Sample Dossier Actd

XYZ PHARMA LTD.

OVERALL ASEAN COMMON TECHNICAL DOSSIER TABLE OF
CONTENTS
OVERALL TABLE OF CONTENTS
S. NO. CONTENTS PAGE NO.
OVERALL TABLE OF CONTENTS 1
PART I ADMINISTRATIVE DATA AND PRODUCT 2
INFORMATION
SECTION A Introduction Profile 3
SECTION B Table of contents 12
SECTION C Documents required for Registration 13
1. Application Form 14
2. Letter of Authorization 21
3. Certifications 22
4. Labelling 25
5. Product Information 29
5.1 Package Insert 29
5.2 Summary of Product Characteristics 39
5.3 Patient Information Leaflet (PIL) 56
PART II QUALITY DOCUMENTS 62

SECTION A Table of contents for Part II 63
SECTION B Quality Overall Summary 64
SECTION C Body of Data 104
S DRUG SUBSTANCE (DS) 105
S1 General Information 105
S2 Manufacturer 108
S3 Characterization 109
S4 Control of drug substance (DS) 113
S5 Reference Standards or Materials 118
S6 Container Closure System 119
S7 Stability 119
P DRUG PRODUCT 121
P1 Description and Composition 121
P2 Pharmaceutical Developments 122
P3 Manufacture 134
P4 Control of Excipients 141
P5 Control of Finished Product 141
P6 Reference Standards or Materials 152
P7 Container Closure System 153
P8 Stability 154
P9 Product Interchangeability (BA/BE) --
SECTION D Key Literature References 160
PARTIII NONCLINICAL DOCUMENTS 161
PART IV CLINICAL DOCUMENTS 163
SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 1 of 164

XYZ PHARMA LTD.

PART I
ADMINISTRATIVE DATA AND
PRODUCT INFORMATION

XYZ PHARMA LTD.

SECTION – A
INTRODUCTION PROFILE

XYZ PHARMA LTD.

Section A: Introduction
Introduction
After two decades of marketing and industry experiences in various sectors of the
Healthcare Industry, a revolutionary movement called "XYZ" was born in 1988. The
company is spearheaded by a group of pharma professionals who have more than two
decades of marketing experience in various multinational pharma companies and have
a revolutionary zeal to excel, firmly committed to bring in only the best products and
only those that surpasses our strict internal quality assessments.
XYZ's state of art WHO-cGMP approved plant. The plant is spread over an area of 5
acres with a built up area of well over 150,000 sq.ft.. It has separate blocks for
Betalactams / Non-Betalactams / Cephalosporins / Oncology / Hormones for
manufacturing of Dry powder injectables, Liquid Injectables in Vials and Ampoules,
Tablets, Capsules, Ointments, Syrups, Eye and Ear drops.
Description:
Ceftriaxone Sodium USP
Physical Properties
A white to yellowish orange crystalline powder freely soluble in water and sparingly
soluble in methanol, very slightly soluble in alcohol
Chemical name: (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)->2-(methoxyimino)

acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]
methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt
hydrate

XYZ PHARMA LTD.

Molecular Formula:
C18H16N8Na2O7S3·3½H2O
Molecular Weight: 661.60

Anhydrous 598.56
SEFTRIL 1000 (Ceftriaxone for Injection USP 1g)
Composition:
Each vial contains:
Sterile Ceftriaxone sodium USP
Equivalent to Anhydrous Ceftriaxone 1g
Pharmacological classification:
Antibacterial
Pharmacology:
Ceftrioxone is third generation cephalosporin with a broad spectrum including many
Gram-positive and Gram-negative bacteria. It is very similar in action to Cefotaxime.
Like other cephalosporins, it works by inhibiting the cross-linkage of peptidoglycans
in non-resistant cell walls and triggers the activation of damaging autolysins.
Mechanism of Action:
Ceftriaxone sodium is a third generation injectable cephalosporin agent. It is a sterile,
semisynthetic, broad-spectrum cephalosporin antibiotic. Ceftriaxone works by
inhibiting the mucopeptide synthesis in the bacterial cell wall. The beta-lactam moiety
of Ceftriaxone binds to carboxypeptidases, endopeptidases, and transpeptidases in the
bacterial cytoplasmic membrane. These enzymes are involved in cell-wall synthesis
and cell division. By binding to these enzymes, Ceftriaxone results in the formation of
defective cell walls and cell death.

XYZ PHARMA LTD.

INDICATIONS:
Before instituting treatment with Ceftriaxone, appropriate specimens should be
obtained for isolation of the causative organism and for determination of its
susceptibility to the drug. Therapy may be instituted prior to obtaining results of
susceptibility testing.
To reduce the development of drug-resistant bacteria and maintain the effectiveness
of Ceftriaxone and other antibacterial drugs, Ceftriaxone should be used only to treat
or prevent infections that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they should be
considered in selecting or modifying antibacterial therapy. In the absence of such
data, local epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.
Ceftriaxone is indicated for the treatment of the following infections when caused by
susceptible organisms:
Lower Respiratory Tract Infections caused by Streptococcus pneumoniae,

Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae,
Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Proteus mirabilis or
Serratia marcescens.
Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus

influenzae (including beta-lactamase producing strains) or Moraxella
catarrhalis (including beta-lactamase producing strains).
Note: In one study lower clinical cure rates were observed with a single dose of
Ceftriaxone compared to 10 days of oral therapy. In a second study comparable cure
rates were observed between single dose Ceftriaxone and the comparator. The
potentially lower clinical cure rate of Ceftriaxone should be balanced against the
potential advantages of parenteral therapy.
Skin And Skin Structure Infections caused by Staphylococcus aureus, Staphylococcus

epidermidis, Streptococcus pyogenes, Viridans group streptococci, Escherichia coli,
Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis,
Morganella morganii,Efficacy for this organism in this organ system was studied in

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fewer than ten infections.Pseudomonas aeruginosa, Serratia marcescens,
Acinetobacter calcoaceticus, Bacteroides fragilis or Peptostreptococcusspecies.
Urinary Tract Infections (complicated and uncomplicated) caused by Escherichia coli,

Proteus mirabilis, Proteus vulgaris, Morganella morganii or Klebsiella pneumoniae.
Uncomplicated Gonorrhea (cervical/urethral and rectal) caused by Neisseria

gonorrhoeae, including both penicillinase- and nonpenicillinase-producing strains,
and pharyngeal gonorrhea caused by nonpenicillinase-producing strains of Neisseria
gonorrhoeae.
Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae. Ceftriaxone, like other

cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when
cephalosporins are used in the treatment of patients with pelvic inflammatory disease
and Chlamydia trachomatis is one of the suspected pathogens, appropriate
antichlamydial coverage should be added.
Bacterial Septicemia caused by Staphylococcus aureus, Streptococcus pneumoniae,
Escherichia coli, Haemophilus influenzae or Klebsiella pneumoniae.
Bone And Joint Infections caused by Staphylococcus aureus, Streptococcus

pneumoniae, Escherichia coli, Proteus mirabilis, Klebsiella pneumonia or
Enterobacter species.
Intra-Abdominal Infections caused by Escherichia coli, Klebsiella pneumoniae,
Bacteroides fragilis, Clostridium species (Note: most strains of Clostridium
difficile are resistant) or Peptostreptococcus species.
Meningitis caused by Haemophilus influenzae, Neisseria meningitides or

Streptococcus pneumoniae. Ceftriaxone has also been used successfully in a limited
number of cases of meningitis and shunt infection caused by Staphylococcus
epidermidis andEscherichia coli.
Surgical prophylaxis: The preoperative administration of a single 1 gm dose of

Ceftriaxone may reduce the incidence of postoperative infections in patients
undergoing surgical procedures classified as contaminated or potentially contaminated

XYZ PHARMA LTD.

(eg,vaginal or abdominal hysterectomy or cholecystectomy for chronic calculous
cholecystitis in high-risk patients, such as those over 70 years of age, with acute
cholecystitis not requiring therapeutic antimicrobials, obstructive jaundice or common
duct bile stones) and in surgical patients for whom infection at the operative site
would present serious risk (eg, during coronary artery bypass surgery). Although
Ceftriaxone has been shown to have been as effective as cefazolin in the prevention of
infection following coronary artery bypass surgery, no placebo-controlled trials have
been conducted to evaluate any cephalosporin antibiotic in the prevention of infection
following coronary artery bypass surgery.
When administered prior to surgical procedures for which it is indicated, a single 1
gm dose of Ceftriaxone provides protection from most infections due to susceptible
organisms throughout the course of the procedure.
Contraindications:
Hypersensitivity to cephalosporins; neonates (28 days of age or younger);
concomitant use with calcium-containing IV solutions, including continuous calcium-
containing infusions, such as parenteral nutrition in neonates
Warnings
Hypersensitivity
Before therapy with Ceftriaxone is instituted, careful inquiry should be made to
determine whether the patient has had previous hypersensitivity reactions to
cephalosporins, penicillins or other drugs. This product should be given cautiously to
penicillin-sensitive patients. Antibiotics should be administered with caution to any
patient who has demonstrated some form of allergy, particularly to drugs. Serious
acute hypersensitivity reactions may require the use of subcutaneous epinephrine and
other emergency measures.
Dosage and administration:

Ceftriaxone may be administered intravenously or intramuscularly.
Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s
solution, to reconstitute Ceftriaxone. Particulate formation can result. Ceftriaxone and
calcium-containing solutions, including continuous calcium-containing infusions such

XYZ PHARMA LTD.

as parenteral nutrition, should not be mixed or co-administered to any patient
irrespective of age, even via different infusion lines at different sites.
Neonates
Hyperbilirubinemic neonates, especially prematures, should not be treated with
Ceftriaxone.
Pediatric Patients
For the treatment of skin and skin structure infections, the recommended total daily
dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day).
The total daily dose should not exceed 2 grams.
For the treatment of acute bacterial otitis media, a single intramuscular dose of 50
mg/kg (not to exceed 1 gram) is recommended.
For the treatment of serious miscellaneous infections other than meningitis, the
recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12
hours. The total daily dose should not exceed 2 grams.
In the treatment of meningitis, it is recommended that the initial therapeutic dose be
100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day
(not to exceed 4 grams daily) is recommended. The daily dose may be administered
once a day (or in equally divided doses every 12 hours). The usual duration of therapy
is 7 to 14 days.
Adults
The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided
doses twice a day) depending on the type and severity of infection. The total daily
dose should not exceed 4 grams.
If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial
coverage should be added, because Ceftriaxone sodium has no activity against this
organism.
For the treatment of uncomplicated gonococcal infections, a single intramuscular dose
of 250 mg is recommended.
For preoperative use (surgical prophylaxis), a single dose of 1 gram administered
intravenously 1/2 to 2 hours before surgery is recommended

XYZ PHARMA LTD.

Generally, Ceftriaxone therapy should be continued for at least 2 days after the signs
and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14
days; in complicated infections, longer therapy may be required.
When treating infections caused by Streptococcus pyogenes, therapy should be
continued for at least 10 days.
No dosage adjustment is necessary for patients with impairment of renal or hepatic
function; however, blood levels should be monitored in patients with severe renal
impairment (eg, dialysis patients) and in patients with both renal and hepatic
dysfunctions.
Adverse Effects
Ceftriaxone is generally well tolerated. In clinical trials, the following adverse
reactions, which were considered to be related to Ceftriaxone therapy or of uncertain
etiology, were observed:
Local Reactions—pain, induration and tenderness was 1% overall. Phlebitis was

reported in <1% after IV administration. The incidence of warmth, tightness or
induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after
IM administration of 250 mg/mL.
Hypersensitivity—rash (1.7%) Less frequently reported (<1%) were pruritus, fever or

chills.
Hematologic—eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%) Less
frequently reported (<1%) were anemia, hemolytic anemia, neutropenia,
lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Gastrointestinal—diarrhea (2.7%) Less frequently reported (<1%) were nausea or
vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may
occur during or after antibacterial treatment.
Hepatic—elevations of SGOT (3.1%) or SGPT (3.3%) Less frequently reported
(<1%) were elevations of alkaline phosphatase and bilirubin.
Renal—elevations of the BUN (1.2%) Less frequently reported (<1%) were
elevations of creatinine and the presence of casts in the urine.
Central Nervous System—headache or dizziness were reported occasionally (<1%).
Genitourinary—moniliasis or vaginitis were reported occasionally (<1%).

XYZ PHARMA LTD.

Miscellaneous—diaphoresis and flushing were reported occasionally (<1%).
Other rarely observed adverse reactions (<0.1%) include abdominal pain,

agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis,
bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria,
hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis,
palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and
serum sickness.
Cases of fatal reactions with Ceftriaxone-calcium precipitates in lung and kidneys in
neonates have been described. In some cases the infusion lines and times of
administration of Ceftriaxone and calcium-containing solutions differed.
Storage conditions:
Store at or below 25o C, Protected from light.
Presentation:
Each vial contains Ceftriaxone Sodium, approximately equivalent to 1gm Ceftriaxone
base & each combipack contains one glass ampoule of sterile water for Injection USP
5 ml & Glass vial with Sterile Ceftriaxone Sodium USP.
MANUFACTURED BY:
XYZ (P) LTD.
Bagbania, Baddi-Nalagarh Road, Distt. Solan (HP)-174 101

XYZ PHARMA LTD.

Section B: Table of Contents Part I
TABLE OF CONTENTS
S. NO. CONTENTS PAGE NO.
PART I ADMINISTRATIVE DATA AND PRODUCT 2

INFORMATION
SECTION A Introduction Profile 3
SECTION B Table of contents 12
SECTION C Documents required for Registration 13
1. Application Form 14
2. Letter of Authorization 21
3. Certifications 22
4. Labelling 25
5. Product Information 29
5.1 Package Insert 29
5.2 Summary of Product Characteristics 39
5.3 Patient Information Leaflet (PIL) 56

XYZ PHARMA LTD.

SECTION – C
DOCUMENTS REQUIRED FOR
REGISTRATION

XYZ PHARMA LTD.

Section C: Guidance on the Administrative Data and Product Information
1. APPLICATION FORM
KINGDOM OF CAMBODIA
MINISTRY OF HEALTH NATION – RELIGION – KING
DIRECTORATE GENERAL FOR HEALTH
DEPARTMENT OF DRUGS AND FOOD
8, Ung Pokun Street , Phnom Penh , Cambodia
Phone : ( 855-23 ) 880247-48
Fax : ( 855-23 ) 880247
APPLICATION FORM FOR MARKETING AUTHORIZATION
A- DETAILS OF APPLICANT AND MANUFACTURER :
1- Applicant’s:
- Name :
___________________________________________________________
- Address :
___________________________________________________________
___________________________________________________________
___________________________________________________________
- Phone :
___________________________________________________________
- Fax :
___________________________________________________________ - E--
- mail :
___________________________________________________________
2- Manufacturer’s*:
- Name : XYZ (P) LIMITED

- Address : ,
Distt. Solan (H.P.) - 174 101, India.
- Phone :
- Fax :
- E-mail :

XYZ PHARMA LTD.

* = Manufacturer responsible for final batch release.
Other manufacturers:
Name & address Role**
N/A
** = e.g. “prepares semi-finished product”, “packaging”, “granulation”,

“manufactures bulk finished dosage form”, “contract research organization”, etc.
B- DETAILS OF PRODUCT:
1- Product Name : Ceftriaxone for Injection USP 1 g

Commercial name : SEFTRIL 1000
INN or Generic Name : Ceftriaxone for Injection USP 1 g
Dosage form and Strength : Each vial contains:
Sterile Ceftriaxone Sodium USP
Equivalent to Anhydrous Ceftriaxone ……1.0 g
2- Product Description:
White powder filled in clear glass vials sealed with rubber closer and flip off
aluminium seals
3- Qualitative & Quantity formula:

Quantity
S. No Ingredients Spec
/unit (g)
Sterile Ceftriaxone
1 1.0 g USP
Sodium

XYZ PHARMA LTD.

C- REQUESTED PHARMACEUTICAL CATEGORY:
√
- Prescription :
-

- Without prescription :
D- INDICATION, POSOLOGY AND ROUTE OF ADMINISTRATION:
1. Therapeutic indications


XYZ PHARMA LTD.


gonorrhoeae.




XYZ PHARMA LTD.


organisms throughout the course of the procedure
2. Posology and method of administration

Neonates
Ceftriaxone.
Pediatric Patients

XYZ PHARMA LTD.

is 7 to 14 days.
Adults
organism.
dysfunctions.

XYZ PHARMA LTD.

E- ATTACHED INFORMATION:
- GMP Certificate
- Certificate of a Pharmaceutical Product √
- Registration Certificate in other countries (if available)
- Summary of product characteristics √
- Technical documents:
1- Quality √
2- Safety
3- Efficacy
- Samples :
2 Commercial boxes for registration purpose.
√
- Registration fee
√
F- PACKING SIZE:
- Commercial packing:
Clear, glass vial of type III, having 10 ml capacity.
- Hospital packing
Clear, glass vial of type III, having 10 ml capacity.
G- SHELF LIFE: 24 months
Date :
Title : Managing Director
Name : Mr. J. Rajamouli
Signature :

XYZ PHARMA LTD.

2. LETTER OF AUTHORIZATION
We,
Product owner’s name: M/s. XYZ (P) LIMITED

& Address : M/s. XYZ (P) LIMITED
Bagbania, Baddi-Nalagarh Road,
Hereby appoint
Applicant’s name :___________________________________
& Address:___________________________________
______________________________________________
To apply for registration of our pharmaceutical product
Product Name : SEFTRIL 1000

(Ceftriaxone for Injection USP 1 g)
Dosage form & Strength : Powder for Solution for Injection (For
intravenously or intramuscularly only)
: Each vial contains:
With the Drug Regulatory Authority in Cambodia on our behalf, they will be the
Marketing Authorization holder of the registration certificate and be responsible for
all matters pertaining to the regulation of this product.
Signature : _____________________________
Date : __________________

XYZ PHARMA LTD.

3. CERTIFICATIONS:
3.4 For imported products:
a. License of pharmaceutical industries/importer/wholesaler (country specific)
==== Refer to attachment “ANNEXURE TO PART 1”====

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b. Certificate of Pharmaceutical Product issued by the competent authority in
the country of origin according to the current WHO format (Appendix III)

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c. Site master file of manufacturer (unless previously submitted within the last 2
years) (country specific)

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4. LABELLING
A Labelling Parameters required for UNIT CARTON

1. Product Name
SEFTRIL 1000 (Ceftriaxone for Injection USP 1 g)
2. Dosage Form
Powder for Solution for Injection
3. Name of Active Ingredient(s)

Ceftriaxone sodium USP
4. Strength of Active Ingredient(s)

: Each vial contains:
5. Batch Number
--------
6. Manufacturing Date
--------
7. Expiration Date
--------
8. Route of Administration
For intravenously or intramuscularly only
9. Storage Condition
Store at or below 25˚C. Protected from light
10. Registration Number

--------

XYZ PHARMA LTD.

11. Name and Address of Marketing Authorisation Holder and / or Product
Owner
12. Name and Address of Manufacturer

XYZ (P) LIMITED
Bagbania, Baddi-Nalagarh Road,
13. Special Labelling (if applicable)

Not Applicable
14. Recommended Daily Allowance (For Vitamins and Minerals)

Not Applicable
15. Warning (if applicable)

Not Applicable
16. Pack sizes (Unit/Volume)

Clear, glass vial of type III, having 10ml capacity

XYZ PHARMA LTD.

B Inner label
====Refer to attachment ART WORK====

XYZ PHARMA LTD.

C Labelling Parameters required for BLISTER/STRIPS
Not applicable

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5. PRODUCT INFORMATION
5.1 Package Insert
SEFTRIL 1000 (Ceftriaxone for Injection USP 1 g)
Composition:
Each vial contains:
Sterile Ceftriaxone sodium USP
Equivalent to Anhydrous Ceftriaxone 1g
Pharmacological classification:
Antibacterial
Pharmacology:
Ceftrioxone is third generation cephalosporin with a broad spectrum including many
Gram-positive and Gram-negative bacteria. It is very similar in action to Cefotaxime.
Like other cephalosporins, it works by inhibiting the cross-linkage of peptidoglycans
in non-resistant cell walls and triggers the activation of damaging autolysins.
Mechanism of Action:
Ceftriaxone sodium is a third generation injectable cephalosporin agent. It is a sterile,
semisynthetic, broad-spectrum cephalosporin antibiotic. Ceftriaxone works by
inhibiting the mucopeptide synthesis in the bacterial cell wall. The beta-lactam moiety
of Ceftriaxone binds to carboxypeptidases, endopeptidases, and transpeptidases in the
bacterial cytoplasmic membrane. These enzymes are involved in cell-wall synthesis
and cell division. By binding to these enzymes, Ceftriaxone results in the formation of
defective cell walls and cell death.
PHARMACOKINETICS:
Ceftriaxone is not absorbed after oral administration and must be given par-enterally.
It is widely distributed throughout the body; CSF levels are higher when meninges are
inflamed. Ceftriaxone crosses the placenta and enters maternal milk in low
concentrations; no documented adverse effects to offspring have been noted.

XYZ PHARMA LTD.

Ceftriaxone is excreted by both renal and non-renal mechanisms and in humans,
elimination half-lives are approximately 6-11 hours. Dosage adjustments generally are
not required for patients with renal insufficiency (unless severely uremic) or with
hepatic impairment.
INDICATIONS:



XYZ PHARMA LTD.



gonorrhoeae.




XYZ PHARMA LTD.


organisms throughout the course of the procedure.
Contraindications:
Hypersensitivity to cephalosporins; neonates (28 days of age or younger);
concomitant use with calcium-containing IV solutions, including continuous calcium-
containing infusions, such as parenteral nutrition in neonates
Warnings
Hypersensitivity
determine whether the patient has had previous hypersensitivity reactions to
cephalosporins, penicillins or other drugs. This product should be given cautiously to
penicillin-sensitive patients. Antibiotics should be administered with caution to any
patient who has demonstrated some form of allergy, particularly to drugs. Serious
acute hypersensitivity reactions may require the use of subcutaneous epinephrine and
other emergency measures.

XYZ PHARMA LTD.

Interaction with Calcium-Containing Products

There are no reports to date of intravascular or pulmonary precipitations in patients,
other than neonates, treated with Ceftriaxone and calcium-containing IV solutions.
However, the theoretical possibility exists for an interaction between Ceftriaxone and
IV calcium-containing solutions in patients other than neonates. Therefore,
Ceftriaxone and calcium-containing solutions, including continuous calcium-
containing infusions such as parenteral nutrition, should not be mixed or co-
administered to any patient irrespective of age, even via different infusion lines at
different sites. As a further theoretical consideration and based on 5 half-lives of
Ceftriaxone, Ceftriaxone and IV calcium-containing solutions should not be
administered within 48 hours of each other in any patient.
No data are available on potential interaction between Ceftriaxone and oral calcium-
containing products or interaction between intramuscular Ceftriaxone and calcium-
containing products (IV or oral)
Clostridium Difficile
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly
all antibacterial agents, including Ceftriaxone, and may range in severity from mild
diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of
the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficilecause increased morbidity and mortality,
as these infections can be refractory to antimicrobial therapy and may require
colectomy. CDAD must be considered in all patients who present with diarrhea
following antibiotic use. Careful medical history is necessary since CDAD has been
reported to occur over two months after the administration of antibacterial agents.If
CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.
difficile may need to be discontinued. Appropriate fluid and electrolyte management,
protein supplementation, antibiotic treatment C. difficile, and surgical evaluation
should be instituted as clinically indicated.

XYZ PHARMA LTD.

PRECAUTIONS
General
Prescribing Ceftriaxone in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria. Although transient
elevations of BUN and serum creatinine have been observed, at the recommended
dosages, the nephrotoxic potential of Ceftriaxone is similar to that of other
cephalosporins.
Ceftriaxone is excreted via both biliary and renal excretion. Therefore, patients with
renal failure normally require no adjustment in dosage when usual doses of
Ceftriaxone are administered, but concentrations of drug in the serum should be
monitored periodically. If evidence of accumulation exists, dosage should be
decreased accordingly.
Dosage adjustments should not be necessary in patients with hepatic dysfunction;

however, in patients with both hepatic dysfunction and significant renal disease,
Ceftriaxone dosage should not exceed 2 gm daily without close monitoring of serum
concentrations.
Alterations in prothrombin times have occurred rarely in patients treated with

Ceftriaxone. Patients with impaired vitamin K synthesis or low vitamin K stores (eg,
chronic hepatic disease and malnutrition) may require monitoring of prothrombin time
during Ceftriaxone treatment. Vitamin K administration (10 mg weekly) may be
necessary if the prothrombin time is prolonged before or during therapy.
Prolonged use of Ceftriaxone may result in overgrowth of nonsusceptible organisms.
Careful observation of the patient is essential. If superinfection occurs during therapy,
appropriate measures should be taken. Ceftriaxone should be prescribed with caution
in individuals with a history of gastrointestinal disease, especially colitis.
There have been reports of sonographic abnormalities in the gallbladder of patients
treated with Ceftriaxone; some of these patients also had symptoms of gallbladder
disease. These abnormalities appear on sonography as an echo without acoustical
shadowing suggesting sludge or as an echo with acoustical shadowing which may be
misinterpreted as gallstones. The chemical nature of the sonographically detected

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material has been determined to be predominantly a Ceftriaxone-calcium salt. The
condition appears to be transient and reversible upon discontinuation of Ceftriaxone
and institution of conservative management.Therefore, Ceftriaxone should be
discontinued in patients who develop signs and symptoms suggestive of gallbladder
disease and/or the sonographic findings described above.
Dosage and administration:

Neonates
Ceftriaxone.
Pediatric Patients
is 7 to 14 days.

XYZ PHARMA LTD.

Adults
organism.
dysfunctions.
Adverse Effects
Ceftriaxone is generally well tolerated. In clinical trials, the following adverse
reactions, which were considered to be related to Ceftriaxone therapy or of uncertain
etiology, were observed:
Local Reactions—pain, induration and tenderness was 1% overall. Phlebitis was

reported in <1% after IV administration. The incidence of warmth, tightness or
induration was 17% (3/17) after IM administration of 350 mg/mL and 5% (1/20) after
IM administration of 250 mg/mL.
Hypersensitivity—rash (1.7%) Less frequently reported (<1%) were pruritus, fever or

chills.

XYZ PHARMA LTD.

Hematologic—eosinophilia (6%), thrombocytosis (5.1%) and leukopenia (2.1%) Less
frequently reported (<1%) were anemia, hemolytic anemia, neutropenia,
lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Gastrointestinal—diarrhea (2.7%) Less frequently reported (<1%) were nausea or
vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may
occur during or after antibacterial treatment.
Hepatic—elevations of SGOT (3.1%) or SGPT (3.3%) Less frequently reported
(<1%) were elevations of alkaline phosphatase and bilirubin.
Renal—elevations of the BUN (1.2%) Less frequently reported (<1%) were
elevations of creatinine and the presence of casts in the urine.
Central Nervous System—headache or dizziness were reported occasionally (<1%).
Genitourinary—moniliasis or vaginitis were reported occasionally (<1%).
Miscellaneous—diaphoresis and flushing were reported occasionally (<1%).
Other rarely observed adverse reactions (<0.1%) include abdominal pain,

agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis,
bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria,
hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis,
palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and
serum sickness.
Cases of fatal reactions with Ceftriaxone-calcium precipitates in lung and kidneys in
neonates have been described. In some cases the infusion lines and times of
administration of Ceftriaxone and calcium-containing solutions differed.
Interactions:
Aminoglycoside antibiotics and diuretics: No impairment of renal function has been
observed in man after simultaneous administration of Ceftriaxone with diuretics. No
interference with the action or increase in nephrotoxicity of aminoglycosides has been
observed during simultaneous administration with Ceftriaxone.
Alcohol: The Ceftriaxone molecule does not contain the N-methylthio-tetrazole
substituent, which has been associated with a disulfiram-like effect, when alcohol is
taken during therapy with certain cephalosporins.
Antibiotics: In an in vitro study, antagonistic effects have been observed with the
combination of chloramphenicol and Ceftriaxone.

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Anticoagulants: As Ceftriaxone has an N-methylthiotriazine side-chain, it might have
the potential to cause hypoprothrombinaemia.Refer to section 4.8, Undesirable
effects.
Interference with Laboratory Tests:

In patients treated with Ceftriaxone, the Coombs' test may rarely become false-
positive and can interfere with blood cross-matching.
Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia.
Likewise, non-enzymatic methods such as copper reduction methods (Benedict's,
Fehling's or Clinitest) for glucose determination in urine may give false-positive
results. For this reason, urine-glucose determination during therapy with Ceftriaxone
should be done enzymatically.
Overdosage:
In the case of overdosage, drug concentrations would not be reduced by
haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment should
be symptomatic.
Storage conditions:
Presentation:
Each vial contains Ceftriaxone Sodium, approximately equivalent to 1gm Ceftriaxone
base & each combipack contains one glass ampoule of sterile water for Injection USP
5 ml & Glass vial with Sterile Ceftriaxone Sodium USP.
MANUFACTURED BY:
XYZ (P) LTD.

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5.2. SUMMARY OF PRODUCT CHARACTERISTICS
(PRODUCT DATA SHEET)
Ceftriaxone Sodium 1g Injection

1. Name of the medicinal product
SEFTRIL-1000 (Ceftriaxone for Injection USP 1g)
2. Qualitative and quantitative composition

Ceftriaxone sodium USPequivalent to 1g Ceftriaxone per vial.
Each gram of Ceftriaxone sodium contains approximately 3.6 mmol sodium.
3. Pharmaceutical form
Vials containing powder for solution for injection or infusion.
4. Clinical particulars
4.1 Therapeutic indications

Ceftriaxone is indicated for the treatment of the following infections when known or
likely to be due to one or more susceptible micro-organisms (see section 5.1) and
when parenteral therapy is required:
Pneumonia
Meningitis
Bone, skin and soft tissue infections
Infections in neutropenic patients
Gonorrhoea
Treatment may be started before the results of susceptibility tests are known.
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
4.2 Posology and method of administration

Ceftriaxone may be administered by deep intramuscular injection, slow intravenous
injection, or as a slow intravenous infusion, after reconstitution of the solution
according to the directions given below. Diluents containing calcium, (e.g. Ringer's

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solution or Hartmann's solution), should not be used to reconstitute Ceftriaxone vials
or to further dilute a reconstituted vial for IV administration because a precipitate can
form. Precipitation of Ceftriaxone-calcium can also occur when Ceftriaxone is mixed
with calcium-containing solutions in the same IV administration line. Therefore,
Ceftriaxone and calcium-containing solutions must not be mixed or administered
simultaneously (see sections 4.3, 4.4 and 6.2).
Dosage and mode of administration should be determined by the severity of the
infection, susceptibility of the causative organism and the patient's condition. Under
most circumstances a once-daily dose - or, in the specified indications, a single dose -
will give satisfactory therapeutic results.
Adults and children 12 years and over
Standard therapeutic dosage: 1g once daily.
Severe infections: 2 - 4g daily, normally as a single dose every 24 hours.
The duration of therapy varies according to the course of the disease. As with
antibiotic therapy in general, administration of Ceftriaxone should be continued for a
minimum of 48 to 72 hours after the patient has become afebrile or evidence of
bacterial eradication has been obtained.
Acute, uncomplicated gonorrhoea: A single dose of 250mg intramuscularly should be
administered. Simultaneous administration of probenecid is not indicated.
Peri-operative prophylaxis: Usually 1g as a single intramuscular or slow intravenous
dose. In colorectal surgery, 2g should be given intramuscularly (dosages greater than
1g should be divided and injected at more than one site), or by slow intravenous
infusion, in conjunction with a suitable agent against anaerobic bacteria.
Elderly
These dosages do not require modification in elderly patients provided that renal and
hepatic function are satisfactory (see below).
Neonates, infants and children up to 12 years
The following dosage schedules are recommended for once daily administration:
Neonates
A daily dose of 20 - 50mg/kg body weight, not to exceed 50mg/kg. In the neonate, the
intravenous dose should be given over 60 minutes to reduce the displacement of
bilirubin from albumin, thereby reducing the potential risk of bilirubin
encephalopathy (see section 4.4).
Infants and children of up to 12 years

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Standard therapeutic dosage: 20 - 50mg/kg body weight once daily.
In severe infections up to 80mg/kg body weight daily may be given. For children with
body weights of 50kg or more, the usual adult dosage should be used. Doses of
50mg/kg or over should be given by slow intravenous infusion over at least 30
minutes. Doses greater than 80mg/kg body weight should be avoided because of the
increased risk of biliary precipitates.
Renal and hepatic impairment
In patients with impaired renal function, there is no need to reduce the dosage of
Ceftriaxone provided liver function is intact. Only in cases of pre-terminal renal
failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to
2g or less.
In patients with liver damage there is no need for the dosage to be reduced provided
renal function is intact.
In severe renal impairment accompanied by hepatic insufficiency, the plasma
concentration of Ceftriaxone should be determined at regular intervals and dosage
adjusted.
In patients undergoing dialysis, no additional supplementary dosing is required
following the dialysis. Serum concentrations should be monitored, however, to
determine whether dosage adjustments are necessary, since the elimination rate in
these patients may be reduced.
4.3 Contraindications
Ceftriaxone is contraindicated in patients with known hypersensitivity to beta-lactam
antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-
reactions should be borne in mind.
Hyperbilirubinaemic newborns and pre-term newborns should not be treated with
Ceftriaxone. In vitro studies have shown that Ceftriaxone can displace bilirubin from
its binding to serum albumin and bilirubin encephalopathy can possibly develop in
these patients.
Ceftriaxone is contraindicated in:
• premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks
of life)
• full-term newborns (up to 28 days of age)

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With jaundice, or who are hypoalbuminaemic or acidotic because these are
conditions in which bilirubin binding is likely to be impaired
If they require (or are expected to require) IV calcium treatment, or calcium-
containing infusions because of the risk of precipitation of Ceftriaxone-calcium (see
sections 4.4, 4.8 and 6.2).
Contraindication of lidocaine must be excluded before intramuscular injection of
Ceftriaxone when lidocaine is used as a solvent.
4.4 Special warnings and precautions for use

determine whether the patient has had any previous hypersensitivity reactions to
Ceftriaxone, any other cephalosporin, or to any penicillin or other beta-lactam drug.
Ceftriaxone is contraindicated in patients who have had a previous hypersensitivity
reaction to any cephalosporin. It is also contraindicated in patients who have had a
previous immediate and/or any severe hypersensitivity reaction to any penicillin or to
any other beta-lactam drug (see Section 4.3). Ceftriaxone should be given with
caution to patients who have had any other type of hypersensitivity reaction to a
penicillin or any other beta-lactam drug. As with other cephalosporins, anaphylactic
shock cannot be ruled out even if a thorough patient history is taken.
Ceftriaxone should be given with caution to patients who have other allergic
diatheses.
Each gram of Ceftriaxone contains 3.6x mmol sodium. To be taken into consideration
in patients on a controlled sodium diet.
Ceftriaxone should be used with caution in individuals with a previous history of
gastro-intestinal disease, particularly colitis.
Clostridium difficile associated diarrhoea (CDAD) has been reported with use of
nearly all antibacterial agents, including Ceftriaxone, and may range in severity from
mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal
flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A
and B which contribute to the development of CDAD. Hypertoxin producing strains
of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be
considered in all patients who present with diarrhoea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months

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after the administration of antibacterial agents. If CDAD is suspected or confirmed,
ongoing antibiotic use not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically
indicated.
Superinfections with non-susceptible micro-organisms may occur as with other
antibacterial agents. Shadows, which have been mistaken for gallstones have been
detected on sonograms of the gallbladder, usually following doses higher than the
standard recommended dose. These shadows are, however, precipitates of calcium
Ceftriaxone which disappear on completion or discontinuation of Ceftriaxone therapy.
Rarely have these findings been associated with symptoms. In symptomatic cases,
conservative nonsurgical management is recommended. Discontinuation of
Ceftriaxone treatment in symptomatic cases should be at the discretion of the
physician.
Cases of fatal reactions with calcium-Ceftriaxone precipitates in lungs and kidneys in
premature and full-term newborns aged less than 1 month have been described. At
least one of them had received Ceftriaxone and calcium at different times and through
different intravenous lines. In the available scientific data, there are no reports of
confirmed intravascular precipitations in patients, other than newborns, treated with
Ceftriaxone and calcium-containing solutions or any other calcium-containing
products. In vitro studies demonstrated that newborns have an increased risk of
precipitation of Ceftriaxone-calcium compared to other age groups.
In patients of any age Ceftriaxone must not be mixed or administered simultaneously
with any calcium-containing IV solutions, even via different infusion lines or at
different infusion sites. However, in patients older than 28 days of age Ceftriaxone
and calcium-containing solutions may be administered sequentially one after another
if infusion lines at different sites are used, or if the infusion lines are replaced or
thoroughly flushed between infusions with physiological salt-solution to avoid
precipitation. In patients requiring continuous infusion with calcium-containing TPN
solutions, healthcare professionals may wish to consider the use of alternative
antibacterial treatments which do not carry a similar risk of precipitation. If use of
Ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN
solutions and Ceftriaxone can be administered simultaneously, albeit via different
infusion lines at different sites. Alternatively, infusion of TPN solution could be

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stopped for the period of Ceftriaxone infusion, considering the advice to flush
infusion lines between solutions (see sections 4.3, 4.8, 5.2 and 6.2).
Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely
reported in patients treated with Ceftriaxone. Most patients presented with risk factors
for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and
total parenteral nutrition. A trigger or cofactor role of Ceftriaxone-related biliary
precipitation cannot be ruled out. In severe renal and hepatic insufficiency, dosage
should be reduced as outlined in section 4.2.
Safety and effectiveness of Ceftriaxone in neonates, infants and children have been
established for the dosages described in section 4.2.
Studies have shown that Ceftriaxone, like some other cephalosporins, can displace
bilirubin from serum albumin. Ceftriaxone should not be used in neonates (especially
prematures) at risk of developing bilirubin encephalopathy.
During prolonged treatment complete blood count should be performed at regular
intervals since cephalosporins as a class tend to be absorbed onto the surface of the
red cell membranes and react with antibodies directed against the drug to produce a
positive Coombs' test and occasionally a rather mild haemolyticanaemia. In this
respect, there may be some cross-reactivity with penicillins.
In case lidocaine is used as a solvent Ceftriaxone solutions should only be used for
intramuscular injection.
The stated dosage should not be exceeded.
4.5 Interaction with other medicinal products and other forms of interaction
No impairment of renal function has so far been observed after concurrent
administration of large doses of Ceftriaxone and potent diuretics (e.g. furosemide).
There is no evidence that Ceftriaxone increases renal toxicity of aminoglycosides. No
effect similar to that of disulfiram has been demonstrated after ingestion of alcohol
subsequent to the administration of Ceftriaxone.
Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with
possible ethanol intolerance and bleeding problems of certain other cephalosporins.
The elimination of Ceftriaxone is not altered by probenecid.
In an in-vitro study antagonistic effects have been observed with the combination of
chloramphenicol and Ceftriaxone.

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Do not use diluents containing calcium, such as Ringer's solution or Hartmann's
solution, to reconstitute Ceftriaxone vials or to further dilute a reconstituted vial for
IV administration because a precipitate can form. Precipitation of Ceftriaxone-
calcium can also occur when Ceftriaxone is mixed with calcium-containing solutions
in the same IV administration line. Ceftriaxone must not be administered
simultaneously with calcium-containing IV solutions, including continuous calcium-
containing infusions such as parenteral nutrition via a Y-site. However, in patients
other than neonates Ceftriaxone and calcium-containing solutions may be
administered sequentially, of one another, if the infusion lines are thoroughly flushed
between infusions with a compatible fluid. In vitro studies using adult and neonatal
plasma from umbilical cord blood demonstrated that neonates have an increased risk
of precipitation of Ceftriaxone-calcium.
Based on literature reports Ceftriaxone is incompatible with amsacrine, vancomycin,
fluconazole and aminoglycosides.
In patients treated with Ceftriaxone the Coombs' test may in rare cases be false-
positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for
galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine
may yield false-positive results. For this reason glucose level determination in urine
during therapy with Ceftriaxone should be carried out enzymatically.
Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives.
Consequently, it is advisable to use supplementary (non-hormonal) contraceptive
measures during treatment and in the month following treatment.
4.6 Pregnancy and lactation

Pregnancy
For Ceftriaxone, limited clinical data on exposed pregnancies are available.
Ceftriaxone crosses the placental barrier. Reproductive studies in animals have shown
no evidence of embryotoxicity, foetotoxicity, teratogenicity or adverse effects on male
or female fertility, birth or perinatal and postnatal development. In primates, no
embryotoxicity or teratogenicity has been observed. Since safety in human pregnancy
is not established Ceftriaxone should not be used unless absolutely indicated.
Lactation
Low concentrations of Ceftriaxone are excreted in human milk. Caution should be
exercised when Ceftriaxone is administered to a nursing woman.

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4.7 Effects on ability to drive and use machines

Since Ceftriaxone sometimes induces dizziness, the ability to drive and use machines
can be impaired.
4.8 Undesirable effects

The undesirable effects usually are mild and short-term.
Systemic side effects:
Gastrointestinal complaints (about 2% of the cases): loose stools or diarrhoea, nausea,
vomiting, stomatitis and glossitis.
Haematological changes (about 2%): eosinophilia, leukopenia, granulocytopenia,
hemolytic anaemia, thrombocytopenia. Unknown frequency: of agranulocytosis (<
500/mm3) have been reported, most of them after 10 days of treatment and following
total doses of 20g or more.
Skin reactions (about 1%): exanthema, allergic dermatitis, pruritus, urticaria, oedema.
Unknown frequency: of severe cutaneous adverse reactions (erythema multiforme,
Stevens Johnson syndrome or Lyell's Syndrome/toxic epidermal necrolysis) have
been reported.
Other, rare side effects:
headache, vertigo and dizziness, symptomatic precipitation of Ceftriaxone calcium
salt in the gallbladder, increase in liver enzymes, glucosuria, haematuria, oliguria,
increase in serum creatinine, genital mycosis, fever, shivering and anaphylactic or
anaphylactoid reactions e.g. bronchospasms.
Ceftriaxone must not be mixed or administered simultaneously with calcium-
containing solutions or products, even via different infusion lines. Rarely, severe, and
in some cases fatal adverse reactions have been reported in preterm and fullterm
newborns (aged <28 days) who had been treated with intravenous Ceftriaxone and
calcium. Precipitations of Ceftriaxone-calcium salt have been observed in lung and
kidneys post-mortem. The high risk of precipitation in newborns is due to their low
blood volume and the longer half-life of Ceftriaxone compared with adults (see
sections 4.3. 4.4 and 5.2).
Superinfection caused by microorganisms non-susceptible to Ceftriaxone (candida,
fungi or other resistant microorganisms) may develop. Pseudomembraneous colitis is
a rare undesirable effect caused by infection with Clostridium difficileduring

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treatment with Ceftriaxone. Therefore, the possibility of the disease should be
considered in patients who present with diarrhoea following antibacterial agent use.
Very rare cases of renal precipitation have been reported, mostly in children older
than 3 years and who have been treated with either high daily doses (e.g. ≥ 80
mg/kg/day) or total doses exceeding 10 grams and presenting other risk factors (e.g.
fluid restrictions, confinement to bed, etc.) The risk of precipitate formation is
increased in immobilized or dehydrated patients. This event may be symptomatic or
asymptomatic, may lead to renal insufficiency and anuria, and is reversible upon
discontinuation of Ceftriaxone.
Precipitation of Ceftriaxone calcium salt in the gallbladder has been observed, mostly
in patients treated with doses higher than the recommended standard dose. In children,
prospective studies have shown a variable incidence of precipitation with intravenous
application, in some studies to above 30 %. The incidence seems to be lower with
slow infusion (20-30 minutes). This effect is usually asymptomatic, but in rare cases,
the precipitations have been accompanied by clinical symptoms such as pain, nausea
and vomiting. Symptomatic treatment is recommended in these cases. Precipitation is
usually reversible upon discontinuation of Ceftriaxone.
There have been isolated reports of pancreatitis.
Coagulation disorders have been reported as very rare side effects.
Local side effects:
In rare cases, phlebitic reactions occurred after i.v. administration. These may be
minimized by slow (2-4 minutes) injection.
Intramuscular injection without lidocaine solution is painful.
Influence on diagnostic tests:
In patients treated with Ceftriaxone the Coombs' test rarely may become false-
positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for
galactosemia. Likewise, nonenzymatic methods for the glucose determination in urine
may give false-positive results. For this reason, urine-glucose determination during
therapy with Ceftriaxone should be done enzymatically.
4.9 Overdose
In the case of overdose nausea, vomiting and diarrhoea can occur. Ceftriaxone
concentration cannot be reduced by haemodialysis or peritoneal dialysis. There is no
specific antidote. Treatment is symptomatic.

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5. Pharmacological properties
5.1 Pharmacodynamic properties
ATC classification:
Pharmacotherapeutic group: cephalosporins and related substances, ATC code:
J01DA13.
Mode of action:
Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall
synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of
bacterial β-lactamases.
Mechanism of resistance:
Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-
lactamases, including those which are able to hydrolyse advanced generation
penicillin derivatives and other cephalosporins. Resistance to Ceftriaxone is encoded
mainly by the production of some beta-lactam hydrolysing enzymes (including
carbapenemases and some ESBLs) especially in Gram-negative organisms. For Gram-
positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly
encoded by cell wall target site alterations. Outside of the advanced generation
parenteral cephalosporins, cross-resistance to other drug classes is generally not
encountered.
Breakpoints:
Current MIC breakpoints used to interpret Ceftriaxone susceptibility data are shown
below. Values quoted comprise mg/L (MIC testing).
European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical
MIC Breakpoints http://www.eucast.org (Database February 2009, last accessed
16/09/2009):
Susceptible/Resistant
Enterobacteriaceae2 1/2
Pseudomonas --
Acinetobacter --
Staphylococcus 3 Note3
Enterococcus --
Streptococcus A, B, C, G 0.5/0.5
Streptococcus 0.5/2

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pneumoniae
Haemophilusinfluenzae 0.12/0.12
Moraxella Catarrhalis 1/2
Neisseria gonorrhoea 0.12/0.12
Neisseria Meningitidis 0.12/0.12
Gram-negative, --
anaerobes
Non-species related 1/2
breakpoints1
S</>R
1. Non-species related breakpoints have been determined mainly on the basis of
PK/PD data and are independent of MIC distributions of specific species. They are for
use only for species that have not been given a species-specific breakpoint and not for
those species where susceptibility testing is not recommended (marked with -- or IE
in the table).
2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance
mediated by most ESBLs and other clinically important beta-lactamases in
Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible
or intermediate with these breakpoints. Laboratories may want to use a test which
specifically screens for the presence of ESBL.
3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin
susceptibility (except ceftazidime which should not be used for staphylococcal
infections).
-- = Susceptibility testing not recommended as the species is a poor target for therapy
with the drug.
IE = There is insufficient evidence that the species in question is a good target for
therapy with the drug.
RD = rationale document listing data used by EUCAST for determining breakpoints.
Susceptibility:
The prevalence of acquired resistance may vary geographically and with time for
selected species and local information on resistance is desirable, particularly when
treating severe infections. As necessary, expert advice should be sought when the
local prevalence of resistance is such that the utility of the agent in at least some types
of infections is questionable.

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Ceftriaxone susceptibility among Gram-positive and Gram-negative bacterial species
in Europe from January 1999-December 2001:
Commonly susceptible species (i.e. resistance < 10% in all EU Member States)
Gram-Positive aerobes :
MSa coagulase negative Staphylococcus spp. (including S. epidermis )*
MSb Staphylococcus aureus*
Group B (Streptococcus agalactiae)
Streptococcus bovis
Streptococcus pneumoniae*
Group A Streptococcus (Streptococcus pyogenes)*
Streptococcus viridans*
Gram-Negative aerobes :
Citrobacter spp. (including C.freundii)
Escherichia coli*
Haemophilusinfluenzae (including beta-lactamase positive isolates)c*
Haemophiluspara-influenzae*
Klebsiella spp. (including K. pneumoniae and K. oxytoca)*
Moraxella catarrhalis*
Morganellamorganii*
Neisseria gonorrhoea (including penicillin-resistant isolates)*
Neisseria meningitidis*
Proteus spp. (including P. mirabilis and P. vulgaris)*
Salmonella spp. (including S. typhimurium)
Serratia spp. (including Serratiamarsescens)*
Shigella spp.
Anaerobes:
Clostridium spp.*
Species for which acquired resistance may be a problem (i.e. resistance ≥ 10% in
at least one EU Member State)
Gram-Negative aerobes:
Pseudomonas aeruginosa +
Enterobacter spp. (including E. aerogenes and E. cloacae)*+
Acinetobacter spp. (including A. baumanii and A. calcoaceticus)*+
Anaerobes:
Bacteroides spp.*
Peptostreptococcus spp.*
Inherently resistant organisms
Gram-Positive aerobes:
MRd coagulase negative Staphylococcus spp. (including S. epidermidis)
MReStaphylococcusaureus
Enterococcus spp.
Gram-Negative aerobes:
Listeria monocytogenes
Mycoplasma spp.
Stenotrophomonasmaltophilia
Ureaplasmaurealyticum

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Others:
Chlamydia spp.
a
Methicillin-susceptible Coagulase-Negative Staphylococcus
b
Methicillin-susceptible Staphylococcus aureus
c
Non-susceptible range (no resistant breakpoints defined)
d
Methicillin-resistant Coagulase-Negative Staphylococcus
e
Methicillin-resistant Staphylococcus aureus
* Species for which the efficacy of Ceftriaxone has been demonstrated both in
vitro and in vivo
+ Species for which high rates of resistance have been observed in one or more
regions within the EU.
5.2 Pharmacokinetic properties

The pharmacokinetics of Ceftriaxone are largely determined by its concentration-
dependent binding to serum albumin. The plasma free (unbound) fraction of the drug
in man is approximately 5% over most of the therapeutic concentration range,
increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content,
the proportion of free Ceftriaxone in interstitial fluid is correspondingly higher than in
plasma.
Plasma concentrations:
Mean peak concentrations after bolus intravenous injection are about 120mg/l
following a 500mg dose and about 200mg/l following a 1g dose; mean levels of
250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of
500mg Ceftriaxone in 1.06% Lignocaine produces mean peak plasma concentrations
of 40–70mg/l within 1 hour. Bioavailability after intramuscular injection is 100%.
Excretion:
Ceftriaxone is eliminated mainly as unchanged Ceftriaxone, approximately 60% of
the dose being excreted in the urine (almost exclusively by glomerular filtration) and
the remainder via the biliary and intestinal tracts. The total plasma clearance is 10-
22ml/min. The renal clearance is 5-12ml/min. The elimination half-life in adults is
about 8 hours. The half-life is not significantly affected by the dose, the route of
administration or by repeated administration.
Pharmacokinetics in special clinical situations:

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In the first week of life, 80% of the dose is excreted in the urine; over the first month,
this falls to levels similar to those in the adult. In infants aged less than 8 days the
average elimination half-life is usually two to three times longer than that of young
adults.
In elderly persons aged over 75 years, the average elimination half-life is usually 2 to
3 times longer than in the young adult group. As with all cephalosporins, a decrease in
renal function in the elderly may lead to an increase in half-life. Evidence gathered to
date with Ceftriaxone however, suggests that no modifications of the dosage regimen
is needed.
In patients with renal or hepatic dysfunction, the pharmacokinetics of Ceftriaxone are
only minimally altered and the elimination half-life is only slightly increased. If
kidney function alone is impaired, biliary elimination of Ceftriaxone is increased; if
liver function alone is impaired, renal elimination is increased.
Cerebrospinal fluid:
Ceftriaxone can cross non-inflamed and inflamed meninges. Concentrations attained
are approximately 4-17% of the simultaneous plasma concentration.
5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to
that already included in other sections of the SPC.
6. Pharmaceutical particulars
6.1 List of excipients

None.
6.2 Incompatibilities
Solutions containing Ceftriaxone should not be mixed with or added to other agents.
In particular diluents containing calcium (e.g. Ringer's solution, Hartmann's solution)
should not be used to reconstitute Ceftriaxone vials or to further dilute a reconstituted
vial for IV administration because a precipitate can form. Ceftriaxone must not be
mixed or administered simultaneously with calcium-containing solutions (see sections
4.2 , 4.3, 4.4 and 4.8).

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6.3 Shelf life

Unopened: 24 months
After reconstitution: Chemical and physical in-use stability has been demonstrated for
4 days at 2-8°C. From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions prior to use
are the responsibility of the user and would not normally be longer than 24 hours at 2-
8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic
conditions.
6.4 Special precautions for storage

After reconstitution: store at 2-8°C.
6.5 Nature and contents of container

Presentation:
Each vial contains Sterile Ceftriaxone Sodium USP, approximately equivalent to 1gm
Ceftriaxone.
6.6 Special precautions for disposal and other handling

Reconstitution: From the calculated dose, determine the appropriate number of vials
to be used.
For the intravenous or intramuscular injection, add the recommended volume of
reconstitution solution specified in the table below and shake well until the contents
of the vial have dissolved completely.
For the intravenous infusion, add 15 ml of reconstitution solution and shake well until
the contents of the vial have dissolved completely.
Draw up this 15 ml of reconstituted solution and add it to 25 ml of reconstitution fluid
in an infusion bag to prepare the patient dose (making a total volume of 40 ml
reconstitution fluid as specified in the table).
The solution should be given by intravenous infusion as detailed in section 4.2.

XYZ PHARMA LTD.

Powd Solution for reconstitution Quantity of Displacem

er solution ent volume
Intramuscular 1g 1% Lignocaine 3.5 ml 0.63ml
injection Hydrochloride Injection BP *
Intravenous injection 1g Water for Injections BP 10 ml 0.63ml
Intravenous infusion 2g Glucose Injection BP 5% 40 ml 1.25ml
0.9% Sodium Chloride Injection
BP
Sodium Chloride and Glucose
Injection BP (0.45% sodium
chloride and 2.5% glucose)
Dextran 6% in Glucose Injection
BP 5%
Hydroxyethyl starch 6-10%
infusions**
* Solutions of Ceftriaxone in lignocaine should not be administered intravenously.
** Formulae; 6% infusion: 30g hydroxyethylstarch, 4.5g sodium chloride, up to
500ml Water for Injections.
10% infusion: 50g hydroxyethylstarch, 4.5g sodium chloride, up to 500ml Water for
Injections.
If other infusion fluids are used, compatibility with Ceftriaxone should be checked.
The solution should be clear, do not use the solution if particles are present.
7. Marketing authorisation holder

------------------------------
8. Marketing authorisation number(s)

------------------------------
9. Date of first authorisation/renewal of the authorisation

------------------------------
10. Date of revision of the text

------------------------------
11. Legal
POM

XYZ PHARMA LTD.

Company information
XYZ (P) LTD.

XYZ PHARMA LTD.

5.3 PATIENT INFORMATION LEAFLET (PIL)
PACKAGE INFORMATION LEAFLET FOR THE USER
SEFTRIL-1000 (Ceftriaxone for Injection USP 1g)

Powder for solution for injection or infusion
Please read all of this leaflet carefully before you start having this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or nurse.
If any of the side effects become serious or troublesome, or if you notice any side
effects not listed in this leaflet, please tell your doctor or nurse.
In this leaflet:
1. What SEFTRIL-1000 is and what it is used for
2. Before you are given SEFTRIL-1000
3. How SEFTRIL-1000 will be given
4. Possible side effects
5. How SEFTRIL-1000 is stored
6. Further information
1. What SEFTRIL-1000 is and what it is used for

SEFTRIL-1000 contains a medicine called ceftriaxone. This belongs to a group of
medicines called antibiotics.
SEFTRIL-1000 is used to treat infections caused by bacteria.
It can be used to treat infections in different parts of the body including the lungs
(pneumonia), blood (septicaemia), skin, other soft body parts (tissues), bone, and for
infections such as meningitis and gonorrhoea (a sexually transmitted infection).
It can be used to treat infections in people with low numbers of white blood cells
(neutropenia).
It can also be given before and after operations to stop infections from happening.
It works by stopping the bacteria from growing properly. This causes the bacteria to
die.

XYZ PHARMA LTD.

2. Before you are given SEFTRIL-1000
You must not be given SEFTRIL-1000 if:
You are allergic (hypersensitive) to Ceftriaxone (the only ingredient in SEFTRIL-
1000).
You are allergic to antibiotics called ‘cephalosporins’. These include cefalexin,
cefaclor and cefuroxime.
You have had a sudden or severe allergic reaction to penicillin or similar antibiotics
(such as amoxicillin or flucloxacillin). The signs include sudden swelling of the throat
or face which might make it difficult to breathe or swallow, sudden swelling of the
hands, feet and ankles, and a severe rash that develops quickly.
You are allergic to lidocaine and you are to be given SEFTRIL-1000 as an injection
into a muscle You must not be given SEFTRIL-1000 if any of the above apply to you.
If you are not sure, talk to your doctor or nurse before having SEFTRIL-1000.
SEFTRIL-1000 must not be given to babies if:

The baby is premature.
The baby is newborn (up to 28 days) and has certain blood problems or jaundice
(yellowing of the skin or the whites of the eyes) or is about to be given another
injection that contains calcium..
Take special care with SEFTRIL-1000

Check with your doctor or nurse before having SEFTRIL-1000 if:
You have had a mild allergic reaction to penicillin or similar antibiotics (such as a
skin rash which may have been itchy).
You are allergic to anything not already mentioned in this leaflet.
You have asthma.
You have recently received or are about to receive calcium.
You have ever had problems with your gut, in particular colitis (inflammation of the
bowel).
You have liver or kidney problems.
You have other illnesses, such as blood problems.
You are on a low sodium diet.
If any of the above apply to you, or if you are not sure, talk to your doctor or nurse
before you have SEFTRIL-1000.

XYZ PHARMA LTD.

Taking other medicines
Please tell your doctor or nurse if you are taking or have recently taken any other
medicines. This includes medicines that you buy without a prescription and herbal
medicines. This is because SEFTRIL-1000 can affect the way some medicines work.
Also some medicines can affect the way SEFTRIL-1000 works.
In particular, tell your doctor or nurse if you are taking any of the following
medicines:
Oral contraceptives (the pill). SEFTRIL-1000 can stop the pill from working, so you
should use extra barrier contraception methods (such as condoms) while you are
taking SEFTRIL-1000 and for one month afterwards.
Chloramphenicol (used to treat infections, particularly of the eyes).
Anticoagulants (medicines used to thin the blood).
Probenecid (used to treat gout).
Amsacrine (an anti-cancer medicine).
Fluconazole (an anti-fungal medicine).
Vancomycin or other antibiotics (used to treat infections).
Pregnancy and breast-feeding
Talk to your doctor before taking this medicine if you are pregnant, might become
pregnant, or are breastfeeding.
Driving and using machines
SEFTRIL-1000 can cause dizziness. Talk to your doctor if any of these happen to you
and do not drive or use any tools or machines.
3. How SEFTRIL-1000 will be given

SEFTRIL-1000 will be given to you by a doctor or nurse. It will be given to you in
one of the following ways:
As an injection into a muscle (such as the muscle in your arm).
By slow injection into one of your veins. This may take between 2 and 4 minutes.
Through a small tube into one of your veins. This is called an ‘intravenous infusion’.
It may take at least 30 minutes.
The number of days or weeks that you are given SEFTRIL-1000 for depends on what
sort of infection you have.
You will usually continue to be given SEFTRIL-1000 for 2 to 3 days after you have
started to recover from your illness.

XYZ PHARMA LTD.

Adults, the elderly and children aged 12 years and over
The usual dose is 1 g (gram) once a day. If you have a severe infection, your doctor
may give you a higher dose (between 2 g and 4 g once a day).
If you are going to have an operation you may be given between 1 g and 2 g in one or
two injections.
The usual treatment for an infection called ‘gonorrhoea’ is one dose of 250 mg
(milligrams), given as an injection into a muscle.
Children up to 12 years
The dose is worked out by the doctor based on the child’s weight. The medicine is
usually given to the child once a day through a small tube into a vein (intravenous
infusion). This usually takes at least 30 minutes.
Newborn babies
The dose is worked out by the doctor based on the baby’s weight. The medicine is
usually given to the baby once a day through a small tube into a vein (intravenous
infusion). This usually takes 1 hour.
People with liver and kidney problems
If you have problems with your liver and kidneys, you may be given a lower dose.
You may need to have blood tests to check that you are getting the dose you need.
If you are given too much SEFTRIL-1000
· If you think you have been given too much SEFTRIL-1000, tell your doctor or
nurse.
If you have any further questions on the use of this medicine, ask your doctor or nurse
4. Possible side effects

Like all medicines, SEFTRIL-1000 can cause side effects, although not everyone will
get them. The following side effects may happen with this medicine.
Severe allergic reactions (uncommon, affect less than 1 in 100 people)
If you have a severe allergic reaction, tell a doctor straight away.
The signs may include:
Sudden swelling of the face, throat, lips or mouth. This can make it difficult to breathe
or swallow.
Sudden swelling of the hands, feet and ankles.
Severe skin rashes (very rare, affect less than 1 in 10,000 people)
If you get a severe skin rash, tell a doctor straight away.

XYZ PHARMA LTD.

The signs may include a severe rash that develops quickly, with blisters or peeling of
the skin and possibly blisters in the mouth.
Other possible side effects:

Common (affect less than 1 in 10 people)
Loose stools or diarrhoea.
Feeling sick or being sick.
Uncommon (affect less than 1 in 100 people)
Other skin reactions. These include a rash which may cover a lot of your body, a
lumpy rash (hives), feeling itchy and swelling.
Rare (affect less than 1 in 1,000 people)
Other types of infection, such as those caused by fungi and yeasts (for example,
thrush).
Blood problems. The signs include feeling tired, bruising easily, being short of breath
and nosebleeds.
Headache.
Feeling dizzy.
A sore mouth.
Inflammation of the tongue (glossitis). The signs include swelling, redness and
soreness of the tongue.
Liver problems (shown in a blood test).
Problems with your gallbladder which may cause pain, feeling sick and being sick.
Kidney problems. These may affect the amount of water (urine) that you pass. Some
people pass less water than usual. Very rarely, people stop passing water altogether.
Blood or sugar in your urine.
Pain or a burning feeling along the vein where SEFTRIL-1000 has been given.
Pain where the injection was given.
A high temperature (fever) or shivering.
Very rare (affect less than 1 in 10,000 people)
Positive results in a Coombs’ test (a test for some blood problems).
Problems with the way your blood clots. The signs include bruising easily and pain
and swelling of your joints.
Changes in the numbers of white cells in your blood. The signs include a sudden high
temperature (fever), shivering and a sore throat.

XYZ PHARMA LTD.

Inflammation of the pancreas (pancreatitis). The signs include severe pain in the
stomach which spreads to your back.
Inflammation of the large bowel (colon). The signs include diarrhoea, usually with
blood and mucus, stomach pain and fever.
If any of the side effects become serious or troublesome, or if you notice any side
effects not listed in this leaflet, please tell your doctor or nurse.
5. How SEFTRIL-1000 is stored

Your doctor or pharmacist is responsible for storing SEFTRIL-1000. They are also
responsible for disposing of any unused SEFTRIL-1000 correctly.
Keep out of the reach and sight of children.
Store at or below 25˚C. Protected from light
Do not use SEFTRIL-1000 after the expiry date printed on the pack.
6. Further information
What SEFTRIL-1000 contains
Each vial contains: Sterile Ceftriaxone Sodium USP equivalent to Anhydrous
Ceftriaxone 1.0 g
White powder (Ceftriaxone sodium USP) is filled in clear glass sealed vials
What SEFTRIL-1000 looks like and contents of the pack

White powder (Ceftriaxone sodium USP) is filled in clear glass sealed vials
Before it is given to the patient, SEFTRIL-1000 is made into a solution by adding
sterile liquid to the vial.
The correct dose is then taken out of the vial. It can be given to the patient either as an
injection or added to a bag of infusion solution which is given through a small tube
into one of your veins.
SEFTRIL-1000 is supplied in packs of 1 vial.
Marketing Authorisation Holder and Manufacturer

XYZ (P) LTD.
This leaflet was last approved in July 2010

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XYZ PHARMA LTD.

PART II QUALITY DOCUMENTS 62

PARTIII NONCLINICAL DOCUMENTS 161

PART IV CLINICAL DOCUMENTS 163

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 1 of 164

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Chemical name: (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)->2-(methoxyimino)

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 4 of 164

Molecular Weight: 661.60

SEFTRIL 1000 (Ceftriaxone for Injection USP 1g)

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Lower Respiratory Tract Infections caused by Streptococcus pneumoniae,

Acute Bacterial Otitis Media caused by Streptococcus pneumoniae, Haemophilus

Skin And Skin Structure Infections caused by Staphylococcus aureus, Staphylococcus

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Urinary Tract Infections (complicated and uncomplicated) caused by Escherichia coli,

Uncomplicated Gonorrhea (cervical/urethral and rectal) caused by Neisseria

Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae. Ceftriaxone, like other

Bone And Joint Infections caused by Staphylococcus aureus, Streptococcus

Meningitis caused by Haemophilus influenzae, Neisseria meningitides or

Surgical prophylaxis: The preoperative administration of a single 1 gm dose of

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Dosage and administration:

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Local Reactions—pain, induration and tenderness was 1% overall. Phlebitis was

Hypersensitivity—rash (1.7%) Less frequently reported (<1%) were pruritus, fever or

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 10 of 164

Other rarely observed adverse reactions (<0.1%) include abdominal pain,

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PART I ADMINISTRATIVE DATA AND PRODUCT 2

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APPLICATION FORM FOR MARKETING AUTHORIZATION

A- DETAILS OF APPLICANT AND MANUFACTURER :

- Name : XYZ (P) LIMITED

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 14 of 164

Name & address Role**

** = e.g. “prepares semi-finished product”, “packaging”, “granulation”,

1- Product Name : Ceftriaxone for Injection USP 1 g

3- Qualitative & Quantity formula:

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 15 of 164

D- INDICATION, POSOLOGY AND ROUTE OF ADMINISTRATION:

Lower Respiratory Tract Infections caused by Streptococcus pneumoniae,

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 16 of 164

Skin And Skin Structure Infections caused by Staphylococcus aureus, Staphylococcus

Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae. Ceftriaxone, like other

Bone And Joint Infections caused by Staphylococcus aureus, Streptococcus

Meningitis caused by Haemophilus influenzae, Neisseria meningitides or

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 17 of 164

Surgical prophylaxis: The preoperative administration of a single 1 gm dose of

2. Posology and method of administration

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G- SHELF LIFE: 24 months

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Product owner’s name: M/s. XYZ (P) LIMITED

To apply for registration of our pharmaceutical product

Product Name : SEFTRIL 1000

SEFTRIL-1000 (Ceftriaxone for Injection USP 1g) Page 21 of 164

a. License of pharmaceutical industries/importer/wholesaler (country specific)

==== Refer to attachment “ANNEXURE TO PART 1”====

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