 3) in bronchial smooth muscle thereby causing
Central nervous system: Fatigue (≥2%) bronchodilation.
Gastrointestinal: Diarrhea (≥2%), nausea (≥2%), Formoterol: Relaxes bronchial smooth muscle by selec-
upper abdominal pain (≥2%) tive action on beta2 receptors with little effect on heart
Genitourinary: Urinary tract infection (2%) rate. Formoterol has a long-acting effect.
Neuromuscular & skeletal: Arthralgia (≥2%), back Pregnancy Risk Factor C
pain (≥2%) Pregnancy Considerations Animal reproduction
Respiratory: Dyspnea (≤5%), upper respiratory tract studies have not been conducted with this combination.
infection (2% to 3%), bronchitis (≥2%), nasopharyng- Refer to individual monographs.
itis (≥2%), pneumonia (≥2%), rhinitis (≥2%), wheez-
ing (≥2%), oropharyngeal pain (2%), sinusitis (1%) Golimumab (goe LIM ue mab)
<1% postmarketing, and/or case reports: Angioedema,
atrial fibrillation, cough, diabetes mellitus, dysuria, Related Information
gastroenteritis, hypersensitivity reaction, insomnia, Rheumatoid Arthritis, Osteoarthritis, and Osteoporosis
limb pain, paradoxical bronchospasm, productive on page 1484
cough, pruritus, skin rash, voice disorder, vomiting Brand Names: US Simponi; Simponi Aria
Mechanism of Action Competitively and reversibly Brand Names: Canada Simponi; Simponi IV
inhibits the action of acetylcholine at muscarinic recep- Pharmacologic Category Antipsoriatic Agent; Anti-
tor subtypes 1 to 3 (greater affinity for subtypes 1 and 3) rheumatic, Disease Modifying; Monoclonal Antibody;
in bronchial smooth muscle thereby causing broncho- Tumor Necrosis Factor (TNF) Blocking Agent
dilation Use
Pharmacodynamics/Kinetics Ankylosing spondylitis (Simponi, Simponi Aria):
Half-life Elimination 33 to 53 hours Treatment of adults with active ankylosin

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for final spine bulk

UPDATES TO THIS EDITION

Handbook for Dentistry

Information contained in this handbook is derived

What information is included in the Sample Prescriptions?

What information is included in the Oral Medicine sections?

How often is Lexicomp information updated?

Richard L. Wynn, BSPharm, PhD

ALPHABETICAL LISTING OF DRUGS............................................................................................................................. 51

ALPHABETICAL LISTING OF NATURAL PRODUCTS.................................................................................................1377

MEDICALLY-COMPROMISED PATIENTS ....................................................................................................................1441

SPECIFIC ORAL CONDITIONS.................................................................................................................................... 1519

Abbreviations and Measurements

PHARMACOLOGIC CATEGORY INDEX .........................................................................................................................1609

ALPHABETICAL INDEX ................................................................................................................................................... 1635

ABOUT THE EDITORS

Timothy F. Meiller, DDS, PhD

Harold L. Crossley, DDS, MS, PhD

DRUG INTERACTIONS EDITORIAL ADVISORY PANEL

EDITORIAL ADVISORY PANEL

Kylie Barnes, PharmD, BCPS Karrie Boss, MSN, RN, CCRN

Tamra Brennan, AGACNP-BC Celeste R. Caulder, PharmD

Ben Caldwell, RPh Michelle Condren, PharmD, BCPPS, AE-C, CDE,

Katie Carls, PharmD, BCPP Ann P. Conrad, ANP-BC, RN, ACRN

Romulo Carvalho Marilyn Cortell, RDH, MS, FAADH

Melanie W. Cucchi, BS, PharmD, RPh Vicki L. Ellingrod, PharmD, BCPP

Jeffrey J. Fong, PharmD, BCPS Shellee A. Grim, PharmD, MS-CTS, BCPS,

Joanna Hudson, PharmD, BCPS, FASN, FCCP, Omer N. Koc, MD

Makiko Iwasawa, PharmD, BCPS Jill M. Kolesar, PharmD, FCCP, BCPS

Jeffrey D. Lewis, PharmD, MACM Joseph Mazur, BScPharm, PharmD, BCPS

Stephanie S. Minich, PharmD, BCOP Charla E. Miller Nowak, RPh, PharmD

Jennifer L. Placencia, PharmD Shannon Saldana, PharmD, MS, BCPP

Tiffeny T. Smith, PharmD Sandra R. Tolbert, PharmD, BCGP

Greg Wiggers, PharmD, PhD Lisa A. Wood, PharmD, BCPS, BCPPS

PREFACE TO THE TWENTY-FIFTH EDITION

DESCRIPTION OF SECTIONS AND FIELDS USED IN

Generic Name US adopted name

NATURAL PRODUCTS: HERBAL AND DIETARY SUPPLEMENTS

ORAL MEDICINE TOPICS

DESCRIPTION OF DENTAL USE

FDA NAME DIFFERENTIATION PROJECT: THE USE OF

Drug Product Recommended Revision

PREVENTING PRESCRIBING ERRORS

A Complete Outpatient Prescription1

Oral Pain - Sample Prescriptions....................................................................................................................................... 32

ORAL PAIN - SAMPLE PRESCRIPTIONS

MILD/MODERATE ORAL PAIN

MODERATE/MODERATELY SEVERE ORAL PAIN

SEVERE ORAL PAIN

ANTIMICROBIAL ORAL RINSE - SAMPLE

BACTERIAL INFECTIONS AND PERIODONTAL

FUNGAL INFECTIONS - SAMPLE PRESCRIPTIONS

FUNGAL INFECTIONS REQUIRING SYSTEMIC THERAPY

PREVENTION OF ENDOCARDITIS AND TO REDUCE THE

SINUS INFECTION TREATMENT - SAMPLE

VIRAL INFECTIONS - SAMPLE PRESCRIPTIONS

HERPES SIMPLEX (RECURRENT)