Ref 2. WHO Histamine-1 Receptor Antagonists

Section 3: Antiallergics and Medicines Used in Anaphylaxis
Histamine-1 receptor antagonists – A critical evaluation to update Section 3
Developed by Harinder Chahal
For WHO Secretariat

Focus of this review
Antihistamines, the first line treatment for conditions such as allergic rhinitis and urticaria, are
amongst the most commonly used medications in the world with more than 40 histamine-1
antagonist agents available. The 18th Expert Committee on the Selection and Use of Essential
Medicines requested an evaluation for the use of chlorphenamine (the systemic first generation
histamine-1-receptor antagonist currently on the EML) versus diphenhydramine.
This review will provide efficacy, safety and cost information on two 1st generation
antihistamines (FGAHs) – chlorphenamine and diphenhydramine. However, considering the
favorable pharmacotherapy and side-effect profile of 2nd generation systemic antihistamines
(SGAHs), this review will also provide an overview of efficacy, safety and cost of three over-the-
counter, SGAHs (cetirizine, loratadine and fexofenadine) and compare them to FGAHs.
This review is intended to answer the following questions.
1. Should Diphenhydramine replace Chlorphenamine on the Essential Medicines List?
2. Should a SGAH be on the WHO Essential Medicines List?
3. If so, should this be an addition or replacement to the FGAH currently on the list?
4. Which SGAH should be listed?
Page 1 of 63
Table of Contents
List of Tables .................................................................................................................................. 1
Acronyms and Abbreviations: ........................................................................................................ 2
Executive Summary ........................................................................................................................ 3
I. Background and Rationale for this review .............................................................................. 6
II. Public health relevance of allergic conditions ..................................................................... 7
III. Methods.............................................................................................................................. 10
IV. Medications, Clinical Efficacy and Safety Evaluation ...................................................... 10
1. Similarities and differences amongst FGAHs and SGAHs ............................................... 10
2. Pharmacokinetic (PK) and Pharmacodynamic (PD) properties of antihistamines ............ 11
3. Comparing chlorphenamine and diphenhydramine ........................................................... 13
4. Treatment of selected common conditions with FGAH and SGAH.................................. 17
A. Allergic Rhinitis .................................................................................................................... 17
B. Urticaria ................................................................................................................................. 23
C. Anaphylaxis (adjunct)............................................................................................................ 28
5. Safety Profile of Antihistamines ........................................................................................ 29
V. Use of Antihistamines in special populations .................................................................... 36
1. Elderly ................................................................................................................................... 36
2. Children and Infants .............................................................................................................. 36
VI. Cost, Regulatory and Current NEML Availability Evaluation .......................................... 41
VII. Summary and Recommendations ...................................................................................... 43
Appendix ....................................................................................................................................... 45
Appendix 1 – Drug-Drug Interactions: 1st Generation Antihistamines .................................... 46
Appendix 2 – Drug-Drug Interactions: 2nd Generation Antihistamines.................................... 48
Appendix 3 – Precautions, Contraindications and Breast Feeding Risk of 1st Generation
Antihistamines........................................................................................................................... 49
Appendix 4 – Precautions, Contraindications and Breast Feeding Risk of 2nd Generation
Antihistamines........................................................................................................................... 50
Appendix 5: Non-allergic conditions treated with Antihistamines ........................................... 51
A. Motion Sickness, Nausea, Emesis ......................................................................................... 51
B. Antitussive uses ..................................................................................................................... 51
C. Insomnia (Night-time sleep aid) ............................................................................................ 52
D. Extrapyramidal Symptoms .................................................................................................... 53
Appendix 6: EML Application Sections ................................................................................... 54
References ..................................................................................................................................... 56
List of Tables
Table 1: Medications under review for safety, efficacy and cost ...................................................................................7
Table 2: FDA approved and off-label indications for antihistamines and strength of evidence and recommendation.8
Table 3: PK and PD properties of antihistamines .........................................................................................................12
Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria .............................................................15
Table 5: Guidelines on Treatment of Allergic Rhinitis ..................................................................................................18
Table 6: Efficacy and safety of SGAH in Allergic Rhinitis ..............................................................................................19
Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria .....................................................................24
Table 8: Efficacy and Safety of SGAHs in Urticaria ......................................................................................................25
Table 9: Comparative side-effect profile of first and second generation antihistamines ............................................31
Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment ....................................................................32
Table 11: Safety in children and breast feeding...........................................................................................................38
Table 12: Cost comparison of 1st and 2nd generation antihistamines........................................................................42
Table 13: Availability of reviewed medications on NEMLs of 15 nations ....................................................................42
Table 14: Treatment Details for Loratadine.................................................................................................................44
Table 15: Dose Adjustments for Loratadine.................................................................................................................44
Acronyms and Abbreviations:
BID – Twice daily
BNF – British National Formulary
DDI – Drug-Drug Interactions
EC – Expert Committee
EML – Essential Medicines List
FDA – Food and Drug Administration
FGAH – First (1st) generation antihistamine
GRADE – Grading of Recommendations Assessment, Development and Evaluation
inj - Injection
IV – Intravenous
LMICs – Low– and Middle–Income Countries
MHRA – Medicines and Healthcare products Regulatory Agency
NEML – National Essential Medicines List
PD – Pharmacodynamics
PK – Pharmacokinetic
PO – Oral
RCT – Randomized Controlled Trial
SGAH – Second (2nd) generation antihistamine
SRA - Stringent Regulatory Authority
tab – Tablet
TGA – Therapeutics Goods Administration
US – United States
WHO – World Health Organization
Page 2 of 63
Executive Summary
This application has reviewed the efficacy and safety of first generation antihistamines (FGAHs)
- chlorphenamine and diphenhydramine for section 3 of EML and EMLc as requested by the 18th
Expert Committee. The application also reviewed the efficacy and safety of three second
generation antihistamines (SGAHs) - loratadine, cetirizine and fexofenadine and compared them
to FGAHs. Evidence for treatment of two common allergic conditions – allergic rhinitis and
urticaria – with these five antihistamines is provided. The application also provides a discussion
on the use of antihistamines in anaphylaxis. The use of these medications in the elderly and
children is also discussed. Finally, the application analyzed the cost of the five medications as
well as their availability of National EMLs of 15 Low and middle income countries (LMICs).
Overall, there is a lack of high quality data to effectively compare and contrast the two FGAHs.
The review found no RCTs that satisfactorily compared efficacy and safety of chlorphenamine
and diphenhydramine for use in allergic rhinitis, urticaria and anaphylaxis. The evidence from
five RCTs does show similar effectiveness and side effect profile of the two medications for both
allergic rhinitis and urticaria. However, the review has shown significant evidence comparing
efficacy and safety of SGAHs with FGAHs. Fifteen RCTs show similar efficacy between the two
classes of medications in treating allergic rhinitis with significantly less side effects (in
frequency and severity) resulting from use of SGAHs. For treatment of urticaria, nine RCTs
showed similar efficacy between FGAHs and SGAHs, with lower incidence of side effects. Six
RCTs, three retrospective studies and one systematic review provide evidence establishing
superior safety profile of SGAHs over that of FGAHs. Significant sedation and psychomotor
impairment is observed with FGAHs compared to SGAHs.
The review provides a detailed discussion on the use of antihistamines in anaphylaxis and
concludes that there is no strong evidence recommending the use of antihistamines for this
indication. There are no RCTs available that evaluate the use of antihistamines in anaphylaxis.
The referenced guidelines strongly recommend the use of epinephrine as first line treatment for
anaphylaxis and only recommend antihistamines as adjunct therapy for possible benefit in
histamine mediated cutaneous reactions.
Due to the anticholinergic side effects, the use of FGAHs in the elderly is strongly discouraged
and SGAHs are recommended for use in allergic conditions. Evidence from 5 RCTs, two
pharmacokinetic studies, a systematic review and guidelines conclude against the use of FGAHs
in infants and children due to risk of sedation and death and establish safety of SGAHs.
For cost and availability, using MSH pricing guide, the monthly treatment cost with loratadine is
more economical than chlorphenamine and 53% of the surveyed LMICs already have a SGAHs
on their respective National EMLs.
Based on the evidence available, this review makes the following recommendations: 1) Retain
chlorphenamine on the EML for adults, and but the age restriction be 6 years ( currently it is 1
Page 3 of 63
year). 2) Delete chlorphenamine from the EMLc. 3) Add loratadine tablet (10mg) and syrup
(1mg/1mL) to the EML and EMLc, with a square box designation. 4) An age restriction of 2
years and older for loratadine is recommended.
Page 4 of 63
Review
Page 5 of 63
I. Background and Rationale for this review
The WHO 18th Expert Committee on the Selection and Use of Essential Medicines (18th EC)
requested a comparative review for chlorphenamine (systemic antihistamine currently on the
EML) versus diphenhydramine, to update Section 3 of the EML titled “Antiallergics and
Medicines Used in Anaphylaxis.”[1]
Allergic conditions such as allergic rhinitis and urticaria are histamine mediated reactions that
may require management with pharmacological agents.[2-4] Histamine is a naturally occurring
compound produced and present all throughout the human body. Likewise, histamine receptors,
H-1, H-2, H-3, and H-4 are expressed throughout the body and in-conjunction with histamine,
play important roles in regulation of functions ranging from embryo development to wound
healing and regeneration. The primary target of the antihistamines under review is the histamine-
1 (H-1) receptor, which is involved in central nervous system functions such as sleep and waking
cycles (circadian rhythm), energy regulation, cognition, memory and in peripheral body
functions such as allergic inflammation and reactions causing H-1 mediated hypotension,
tachycardia, flushing and headache via its effects on the cardiovascular system.[3-7]
More than 40 histamine-1 antagonist antihistamine agents are available worldwide.[3, 5, 8, 9]

The FDA (an SRA) has approved several uses of antihistamines as listed in Table 2 below;
however, this review will focus on three conditions within the purview of section 3 of the EML,
1) allergic rhinitis 2) urticaria and 3) anaphylaxis. There are several other off-label indications
for these medications listed in Table 2 below.[3, 8-19] A discussion on treatment of selected off-
label and non-histamine mediated conditions is available in appendix 5. Table 2 also provides a
detailed look at the level of evidence and recommendation of treatment of FDA approved and
off-label indications.[10] The FDA was selected for this assessment due to its status as
recognized SRA, availability of online FDA databases and due to the availability of the
information in English. UK, Australia and Canada SRAs as well as PubMed databases, Cochrane
library, BNF, Micromedex and Lexi-Comp were also searched for pertinent information and
evidence. [8-10, 20-22]
This review will compare efficacy, safety and cost of two 1st generation antihistamines (FGAHs)
chlorphenamine and diphenhydramine for use as anti-allergics and in anaphylaxis. Considering
the favorable, pharmacotherapy and side-effect profile of the 2nd generation systemic
antihistamines (SGAHs), this review will also provide an overview of efficacy, safety and cost of
three SGAH (cetirizine, loratadine and fexofenadine) and compare them to FGAHs for use as
anti-allergics and in anaphylaxis.[3, 5, 7, 23-28]
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The two FGAH are reviewed
Table 1: Medications under review for safety, efficacy and cost
because they are requested by
the EC and the three SGAH Agent(s) or Class Comparative
were selected for review due to Medication or Class
Comparison
their classification as over-the- 1 Chlorphenamine vs. Diphenhydramine
counter (OTC) medications by 2 FGAH: SGAH: cetirizine,
the FDA and their off-patent chlorphenamine and vs. loratadine and
status.[9] OTC medications are diphenhydramine fexofenadine
defined as medications that are
safe and effective for use by the general public without seeking treatment by a health
professional.[9] Given that anti-histamines are amongst the most commonly used medications in
the world, their OTC status is an important consideration especially in situations where access to
qualified prescribers may be limited. Table 1 summarizes the medications under review.
Appendix 6 on page 54 contains a list of EML application questions with section by section
references to this review.
II. Public health relevance of allergic conditions

World Allergy Association, an international umbrella organization for regional and national
allergy and clinical immunology societies, in a 2011 report states that the prevalence of allergic
conditions such as rhinitis, anaphylaxis, food and medicine allergies and urticaria is rising
worldwide in both developing and developed nations.[29-31] It is estimated that between 30-
40% of the world’s population suffers from an allergic condition at any given time; within
Europe alone, 87 million people suffer from allergies and 80-90% of asthmatics are also living
with allergic rhinitis, a systemic inflammatory condition that significantly impacts quality of life,
while 10-30% of adults and 40% of children worldwide suffer from non-infectious rhinitis.[4, 29,
32] Worldwide, an estimated 40-50% of schoolchildren are expected to be sensitized to one or
more of the common allergens.[4, 29] Furthermore, the worldwide prevalence of chronic
idiopathic urticaria, characterized by hives, wheals and pruritus, is estimated to be up to 0.5%,
with the average duration of the disease between 3-7 years.[29] However, many chronic allergic
conditions are underdiagnosed and undertreated, possibly due to lack of awareness, therefore,
underestimating the impact of allergic diseases on health and on the quality of life for the
patients.[29] For example, moderate to severe allergic rhinitis has been shown to be consistently
underdiagnosed and undertreated; a condition that has the potential to induce sleep disorders,
sinusitis, acute and serious otitis media, asthma and other medical complications due to its
association with larger inflammatory process affecting other organ systems.[4]
Page 7 of 63
Table 2: FDA approved and off-label indications for antihistamines and strength of evidence and recommendation
Medication FDA Approved Indication and Strength of Recommendation and Off-Label (Non-FDA approved) Indication and Strength of
Evidence (R/E) Recommendation and Evidence (R/E)
Diphenhydramine Indication Adults (R/E) Children (R/E) Indication Adults (R/E) Children (R/E)
Allergic rhinitis Yes (Class IIb / Yes (Class IIb / Category Chemotherapy-induced No (Class IIb / No evidence
Category B) B) nausea and vomiting Category B)
Anaphylaxis; Yes (Class IIb / Yes (Class IIb / Category Extrapyramidal disease - No (Class IIb / No evidence
Adjunct Category B) B) Medication-induced Category B)
movement disorder
Common cold Yes (Class IIb / Yes (>6yr of age) (Class Hyperemesis gravidarum No (Class IIb / No evidence
Category B) IIb / Category B) Category B)
Insomnia Yes (Class IIb / Yes (>12yr of age) Local anesthesia No (Class IIb / No evidence
Category B) (Class IIb / Category B) Category B)
Motion sickness Yes (Class IIb / Yes (Class IIb / Category
Category B) B)
Parkinsonism Yes (Class IIb / Not FDA approved
Category B)
Pruritus of skin Yes (Class IIa / Yes topical formulation
Category B) only, 2 y and older
(Class IIa / Category B)
Chlorphenamine Allergic rhinitis Yes (Class IIa / Yes (>6yr of age) (Class Contrast media adverse No (Class IIb / No (Class IIb /
Category B) IIa / Category B) reaction Category B) Category B)
Common cold Yes (Class IIb / Yes (>6yr of age) (Class Systemic mast cell disease No (Class IIb / No (Class IIb /
Category B) IIb / Category B) Category B) Category B)
Loratadine Idiopathic urticaria, Yes (Class IIb / Category Yes (>2yr of age) (Class Asthma No (Class IIb / No (Class IIb /
chronic B) IIb / Category B) Category B) Category B)
Allergic rhinitis Yes (Class IIa / Category Yes (>2yr of age) (Class Eosinophilic non-allergic No evidence No evidence
B) IIa / Category B) rhinitis
Cetirizine Allergic rhinitis Yes (Class IIa / Category Yes (>6months of age) Asthma, adjunct No (Class IIa / No evidence
(Perennial) B) (Class IIa / Category B) Category B)
Page 8 of 63
Allergic rhinitis Yes (Class IIa / Category Yes (>2yr of age) (Class Atopic dermatitis No (Class IIb / No (Class IIb /
(Seasonal) B) IIa / Category B) Category B) Category B)
Urticaria, chronic Yes (Class IIa / Category Yes (>6months) (Class Urticaria, acute No (Class IIb / No evidence
B) IIa / Category B) Category B)
Fexofenadine Idiopathic urticaria, Yes (Class IIa / Category Yes (>6yr, oral tablets, Hymenoptera No (Class IIb / No evidence
chronic B) orally disintegrating immunotherapy, Category B)
tablets; 6 months to 11 Pretreatment
years, oral suspension
(Class IIa / Category B)
Allergic rhinitis Yes (Class IIa / Category Yes 6yr and older, oral Allergic rhinitis (Perennial) No (Class IIb / No evidence
(Seasonal) B) tablets, orally Category B)
disintegrating tablets; 2
to 11 years, oral
suspension (Class IIa /
Category B)
Strength of Recommendation Strength of Evidence

Class I - Recommended Category A
 The given test or treatment has been proven to be useful, and should be  Category A evidence is based on data derived from: Meta-analyses of randomized
performed or administered. controlled trials with homogeneity with regard to the directions and degrees of results
Class IIa - Recommended, In Most Cases between individual studies. Multiple, well-done randomized clinical trials involving large
 The given test, or treatment is generally considered to be useful, and is numbers of patients.
indicated in most cases. Category B
Class IIb - Recommended, In Some Cases  Category B evidence is based on data derived from: Meta-analyses of randomized
 The given test, or treatment may be useful, and is indicated in some, but not controlled trials with conflicting conclusions with regard to the directions and degrees of
most, cases. results between individual studies. Randomized controlled trials that involved small
numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate,
Class III - Not Recommended flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies,
 The given test, or treatment is not useful, and should be avoided. observational studies).
Class Indeterminate - Evidence Inconclusive Category C
 Category C evidence is based on data derived from: Expert opinion or consensus, case
reports or case series.
No Evidence
The approved and off-label indications for antihistamine agents, along with the strength of recommendations and evidence are based on information by Micromedex, an online clinical
pharmacy information database.[10]
Page 9 of 63
III. Methods
A search was conducted using all PubMed databases and Cochrane databases for reviews,
observational studies and RCTs:
1. Comparing chlorphenamine and diphenhydramine for safety and efficacy.

2. Providing information on safety and efficacy of FGAH or SGAH as monotherapy
against placebo.
3. Comparing FGAH to SGAH for safety and efficacy.
4. Use of FGAH and SGAH for allergic rhinitis, urticaria and anaphylaxis.
5. Use of FGAH and SGAH in special populations, children and the elderly.
6. Antihistamines used for treatment of extrapyramidal symptoms, motion sickness,
antitussive.
The online databases of four stringent regulatory authorities were also searched for pertinent
information: FDA (United States), TGA (Australia), MHRA (UK) and Health Canada. Other
online databases searched were: British National Formulary, and Micromedex and Lexi-Comp
(clinical pharmacy databases). All SRAs and databases were selected based on their online
availability in English.
The following search terms were used: first generation antihistamines; chlorphenamine; chlor-
trimeton; diphenhydramine; second generation antihistamines; cetirizine; loratadine;
fexofenadine; allegra; zyrtec; claritin; safety and efficacy of medications under review;
pharmacokinetic and pharmacodynamics of medications under review; allergic rhinitis; rhinitis;
urticaria; chronic urticaria; extrapyramidal symptoms; EPS; akathisia; dystonic reactions;
dystonia; pseudoparkinsonism; antipsychotic induced EPS; anaphylaxis; food allergies and
antihistamines; motion sickness and antihistamine; nausea/vomiting/emesis and antihistamine
use; antitussive; cough suppression and antihistamine use. A title review was conducted to
identify relevant results followed by an abstract review.
IV. Medications, Clinical Efficacy and Safety Evaluation

1. Similarities and differences amongst FGAHs and SGAHs
Both FGAHs and SGAHs agents act as antagonists (also known as inverse agonists) to
the H-1 receptor. These agents attach to the H-1 receptor, however, they do not activate
the chemical cascade that histamine activates when attached to the same receptor.[3-5, 8]
Instead, the antihistamines work to keep the receptors in their inactivated form and
compete with histamine from attaching and initiating the cascade, thus shifting the
equilibrium of the H-1 receptors towards the inactive state thus preventing histamine-
mediated allergic reactions.[3, 8] Despite their similar mechanism of action on the H-1
receptors, the overall cumulative effects of FGAHs and SGAHs on the human body tend
Page 10 of 63
to differ significantly. The SGAHs are related and in some cases are derivatives or
metabolites of their predecessors, the FGAHs.[3]
The major distinction made between these medicine classes is on the basis of their side-
effect of sedation. The FGAHs are referred to as ‘sedating’ while the SGAHs as ‘non-
sedating.’[3] This broad distinction is based on two primary differences between these
medicine classes: 1) SGAHs are far more specific to H-1 receptors compared to their
older counterparts that also exhibit an affinity for muscarinic, serotonin and alpha-
adrenergic receptors. [3, 26] And 2) FGAHs are considered lipophilic compounds that are
able to cross the blood brain barrier as opposed to the SGAHs, which lack this ability. [3,
8, 26] These differences in receptor specificity and liphophilicity cause FGAHs to display
significant central nervous system, cardiovascular system, and gastrointestinal system
side-effects discussed below.[3, 8, 26]
2. Pharmacokinetic (PK) and Pharmacodynamic (PD) properties of antihistamines

Table 3 highlights PK and PD factors of FGAH and SGAH, with a focus on
chlorphenamine, diphenhydramine, cetirizine, loratadine and fexofenadine. [3, 8-10, 15,
33, 34] This table presents the comparative pharmacological profile for agents in this
review along with their potential for onset of action, duration of action, drug-drug
interactions, drug-disease interaction (renal and hepatic insufficiencies), and pregnancy
categories.
Page 11 of 63
Table 3: PK and PD properties of antihistamines
1st generation antihistamines 2nd generation antihistamines

PK/PD Property Chlorphenamine Diphenhydramine Cetirizine Loratadine Fexofenadine
Duration of Action Up to 24h Less than 12h 24h 24h 24h
Volume of Distribution Children 4-7L/kg; Children 22L/kg; Adults 0.56L/kg Variable Not available
Adults 6-12L/kg 17L/kg; Elderly 14L/kg
Protein Binding 33% 98.5% 93% 97% 60 to 70%
Metabolism Hepatic, significant first- Hepatic, significant first- Hepatic (limited) Hepatic (extensive) Hepatic (minimal)
pass effect pass effect
Absorption Good Moderate 42 to 62% Rapid Rapid Rapid
(Bioavailability)
Half-life 27h Children 5h; Adults 9h; 8h 12-15h 14h
Elderly 13.5h.
Time to Peak Onset of action 3h; time Onset of action 2h; time to Onset of action 0.7h; Onset of action 2h; Onset of action 1h;
to peak 2-3h peak 2h time to peak 1h time to peak 1h time to peak 2.6h
Excretion Urine Urine Urine (70%) and feces Urine (40%) and Feces (80%) and urine
(10%) feces (40%) (11%)
Dose adjustment in renal Data not available Yes Yes Yes Yes
impairment
Dose adjustment in Data not available Yes Yes Yes No
hepatic impairment
Clinically relevant drug- Possible Possible Unlikely Possible Unlikely
drug interactions
Pregnancy category Category B1 Category B1 Category B1 Category B1 Category C2
(FDA)
Pregnancy category Category A3 Category A3 Category B24 Category B15 Category B24
(TGA)
1
FDA category B: Medications for which animal studies have shown no adverse effects to fetus and no studies in humans exist or for which studies have shown adverse effects
in animals but not in humans. 2FDA Category C: Medications for which animal studies have shown adverse effects but studies in humans are not available or for medications
that have no data for humans or animals.
3
TGA category A: Medications which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of
malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of
fetal damage. 4TGA category B2: Medications which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the
frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but
available data show no evidence of an increased occurrence of fetal damage. 5TGA category B1: Drugs which have been taken by only a limited number of pregnant women and
women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in
animals have not shown evidence of an increased occurrence of fetal damage.
Page 12 of 63
3. Comparing chlorphenamine and diphenhydramine
It should be noted that the FGAHs came into existence over 6 decades and most of the
40-plus antihistamine agents available have never been optimally studied in RCTs and
some of these agents and their indications were approved for use prior to the current
standards for medication approval processes requiring RCTs to demonstrate safety and
efficacy in adults and children.[35, 36]
Efficacy and Safety: No trials comparing these two agents in terms of efficacy or safety
for allergic rhinitis, urticaria or anaphylaxis were found. However, their efficacy as anti-
histamine agents for treatment of allergic rhinitis and urticaria and their safety via side-
effect profile as a class is well established in literature.[25, 37-40] An RCT including 64
Nigerian patients with allergic rhinitis found chlorphenamine to be significantly better
than vitamin C (control) at relieving symptoms.[37] Another RCT with 15 elderly
patients, found both diphenhydramine and chlorphenamine to significantly better than
placebo in suppressing histamine-induced cutaneous allergic reactions.[25] A multicenter
RCT with 188 chronic urticaria participants found hydroxyzine (a FGAH) to be as
effective as cetirizine and more effective than placebo to control urticaria symptoms.[40]
Table 4 below summarizes several RCTs examining efficacy and side-effects of FGAHs
in treatment of allergic rhinitis and urticaria.
Given their status, chlorphenamine and diphenhydramine may appropriately be referred

to as FGAHs and explored as a class rather than individual agents. Both agents have
similar efficacy in treatment of histamine mediated allergic disorders and with similar
side effect profile.[3, 4, 18, 41, 42] However, one recent systematic review concluded
that chlorphenamine is likely to cause greater impairment of cognitive function and
psychomotor performance than diphenhydramine.[4] Section IV-5 and Table 9 below
discuss the safety profile of these agents in detail.
Mechanism of Action and PK/PD: Section IV-1 closely examined the mechanism of
action of antihistamines. Table 3 shows the pharmacokinetics and pharmacodynamics
data on diphenhydramine and chlorphenamine. There is less data available on the PK and
PD profile of chlorphenamine compared to diphenhydramine. Data are still lacking for
dosing of chlorphenamine in hepatic and renal insufficiency.
Pregnancy Category: Table 3 above also shows the pregnancy categories assigned to
these agents by the FDA and TGA. FDA categorizes all antihistamines under review as
category B, with the exception of fexofenadine, which is considered category C. TGA
considers the FGAHs as category A, cetirizine and fexofenadine as category B2 and
loratadine as category B1.
Indications: The primary differences between these two FGAHs are best defined in Table
2. Diphenhydramine has been approved by an SRA (FDA) for 7 conditions while
Page 13 of 63
chlorphenamine has been approved for 2 conditions. Chlorphenamine is approved for use
in allergic rhinitis, urticarial allergic reactions and for adjunct use in anaphylaxis in the
United Kingdom.[43] The reasons for this difference in approved indications by different
SRAs may be numerous, including but not limited to, original manufacture’s incentives
for seeking multiple indications and gaining market share, competitiveness of the market,
and availability of data. Furthermore, as Table 2 illustrates, in addition to approved
indications, there is data available on diphenhydramine for off-label use in 4 conditions,
compared to the data available for the use of chlorphenamine in 2 off-label conditions.
Cost and Availability: The comparative cost and availability of these agents on the
NEMLs is provided in Table 12 and Table 13 below, respectively.
In section III – 4 below, FGAHs, chlorphenamine and diphenhydramine are examined for
specific uses in selected common conditions and their efficacy and safety profile will be
compared with SGAHs.
Page 14 of 63
Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria
Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria

Publication Study Design Study Population Medications/Doses Objective(s) Results
Controlled clinical Randomized 64 Nigerian Loratadine + Vitamin To assess Loratadine was significantly better than Vit. C. alone (P =
study of the efficacy controlled trial patients with C efficacy and 0.0002).
of loratadine in allergic rhinitis tolerance of
Nigerian patients Chlorphenamine + loratadine Chlorpheniramine was also significantly better than Vit. C.
with allergic rhinitis. Vitamin C alone (P = 0.039).
Nwawolo, C. C.,
Olusesi, A. D. Vitamin C Loratadine was significantly better than chlorpheniramine (P
(2001)[37] = 0.046).
Drowsiness was noted in 19.2% of patients on loratadine

compared with 57.1% of patients on chlorpheniramine.
Efficacy and safety Randomized Twenty- Loratadine 0.11-0.24 Safety and effica Both loratadine and dexchlorpheniramine were effective in
of loratadine controlled trial one children with mg/kg ideal body cy of loratadine reducing nasal and ocular symptoms in allergic children.
suspension in the allergic rhinitis weight once daily compared to
treatment of children dexchlorphenira Substantial improvement in allergy symptoms was observed at
with allergic rhinitis. Dexchlorpheniramine mine in children. the first evaluation (day 3 of treatment) and was maintained
Boner, A.L. (1989) 0.10-0.23 mg/kg every for the study duration.
[38] 8h
No abnormality in lab parameters was observed.
for 14 days
Drowsiness was present only in the dexchlorpheniramine-
treated group.
Central nervous Rrandomized, 15 healthy elderly Cetirizine 10 mg, To compare Performance was affected by FGAH more than SGAH in
system effects of H1- double-blind, single- subjects (mean age effects of study increasing to decreasing order as follow: chlorphenamine >
receptor antagonists dose, placebo- 71 +/- 5 years) Loratadine 10 mg, medications on diphenhydramine > loratadine > placebo > cetirizine.
in the elderly. controlled, 5-way performance,
Simons, F. E., et al., crossover study Diphenhydramine 50 somnolence, and Somnolence ranked from more to less with medications as
(1999) [25] mg, peripheral H1- follows: diphenhydramine > chlorphenamine > cetirizine >
blockade. loratadine > placebo.
Chlorphenamine 8 mg,
or All H1-receptor antagonists suppressed the histamine-induced
wheal and flare significantly compared to placebo.
Placebo
Benefit/risk ratio of Double-blind, 15 children with Terfenadine 60 mg, To compare Both terfenadine and chlorphenamine suppressed the
the antihistamines single-dose, allergic rhinitis effects of study histamine-induced wheal and flare compared with baseline
(H1-receptor placebo-controlled, (mean age, 8.5 +/- Chlorphenamine, 4 medications on and with placebo; terfenadine was significantly more effective
antagonists) three-way crossover 1.4 years) mg, or performance, (p < 0.05).
terfenadine and study somnolence, and
chlorpheniramine in Placebo peripheral H1- Terfenadine did not impact performance in contrast to
children. blockade chlorphenamine and placebo.
Page 15 of 63
Simons, F. E., et al.,
(1994) [39] Terfenadine and placebo did not increase somnolence
compared with baseline, but chlorphenamine did.
Cetirizine versus Multicenter, 188 patients at least Cetirizine 10 mg once To compare the Cetirizine and hydroxyzine had a significant reduction in
hydroxyzine and randomized, double- 12 years of age, daily, safety and urticaria symptoms of lesions and pruritus at weeks 1, 2, and 3
placebo in chronic blind, double- with symptomatic efficacy of compared to placebo (p<0.04).
idiopathic urticaria. dummy, placebo- chronic idiopathic Hydroxyzine 25 mg cetirizine with
Breneman, D. L. controlled urticaria that had three times daily, or that of Both agents showed significant improvement in urticaria
(1996) [40] occurred hydroxyzine and symptoms at the end of 4 weeks compared to placebo group (p
episodically for at Placebo for 4 weeks placebo in the < 0.001).
least 6 weeks. treatment of
chronic 4 patients in the hydroxyzine group, 1 patient in the cetirizine
idiopathic group, and 1 patient in the placebo group discontinued the
urticaria. study because of sedation.
Urticaria: clinical Multicenter, double- Patients with Cetirizine 5 to To evaluate Cetirizine was equivalent in efficacy to hydroxyzine.
efficacy of cetirizine blind, placebo- chronic urticaria 20mg/day, safety and
in comparison with controlled efficacy of The incidence of somnolence in the cetirizine group was not
hydroxyzine and Hydroxyzine 25 to cetirizine significantly different from that of the placebo group.
placeb. 75mg/day compared to
Kalivas J, et al. hydroxyzine in In the hydroxyzine group, the incidence of somnolence was
(1990) [44] or Placebo for 4 weeks treatment of significantly higher than that in the placebo group (p = 0.001).
urticaria
Cetirizine has a greater safety margin over hydroxyzine.
Page 16 of 63
4. Treatment of selected common conditions with FGAH and SGAH
A. Allergic Rhinitis
Allergic rhinitis is a common condition affecting up to 30% of adults and 40% of
children worldwide and complicating asthma management in up to 90% asthmatics who
also suffer from allergic rhinitis.[29, 45] Allergic rhinitis has tremendous effect on a
patient’s quality of life; it can impact social life, sleep, academics and work and
contribute to substantial indirect economic impact.[32] FGAHs are widely used in adults
and children for management of allergic rhinitis.[35] Several classes of medications are
used for the treatment of allergic rhinitis including antihistamines, corticosteroids, mast
cell stabilizers, decongestants, nasal anticholinergics and leukotriene-receptor
agonists.[46] Inhaled glucocorticosteroids are considered to be the most effective
medications for the treatment of allergic rhinitis in both adults and children.[32, 47]
SGAHs are the preferred and recommended medications by multiple guidelines,
including guidelines developed in collaboration with WHO, as the first-line treatment
option for allergic rhinitis; and due to the adverse effects and safety concerns of FGAHs,
guidelines recommend that FGAHs should be avoided.[4, 32, 46, 48-51] The GRADE
recommendation for use of SGAHs in AR is strong.[46] Table 5 below summarizes
guidelines and their recommendations for the use of SGAHs while avoiding use of
FGAH for this indication, limiting their usefulness.
Table 6 below summarizes the RCT data showing efficacy of SGAHs for the treatment of
AR, including as compared to FGAHs. Although there is a lack of data to determine
substantial differences within distinct chemicals in SGAH class, but they appear to be
equally effective and safe.[2, 3] However, a 28-day prospective, randomized, double-
blind, parallel-group studied efficacy of loratadine versus cetirizine in 80 children 2 to 6
years of age, with perennial allergic rhinitis and found that while both treatments were
effective, cetirizine provided significant, greater relief for symptoms of rhinorrhea,
sneezing, nasal obstruction and nasal pruritus compared to loratadine.[52] A post hoc
analysis of a multi-center, randomized, placebo-controlled, double-blind, double-dummy
study comparing loratadine and fexofenadine in 835 seasonal allergic rhinitis patients
between 12 and 60 years old found that loratadine was significantly more effective in
providing relief over fexofenadine by day 2 of treatment period; possibly indicating faster
clinical onset of loratadine.[53]
Page 17 of 63
Table 5: Guidelines on Treatment of Allergic Rhinitis
Guidelines Treatment of AR Evidence Level and

Recommendation
Allergic Rhinitis and its Impact on Asthma First line therapy: 2nd GRADE: strong recommendation with
(ARIA) guidelines: 2010 Revision [46] generation antihistamine low-quality evidence
International Primary Care Respiratory 2nd generation Strong Evidence for efficacy:
Group (IPCRG) Guidelines: management of antihistamines preferred provided by generally consistent
allergic rhinitis. 2006 [51] therapy findings on multiple, high quality
scientific studies.
British Society for Allergy and Clinical First line therapy: 2nd Recommendation level: A (High)
Immunology (BSACI) Standards of Care generation antihistamine
Committee guideline on the management of
allergic and non-allergic rhinitis (2010) [50]
Page 18 of 63
Table 6: Efficacy and safety of SGAH in Allergic Rhinitis
Efficacy and safety of SGAH in Allergic Rhinitis

Double-blind, Multicenter, double- 722 adults with Fexofenadine 120 mg Compared Both doses of fexofenadine were superior to placebo in
placebo-controlled blind, parallel- seasonal allergic once daily, the efficacy and reducing the total symptom score.
study comparing the group, placebo- rhinitis safety of fexofen
efficacy and safety of controlled trial Fexofenadine 180 mg adine (120 and 1 Efficacy was maintained for 24 hours.
fexofenadine once daily, or 80mg once daily)
hydrochloride and cetirizine (10 There were no differences in efficacy between the 2 doses
(120 and 180 mg onc Cetirizine 10 mg once daily) of fexofenadine or between either dose of fexofenadine
e daily) and cetirizine mg once daily (active in the treatment and cetirizine.
in seasonal allergic control) of seasonal
rhinitis. allergic rhinitis. There was no major side effect, but the combined incidence of
Howarth, P. H., et Placebo, for 14 days drowsiness or fatigue was greater with cetirizine (9%) than
al. (1999)[54] with placebo (4%) (P =.07) or fexofenadine (4%) (P =.02).
Comparison of the Multinational, 688 adults with Fexofenadine 120 mg Compared Both fexofenadine (both P ≤ 0.0001) and loratadine (P ≤ 0.001
efficacy, safety and double-blind, seasonal allergic once daily, efficacy, safety a and P ≤ 0.005, reduced symptoms of seasonal allergic rhinitis
quality of life randomized, placebo rhinitis nd impact compared with placebo (n = 639).
provided by -controlled, parallel Loratadine 10 mg once on quality of
fexofenadine group study daily, or life (QoL) Fexofenadine was found to better than loratadine in improving
hydrochloride 120 in seasonal 24-h reflective itchy, watery, red eyes, as well as relieving
mg, loratadine 10 mg Placebo, once daily, allergic rhinitis nasal congestion (P ≤ 0.05). Fexofenadine was also
and placebo for 14 days patients (SAR) significantly better than loratadine (P ≤ 0.03) and placebo (P ≤
administered once of fexofenadine a 0.005) in improving QoL, and the differences were of a
daily for the nd loratadine (wi magnitude considered to be clinically relevant.
treatment of seasonal th placebo),
allergic rhinitis. when administer Loratadine did not have statistically significant effect on QoL
Van Cauwenberge, ed once daily. compared with placebo.
P., Juniper E. R.
(2000)[55] The incidence of adverse events was low and similar across
all treatment groups.
Controlled clinical Randomized 64 Nigerian Loratadine + Vitamin To assess Loratadine was significantly better than Vit. C. alone (P =
study of the efficacy controlled trial patients with C efficacy and 0.0002).
of loratadine in allergic rhinitis tolerance of
Nigerian patients Chlorphenamine + loratadine Chlorpheniramine was also significantly better than Vit. C.
with allergic rhinitis. Vitamin C alone (P = 0.039).
Nwawolo, C. C.,
Olusesi, A. D. Vitamin C Loratadine was significantly better than chlorpheniramine (P
(2001)[37] = 0.046).
Drowsiness was noted in 19.2% of patients on loratadine

compared with 57.1% of patients on chlorpheniramine.
Loratadine provides Multi-center, 835 patients aged Loratadine 10mg once Evaluate efficacy Significantly greater mean reductions from baseline were
Page 19 of 63
early symptom randomized, 12-60 years with a daily of loratadine shown with loratadine compared with fexofenadine in average
control in seasonal placebo-controlled, 2 years or longer versus daily, total symptom score on days 2 (-3.51 versus -2.84,
allergic rhinitis. double-blind, double history of seasonal Fexofenadine 60mg fexofenadine and respectively; p < 0.002).
Kaiser HB, et al. dummy study (Post allergic rhinitis twice daily placebo in
(2008) [53] hoc analysis) treatment of Loratadine was significantly more effective than placebo for
or Placebo for 7 days allergic rhinitis. all time points (p < 0.001).
Early, sustained symptom relief was seen with loratadine,

suggesting that it may be more effective for treating SAR
symptoms.
Efficacy and safety Randomized Twenty- Loratadine 0.11-0.24 Safety and effica Both loratadine and dexchlorpheniramine were effective in
of loratadine controlled trial one children with mg/kg ideal body cy of loratadine c reducing nasal and ocular symptoms in allergic children.
suspension in the allergic rhinitis weight once daily ompared to
treatment of children dexchlorphenira Substantial improvement in allergy symptoms was observed at
with allergic rhinitis. Dexchlorpheniramine mine in children. the first evaluation (day 3 of treatment) and was maintained
Boner, A.L. (1989) 0.10-0.23 mg/kg every for the study duration.
[38] 8h
No abnormality in lab parameters was observed.
for 14 days
Drowsiness was present only in the dexchlorpheniramine-
treated group.
Comparison of the Randomized, single- 41 children (30 Loratadine 10 mg (5 Evaluate the A significant improvement (p<0.01) in allergy symptoms was
effects of loratadine blind, parallel-group boys and 11 girls, mg in patients with efficacy and observed from the third day for both medications;
and astemizole in the study aged 6-14 years) body weight less than safety of a once-
treatment of children with seasonal or equal to 30 kg) once daily dose of There was no significant difference between medications,
with seasonal allergic daily loratadine and although loratadine led to a greater reduction in symptoms.
allergic rhinoconjunctivitis. astemizole
rhinoconjunctivitis . Astemizole 2 mg/10 Therapeutic response in loratadine group was 83.3% and in
Boner AL, et al. kg body weight once astemizole group was 58.8%.
(1992) [56] daily for 14 days
9 of the children on astemizole and 4 children on loratadine
complained of side effects; 3 patients in the astemizole group
were withdrawn from treatment because of adverse effects.
No abnormal changes in lab values were observed in either

group
A comparative study Randomized, third- 96 children 3- to 6- Loratadine 5mg once Evaluate the Both treatments were effective in relieving individual nasal
of the efficacy and party-blind, year-old children daily, efficacy and and nonnasal symptoms. There were no statistically
safety of loratadine placebo-controlled, safety of significant differences between the two groups in the total
syrup and parallel-group study Loratadine 10mg once loratadine and symptom scores at any point during the study.
terfenadine daily, terfenadine
suspension in the Therapeutic response to loratadine 82% and to terfenadine
treatment of 3- to 6- Terfenadine 15mg, was 60%.
year-old children twice daily, for 14
Page 20 of 63
with seasonal days. Adverse events were not significantly different between the
allergic rhinitis. two treatment groups.
Lutsky BN, et al.
(1993)[57] There were no reports of sedation or dry mouth in either
group.
A double-blind, The aim of this 60 children 3 to 12 Loratadine syrup 5 mg Evaluate the The total symptom score (TSS) (comprising of sneezing,
placebo controlled, double-blind, years old with effectiveness and rhinorrhea, nasal congestion, nasal itching and ocular
and randomized placebo-controlled, allergic rhinitis Loratadine syrup 10 safety of symptoms) of the loratadine syrup group at day 7 and day 21
study of loratadine parallel, randomized mg daily, loratadine syrup was lower than those of the placebo group (p = 0.003, p =
(Clarityne) syrup for study 0.06).
the treatment of Or placebo for 3
allergic rhinitis in weeks. No adverse reactions were recorded in both groups.
children aged 3to 12
years. Yang YH, et
al. (2001)[58]
Fexofenadine is Multinational, 935 children, 6-11 Fexofenadine 30 mg Assess the Fexofenadine was significantly superior to placebo to reduce
efficacious and safe randomized, years of age with twice daily efficacy and symptoms of allergic rhinitis (p ≤0.0001).
in children (aged 6- placebo-controlled, seasonal allergic safety of
11 years) with parallel-group, rhinitis or placebo twice daily fexofenadine in Reduction is individual symptom scores was superior
seasonal allergic double-blind study for 14 days. children with compared with placebo (p <.05), including nasal congestion (p
rhinitis. Wahn U, et seasonal allergic <.05).
al. (2003) [59] rhinitis.
There was no significant difference in adverse events between
fexofenadine and placebo.
The efficacy and Multi-center, open- 100 Asian Fexofenadine 30 mg Evaluate efficacy With fexofenadine, there was a statistically significant
safety of 30 mg label, non- (Thailand) twice-daily and safety of a improvement for the total symptom score with or without
fexofenadine HCl bid comparative study children, 6-11 twice-daily oral blocked nose and for each symptom score such as blocked
in pediatric patients years of age dose of nose, sneezing, rhinorrhea, itchy nose/palate and/or throat, and
with allergic rhinitis. diagnosed with fexofenadine itchy/watery/red eyes from baseline to week 1 and week 2. (p
Ngamphaiboon J, et seasonal or < 0.01)
al. (2005)[60] perennial allergic
rhinitis.
Cetirizine for Multi-center, 107 children of Cetirizine drops 5mg Evaluate the Cetirizine was more effective than placebo for each symptom
seasonal allergic double-blind, both sexes between once daily safety and evaluated (p=0.04) Cetirizine provided more symptom free
rhinitis in children placebo-controlled, 2 and 6 years of efficacy of days than did placebo (p = 0.002).
aged 2-6 years. parallel group study age with pollen- or placebo once daily cetirizine
Allegra L, et al. induced seasonal for 14 days Both treatments were tolerated well. 3 patients on cetirizine
(1993)[61] allergic rhinitis and none on placebo experienced mild somnolence.
A placebo-controlled Multi-center, 124 children of Cetirizine 5mg twice Assessment of Cetirizine provided more mean symptom free days than did
trial of cetirizine in double-blind, both sexes aged daily, efficacy of placebo, 56.2% and 29.7%, respectively. This 26.5%
seasonal allergic placebo-controlled, between 6 and 12 cetirizine difference was considered clinically significant.
rhino-conjunctivitis parallel group study years with pollen- or placebo twice daily
Page 21 of 63
in children aged 6 to associated rhino- for 14 days Improvement in individual daily symptoms was greater for
12 years. Masi M, et conjunctivitis cetirizine than placebo.
al. (1993)[62]
Once-daily Randomized, 209 children, 6 to Cetirizine syrup (5 or Evaluate the Cetirizine 10 mg produced a significantly greater mean total
cetirizine effective in double-blind, 11 years of age 10 mg daily) safety and symptom severity (TSS) reduction than placebo (P < 0.05)
the treatment of placebo-controlled with seasonal efficacy of over the treatment period.
seasonal allergic trial allergic rhinitis or placebo for 4 weeks cetirizine syrup
rhinitis in children Cetirizine 5 mg once daily produced mean reductions in
aged 6 to 11 years: a weekly TSS, however, this did not differ statistically from
randomized, double- placebo.
blind, placebo-
controlled study. The most commonly reported adverse reactions to both
Pearlman DS, et al. cetirizine and placebo were headache, pharyngitis, and
(1997)[63] abdominal pain; these incidences were not statistically
between treatment and placebo.
The health related Multicenter, open- 544 children, 6 to Cetirizine syrup 10 mg Assessment of Cetirizine provided significant improvements in HRQL in all
quality of life effects label, non- 11 years of age once daily for 4 weeks health-related age groups (6-7, 8-9, 10-11 years) (p < 0.001) during the
of once-daily comparative study with seasonal quality of life treatment period.
cetirizine HCl syrup allergic rhinitis (HRQL)
in children with
seasonal allergic
rhinitis. Gillman SA,
et al. (2002)[64]
Double-blind prospective, 80 children, 2 to 6 Cetirizine 0.2mg/kg Evaluate Cetirizine produced significantly greater inhibition of the
comparison of randomized, double- years of age, with comparative wheal response compared with loratadine (P <.0001)
cetirizine and blind, longitudinal, perennial allergic Loratadine 0.2mg/kg efficacy and
loratadine in parallel-group study rhinitis safety of Cetirizine and loratadine produced comparable improvements
children ages 2 to 6 for 28 days cetirizine and in symptoms
years with perennial loratadine.
allergic rhinitis. Cetirizine was more effective than loratadine in relieving the
Sienra-Monge, J.J., symptoms of rhinorrhea, sneezing, nasal obstruction, and
et al. (1999)[52] nasal pruritus (P <. 0001)
Both treatments were well tolerated; 2 patients in cetirizine

group withdrew from the study due to adverse events
Page 22 of 63
B. Urticaria
Urticaria is a group of diseases which result from a large variety of underlying causes and
can be induced by a diverse range of factors, and with variable clinical presentation,
generally with wheals and hives.[14, 29] The goal of the treatment for all presentations of
urticaria is the same – complete symptom relief. However, given the idiopathic nature of
most urticaria cases, the treatment generally consists of symptomatic relief with
pharmacotherapy and avoidance of inducing triggers.[13, 14, 65] Recommended first line
treatment agents are SGAH such as loratadine, cetirizine and fexofenadine, with
diphenhydramine and chlorphenamine as adjunct treatments.[4, 10, 13, 14, 65] The
evidence for efficacy and safety of SGAHs in treating urticaria or cutaneous histamine
reactions in reviews and RCTs is well established as reduction in pruritus and number of
wheals following SGAH treatment.[3, 25, 39, 40, 44, 65-73]
The quality of evidence for treating acute urticaria with SGAH is low; however, the
recommendation for the intervention is strong.[14] For the treatment of chronic urticaria
with a SGAH the level of evidence is high and the recommendation for the intervention is
strong.[2] A review using GRADE criteria found high quality of evidence with a strong
recommendation for the efficacy and safety of SGAHs in treatment of chronic
urticaria.[2] SGAHs have similar efficacy in treatment of chronic urticaria as their
predecessors, FGAHs, with reduced side-effect burden.[3, 74] A double-blind RCT
showed that fexofenadine was more effective at penetrating the skin than
diphenhydramine, therefore, likely able to provide more effective activity on H-1
receptors in the skin.[75] Another double-blind RCT compared fexofenadine, loratadine
and chlorphenamine and found higher distribution of SGAHs in the skin and their
superiority in suppression of wheals and flares compared to FGAH.[76] However, a
literature review concluded that both first and second generation antihistamines appear to
have similar efficacy in treatment of chronic urticaria.[3] And a 4-week multicenter,
randomized, double-blind, double-dummy, placebo-controlled safety and efficacy study
comparing cetirizine 10mg once daily and hydroxyzine (a FGAH) 25mg three times
daily, found the two treatments to be equally effective in reduction resolution for chronic
urticaria compared to placebo.[40] However, the study found a significant difference in
reduction of urticaria and pruritus episodes within 1 day of cetirizine treatment compared
to hydroxyzine and placebo.[40]
Table 7 below summarizes guidelines recommendations and Table 8 below provides

details of RCTs evaluating efficacy and safety of treatment of urticaria with SGAH
versus controls.
Page 23 of 63
Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria
Guidelines/Systematic Review Treatment of Urticaria Evidence Level and Recommendation

EAACI/GA2LEN/EDF/WAO First line therapy: 2nd GRADE: Strong recommendation with low-
guideline: management of urticaria generation antihistamine quality evidence
(2009)[14]
Avoid 1st generation GRADE: Strong recommendation with high
antihistamines quality evidence
Second-generation H1- 2nd generation GRADE: Strong recommendation with high
antihistamines in chronic urticaria: antihistamines quality evidence
an evidence-based review.
Kavosh, E. R. and Khan, D. A.
(2011) [2]
Page 24 of 63
Table 8: Efficacy and Safety of SGAHs in Urticaria
Efficacy and Safety of SGAHs in Urticaria

Central nervous Randomized, 15 healthy elderly Cetirizine 10 mg, To compare effects of study Performance was affected by FGAH more than
system effects of double-blind, subjects (mean medications on performance, SGAH in increasing to decreasing order as follow:
H1-receptor single-dose, age 71 +/- 5 years) Loratadine 10 mg, somnolence, and peripheral H1- chlorphenamine > diphenhydramine > loratadine >
antagonists in the placebo- blockade. placebo > cetirizine.
elderly. Simons, controlled, 5- Diphenhydramine 50
F. E., et al., way crossover mg, Somnolence ranked from more to less with
(1999) [25] study medications as follows: diphenhydramine >
Chlorphenamine 8 chlorphenamine > cetirizine > loratadine > placebo.
mg, or
All H1-receptor antagonists suppressed the histamine-
Placebo induced wheal and flare significantly compared to
placebo.
Benefit/risk ratio Double-blind, 15 children with Terfenadine 60 mg, To compare effects of study Both terfenadine and chlorphenamine suppressed the
of the single-dose, allergic rhinitis medications on performance, histamine-induced wheal and flare compared with
antihistamines placebo- (mean age, 8.5 +/- Chlorphenamine, 4 somnolence, and peripheral H1- baseline and with placebo; terfenadine was
(H1-receptor controlled, 1.4 years) mg, or blockade significantly more effective (p < 0.05).
antagonists) three-way
terfenadine and crossover study Placebo Terfenadine did not impact performance in contrast to
chlorpheniramine chlorphenamine and placebo.
in children.
Simons, F. E., et Terfenadine and placebo did not increase somnolence
al., (1994) [39] compared with baseline, but chlorphenamine did.
Cetirizine versus Multicenter, 188 patients at Cetirizine 10 mg once To compare the safety and efficacy Cetirizine and hydroxyzine had a significant
hydroxyzine and randomized, least 12 years of daily, of cetirizine with that of reduction in urticaria symptoms of lesions and
placebo in double-blind, age, with hydroxyzine and placebo in the pruritus at weeks 1, 2, and 3 compared to placebo
chronic double-dummy, symptomatic Hydroxyzine 25 mg treatment of chronic idiopathic (p<0.04).
idiopathic placebo- chronic idiopathic three times daily, or urticaria.
urticaria. controlled urticaria that had Cetirizine reduced symptoms of urticaria after one
Breneman, D. L. occurred Placebo for 4 weeks day of treatment over hydroxyzine. (p=0.002).
(1996) [40] episodically for at
least 6 weeks. Both agents showed significant improvement in
urticaria symptoms at the end of 4 weeks compared to
placebo group (p < 0.001).
4 patients in the hydroxyzine group, 1 patient in the

cetirizine group, and 1 patient in the placebo group
discontinued the study because of sedation.
A double-blind, Multicenter, 439 patients with Fexofenadine 20, 60, Evaluate the safety and efficacy of All 4 doses of fexofenadine were statistically superior
placebo- placebo- moderate to severe 120, or 240 mg twice fexofenadine for the treatment of to placebo (P ≤ 0.0238) in relieving symptoms of
controlled trial of controlled pruritus and daily chronic urticaria symptoms. urticaria.
Page 25 of 63
fexofenadine HCl study urticaria
in the treatment or Placebo for 4 Less interference with sleep and daily activities was
of chronic weeks observed with fexofenadine over placebo (P
idiopathic ≤0.0001).
urticaria.
Finn AF Jr, et al. Efficacy results were similar in the 60, 120, and 240-
(1999) [72] mg groups and were quantitatively better than those
in the 20mg group.
Adverse events were mild and occurred with similar

incidence in all treatment groups.
Doses of 60 mg twice a day or greater are most

effective.
Fexofenadine Multi-center, 418 patients with Fexofenadine 20, 60, Assess safety and efficacy of All four fexofenadine doses were statistically superior
HCl is safe and double-blind, urticaria 120, or 240 mg twice fexofenadine in chronic idiopathic to placebo (P ≤ 0.0115) for reducing pruritus and
effective for randomized, daily urticaria. number of wheals scores over the 4-week treatment
treatment of placebo- period.
chronic controlled or Placebo for 4
idiopathic study weeks Greater reductions in urticaria symptoms occurred
urticaria. with 60, 120 and 240 mg fexofenadine groups than in
Nelson HS, et al. the 20 mg group.
(2000) [73]
Less interference with sleep and daily activities was
observed with fexofenadine versus placebo (P ≤
0.0014).
Adverse events occurred with similar incidence in all

treatment groups, with no dose-related increases in
any event.
Fexofenadine, twice-daily doses of 60 mg or greater

were most effective.
A comparison of Double-blind, 30 patients with Cetirizine 10 mg once Evaluate the efficacy of cetirizine Cetirizine was more effective than terfenadine in
the efficacy of randomized, chronic idiopathic daily and terfenadine in chronic controlling urticaria symptoms. Symptoms assessed
cetirizine and parallel study urticaria idiopathic urticaria on a 4-point scale showed a better improvement in the
terfenadine: a or Terfenadine 60 mg cetirizine group.
double-blind, twice daily for 20
controlled study days The number and severity of side-effects were similar
of chronic in both treatment groups.
idiopathic
urticaria
Andri L, et al.
(1993)[69]
Page 26 of 63
Cetirizine and Multicenter, 187 total patients Cetirizine 10mg once Compare the efficacy of cetirizine Both cetirizine and astemizole were significantly
astemizole randomized, with chronic daily and astemizole in relieving the superior to placebo in relieving symptoms of chronic
therapy for double-blind idiopathic symptoms of chronic idiopathic idiopathic urticaria with more rapid clinical benefit
chronic trial urticaria; Astemizole 10mg urticaria with cetirizine.
idiopathic once daily
urticaria: a 180 included in Both active treatments were well tolerated, and the
double-blind, the safety analysis or Placebo for 4 incidence of somnolence did not differ statistically
placebo- and 177 included weeks between cetirizine (14.5%) and astemizole (10.3%).
controlled, in efficacy
comparative trial. analysis
Breneman D, et
al. (1995)[70]
Urticaria: clinical Multicenter, Patients with Cetirizine 5 to To evaluate safety and efficacy of Cetirizine was equivalent in efficacy to hydroxyzine.
efficacy of double-blind, chronic urticaria 20mg/day, cetirizine compared to hydroxyzine
cetirizine in placebo- in treatment of urticaria The incidence of somnolence in the cetirizine group
comparison with controlled Hydroxyzine 25 to was not significantly different from that of the
hydroxyzine and 75mg/day placebo group.
placeb.
Kalivas J, et al. or Placebo for 4 In the hydroxyzine group, the incidence of
(1990) [44] weeks somnolence was significantly higher than that in the
placebo group (p = 0.001).
Cetirizine has a greater safety margin over

hydroxyzine.
Randomized Randomized, 160 patients aged Desloratadine 5mg Evaluate the efficacy of 5 mg of Treatment groups significantly reduced number of
placebo- double-blind, 18 to 69 years once daily (n = 40), desloratadine administered once hives and size of largest hive compared to placebo.
controlled trial double-dummy, (mean +/- SD, daily either as monotherapy or
comparing placebo- 43.9 +/- 13.4 Montelukast 10mg combined with a leukotriene Only groups receiving desloratadine significantly
desloratadine and controlled, years) with a once daily (n = 40), antagonist, 10 mg of montelukast reduced pruritus.
montelukast in parallel-group history of daily, and 10 mg of montelukast
monotherapy and study moderate chronic Desloratadine 5mg (n administered daily as monotherapy There were no significant differences between the
desloratadine idiopathic urticaria = 40) in the morning for the treatment of patients group treated with montelukast alone and the placebo
plus montelukast plus montelukast in affected by CIU with placebo. group for pruritus and size of largest hive.
in combined the evening,
therapy for 27 of the 40 patients in the montelukast group and 35
chronic or matched placebo (n of the 40 patients in the placebo group discontinued
idiopathic = 40). the treatment. No patients in the desloratadine study
urticaria. discontinued the study.
Di Lorenzo G, et
al. (2004) [71]
Page 27 of 63
C. Anaphylaxis (adjunct)
Anaphylaxis is a severe, life-threatening condition resulting from exposure to an
allergen that causes a systemic allergic reaction and has the potential to cause
death by compromising the pulmonary and cardiovascular systems.[12, 77-79]
The response to the allergen itself is intense and widespread resulting in
involvement of dermatologic, respiratory, cardiovascular, gastrointestinal, and
nervous systems. Treatment of this condition is an absolute necessity to prevent
loss of life.[12, 77-79] Antihistamines have been in use for adjunctive treatment
of anaphylaxis since before the advent of evidence based practice. FGAHs,
specifically diphenhydramine and chlorphenamine, due to their availability as
parenteral formulations, have been used widely and they continue to be listed on
guidelines as adjunctive treatment.[19, 80-83] When considering the use of
antihistamines in anaphylaxis, the World Allergy Organization states that:
“In anaphylaxis, H1-antihistamines relieve itching, flushing, urticaria,

angioedema, and nasal and eye symptoms; however, they should not be
substituted for epinephrine because they are not life-saving; that is, they
do not prevent or relieve upper airway obstruction, hypotension, or shock.
Some guidelines do not recommend H1-antihistamine treatment in
anaphylaxis, citing lack of supporting evidence from randomized
controlled trials that meet current standards. Others recommend various
H1-antihistamines in various intravenous and oral dosing regimens.
... There are concerns about their slow onset of action relative to
epinephrine, and about potential harmful central nervous system effects,
for example, somnolence and impairment of cognitive function caused by
first-generation H1-antihistamines given in usual doses." [19]
Other published literature agrees with the World Allergy Association in stating
that while H-1 antagonists, both FGAHs and SGAHs, may be useful in controlling
cutaneous manifestations of anaphylaxis, there is no direct outcome data showing
the effectiveness of antihistamines in anaphylaxis.[80, 81] Furthermore,
epinephrine has far more clinical evidence to support its use over H-1
antihistamines in treatment of anaphylaxis.[16] And while H-1 antihistamines are
useful for relieving itching and urticaria, they do not relieve stridor, shortness of
breath, wheezing, GI symptoms, or shock.[16]
A Cochrane review concluded that there is no evidence from RCTs for the use of
H-1 antagonists in treatment of anaphylaxis.[82] Additionally, as discussed
previously in this document, FGAHs are notorious for causing sedation and
cognitive and psychomotor impairment, these side-effects may contribute to
decreased awareness of anaphylaxis symptoms.[16] Guidelines state that if use of
Page 28 of 63
an H-1 antagonist is indicated in this setting, an alternative dosing with a less-
sedating, oral SGAH such as cetirizine, may be recommended given its relatively
rapid onset of action.[16]
In the management of anaphylaxis in children, the European Academy of

Allergology and Clinical Immunology, recommends that an H-1 antagonist,
ideally in the liquid form and non-sedating, should be administered, but
acknowledges lack of evidence for efficacy in anaphylaxis and supports use of
epinephrine as first line therapy.[81] However, in a community setting, the
Academy recommends the use of an H-1 antagonist syrup at the first signs of an
allergic reaction.[81] All non-sedating SGAHs considered in this discussion have
a syrup formulation. However, only diphenhydramine and chlorphenamine have
parenteral formulations.[81]
The above discussion illustrates not only the lack of evidence and support for use
of H-1 antagonist in anaphylaxis, but also shows that if it is to be used, a non-
sedating SGAH may be used as well unless a parenteral formulation is indicated.
5. Safety Profile of Antihistamines

Table 9 below lists a side-by-side comparison of major side-effects observed with
antihistamine agents by class. Due to the multiple functions of H-1 receptor, the use anti-
histamine agents leads to many desired therapeutic and undesired side-effects.[7, 25, 35,
84] As mentioned above, the FGAHs, such as diphenhydramine and chlorphenamine, are
lipophilic molecules, a chemical property that allows them to cross the blood-brain
barrier resulting in the observed central nervous system side-effects such as drowsiness,
somnolence, reduced mental alertness, and impaired memory and motor performance.
Furthermore, it is important to note that these side effects are present with lowest and
therapeutic doses of FGAHs as recommended by the manufacturers.[35, 85] Positron
emission tomography studies have confirmed that FGAHs can occupy between 45% and
70% of brain H-1 receptors and lead to prolonged effects on performance impacting daily
activities.[86, 87] These agents also lack specificity for the H1 receptor and have
significant anti-muscarinic, anti-alpha-adrenergic and anti-serotonin effects leading to
symptoms such as mydriasis, photophobia, and diplopia, xerostomia, tachycardia,
constipation, urinary retention, agitation, and confusion. Conversely, SGAH have
reduced capacity to cross the blood-brain barrier and exhibit a greater specificity for
the H1 receptor, limiting the frequency and the magnitude of the side-effects observed
with FGAH. Second-generation H1 receptor antagonists such as cetirizine, loratadine and
fexofenadine provide good selective H1 receptor blockade without anticholinergic or
alpha-adrenergic or serotonergic antagonist activity. [3-5, 8, 15, 18, 23-26, 39, 42, 84, 88-
99]
Page 29 of 63
With specific attention to the sedation side-effect, a double-blind RCT determined effects
of diphenhydramine (FGAH), fexofenadine (SGAH) or alcohol on 40 licensed drivers
with seasonal allergic rhinitis.[100] The study found slower response time with alcohol
and diphenhydramine than with fexofenadine. Furthermore, the study established that
diphenhydramine caused greater impairment in driving than did alcohol.[100] Additional
studies have found that FGAHs, specifically chlorphenamine and diphenhydramine, are
also associated with loss of productivity in the workplace, injuries and deaths in both
aviation and traffic related accidents.[101-104] In fact, the International Civil Aviation
Organization recommends that aircraft operators requiring antihistamine medications be
treated with a non-sedating SGAH such as fexofenadine or loratadine.[35] While SGAHs
are widely regarded as non-sedating, it is possible for sedation to occur with these agents
when their maximum recommended doses are exceeded.[4, 90, 105, 106] A double-blind,
cross-over trial comparing impairment of driving performance with cetirizine 10mg,
loratadine 10mg or placebo, concluded that at these doses, cetirizine has the potential to
cause mild impairment of performance but not loratadine.[107] Table 10 below
summarizes several studies providing evidence on sedation properties of FGAHs and
comparisons to SGAHs.
Furthermore, chlorphenamine and diphenhydramine are capable of increasing dopamine

activity in the brain, leading to ‘cocaine-like behavioral effects’ when these medications
are abused.[108] FGAH are also implicated in accidental and intentional deaths of
infants, as well as suicides in teenagers and adults.[35, 109] While cardiotoxicity is not a
class effect, significant concerns continue to exist regarding safety of some antihistamine
agents, including high doses of diphenhydramine.[32]
Another venue for side effects results from the significant cytochrome (hepatic) P-450
isozymes mediated metabolism of FGAHs; this makes them exceedingly likely to
participate in or be responsible for clinically relevant drug-drug interactions. For
example, diphenhydramine is a cytochrome 2D6 enzyme inhibitor which can lead to
increased plasma levels of metoprolol, an anti-hypertensive.[110] Appendices 1 and 2 list
detailed drug-drug interactions (DDIs), including severity of interactions for the five
medications reviewed. The medication interaction tables include possible clinically
important interactions and the associated level of documentation. These DDI tables
illustrate the contrast difference between DDIs for FGAHs and SGAHs.
Diphenhydramine and chlorphenamine are concerning for 13 and 6 medication
interactions, respectively; while loratadine, cetirizine and fexofenadine have 2, 1 and 3
interactions, respectively.
Finally, appendices 3 and 4 detail the precautions, contraindications and breast feeding
safety information of both FGAHs and SGAHs. Both diphenhydramine and
chlorphenamine should be avoided during breastfeeding. For SGAHs, loratadine and
fexofenadine are deemed safe for breast-fed infants, while the risk to the infant has not
Page 30 of 63
been elucidated with cetirizine and should be avoided. This data further establish the
superior safety profile of SGAHs.
Given this comparison, it is apparent that SGAHs have a better safety and tolerability
profiles, and have at least similar efficacy compared with FGAHs.
Table 9: Comparative side-effect profile of first and second generation antihistamines
Side-effect 1st Generation Antihistamines 2nd Generation Antihistamines

Central With therapeutic doses may cause drowsiness, fatigue, Adverse effects such as drowsiness
Nervous somnolence, dizziness; impairment of cognitive may occur at higher doses.
System function, memory, and psychomotor performance;
headache, dystonia, dyskinesia, agitation, confusion, and No adverse effects reported in
hallucinations. newborns or nursing infants.
May cause adverse effects in newborns if taken

by mother immediately before parturition; may cause
irritability, drowsiness, or respiratory depression in
nursing infants
Cardiovascular Dose-related sinus tachycardia; reflex tachycardia and No major concern in the United
System supraventricular arrhythmias; dose related prolongation States since regulatory approval
of the QT interval and ventricular arrhythmias reported was withdrawn for astemizole and
for diphenhydramine other 1st generation agents. terfenadine.
Anti- After therapeutic doses, may cause pupillary dilatation, Rare, no major concerns for anti-
Cholinergic dry eyes, dry mouth, urinary retention and hesitancy, cholinergic side-effects.
gastrointestinal motility, constipation, erectile
dysfunction, memory deficits; peripheral vasodilatation,
postural hypotension, dizziness; contraindicated in
patients with glaucoma or prostatic hypertrophy.
Overdose Central nervous system effects — extreme drowsiness, No serious toxic effects or deaths
lethargy, confusion, delirium, and coma in adults; reported.
paradoxical excitation, irritability, hyperactivity,
insomnia, hallucinations, and seizures in infants and
young children; in adults and children, central nervous
system effects predominate over cardiac adverse effects;
death may occur within hours
after ingestion of medicine in untreated patients
Table adapted with modifications from Simons, ER [3]
Page 31 of 63
Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment
Side-effects: Sedation, drowsiness, psychomotor impairment

Effects of Randomized, 40 licensed drivers One dose of To measure coherence, drowsiness Coherence: Participants had significantly better
fexofenadine, double-blind, with seasonal Fexofenadine 60 mg, and other driving measure with coherence after taking alcohol or fexofenadine than
diphenhydramine, double-dummy, allergic rhinitis study medications. after taking diphenhydramine.
and alcohol on four-treatment, between 25 to 44 Diphenhydramine 50
driving four-period years of age. mg, Lane keeping (steering instability and crossing the
performance. A crossover trial. center line) was impaired after alcohol and
randomized, Alcohol diphenhydramine use compared with fexofenadine
placebo-controlled (approximately 0.1% use.
trial in the Iowa blood alcohol
driving simulator. concentration),
Weiler, J.M., et
al., (2000) [100] or Placebo
Central nervous Randomized, 15 healthy elderly Cetirizine 10 mg, To compare effects of study Performance was affected by FGAH more than
mg,
or Placebo induced wheal and flare significantly compared to
placebo.
Benefit/risk ratio Double-blind, 15 children with Terfenadine 60 mg, To compare effects of study Both terfenadine and chlorphenamine suppressed the
of the single-dose, allergic rhinitis medications on performance, histamine-induced wheal and flare compared with
antihistamines placebo- (mean age, 8.5 +/- Chlorphenamine, 4 somnolence, and peripheral H1- baseline and with placebo; terfenadine was
(H1-receptor controlled, 1.4 years) mg, blockade significantly more effective (p < 0.05).
antagonists) three-way
terfenadine and crossover study or Placebo Terfenadine did not impact performance in contrast to
chlorpheniramine chlorphenamine and placebo.
in children.
Simons, F. E., et Terfenadine and placebo did not increase somnolence
al., (1994) [39] compared with baseline, but chlorphenamine did.
Increased risk of A retrospective 12,106 patients N/A Rates of serious injuries in the The rate of all injuries was 308 per 1,000 person-
serious injury cohort study with initial diphenhydramine cohort after and years in the diphenhydramine cohort versus 137 per
following an antihistamine before the first prescription 1,000 person-years in the loratadine cohort.
initial prescription prescription for compared to the rates of injuries in
for diphenhydramine the loratadine cohort after and The percentage of the injuries attributable to
diphenhydramine. and 24,968 before the first prescription. diphenhydramine was 55% (CL 41, 65)
Page 32 of 63
Finkle, W. D., et patients with
al., (2002) [102] initial
antihistamine
prescription for
loratadine.
Prevalence of Retrospective A postmortem Chlorphenamine To detect the presence of There were 47 (2.2%) accidents involving
chlorpheniramine toxicology chlorphenamine in blood and liver chlorphenamine. Of these, 16 had only
in aviation database-- chlorphenamine at 109 ng.ml-1 (n = 4) in blood and
accident pilot maintained at the 1412 ng.g-1 (n = 12) in liver. Other medications were
fatalities, 1991- Civil Aeromedical also present in the remaining 31 cases, but
1996. Soper, J. Institute--was chlorphenamine concentrations were 93 ng.ml-1 (n =
W., et al. (2000) examined for the 18) in blood and 747 ng.g-1 (n = 12) in liver.
[103] presence of
chlorphenamine in 95% of all quantitated blood values were at or above
the fatalities, the therapeutic level. The average blood value was
occurred during approximately 10 times higher than the therapeutic
1991-1996. value.
Chlorphenamine was present in some aviation

fatalities at levels higher than therapeutic levels.
First-generation Retrospective The Civil First generation anti- To detect the presence of one of the Of 5383 fatal aviation accidents reviewed, there were
H1 antihistamines Aerospace histamines: study medications in blood 338 accidents wherein pilot fatalities (cases) were
found in pilot Medical Institute's brompheniramine, found to contain one of the study medications.
fatalities of civil (CAMI's) chlorphenamine,
aviation accidents, Toxicology diphenhydramine, Antihistamines were detected alone in 103 fatalities
1990-2005. Sen, Database was doxylamine, (1 antihistamine in 94 and 2 antihistamines in 9),
A., et al. (2007) examined for the pheniramine, while other drug(s) and/or ethanol were also present
[104] presence of the phenyltoloxamine, in an additional 235 fatalities.
first-generation promethazine, and
antihistamines in triprolidine. The antihistamines were found in approximately 4
pilot fatalities of and 11% of the fatalities/accidents in 1990 and in
civil aircraft 2004, respectively.
accidents that
occurred during a The use of antihistamine(s) was determined by the
16-yr (1990-2005) National Transportation Safety Board to be the cause
period. of 13 and a factor in 50 of the 338 accidents.
Differential Double-blind, 24 healthy adult Terfenadine 60 mg, Assess the latency of the P3- Baseline P3 latency (millisecond) means (+/- mean
cognitive effects randomized, subjects evoked potential with the study standard error) pretreatment was 310 (+/- 1.7).
of terfenadine and three-period Chlorphenamine medications. (The P3 is a
chlorpheniramine. crossover maleate 8 mg, cognitively evoked Post treatment the P3 latencies were for placebo, 313
Meador, K. J., et electroencephalographic response (+/- 3); for terfenadine, 320 (+/- 3); and for
al. (1989) [88] or Placebo that is an objective and sensitive chlorphenamine, 333 (+/- 3).
measure of sustained attention and
cerebral processing speed. Disease Compared to terfenadine, chlorphenamine caused
Page 33 of 63
and drug states that adversely much higher P3 latency. Both medications increased
affect the central nervous system the P3 latency compared to placebo and baseline.
can slow P3 latency.)
Loratadine in the Systematic Pooled: Various doses: Assess sedation and performance Pooled data showed sedation in 25 of 517 patients
high performance Review Adult subjects: Loratadine 10mg, impairment with study given 10 mg of loratadine, and 24 of 510 patients
aerospace 517 treated with 20mg and 40mg medications. given placebo, with a relative risk of 1.03.
environment. loratadine and 510
Hansen, G.R. given placebo or Placebo Patients treated with 10 mg of loratadine did not have
(1999) [106] excess sleepiness induced; patients treated with 40
mg of loratadine did.
Using 10 different methods, 20 studies did not find

performance impairment in subjects given 10 mg of
loratadine.
Two performance studies, digit substitution and

driving, showed impairment with 20 mg and 40 mg of
loratadine, respectively.
Ingesting 10 mg of loratadine daily does not appear to

have sedative effects or impair cognitive-motor
performance.
Effects of 6-way, double- Sixteen healthy Cetirizine 10 mg, Assess driving performance with Alcohol significantly affected almost every
loratadine and blind cross- male and female study medications. performance measure.
cetirizine on over trial Loratadine 10 mg
actual driving and Cetirizine effects on driving performance resembled
psychometric test Alcohol those of alcohol. It caused the subjects to operate with
performance, and significantly greater variability in speed and lateral
EEG during or Placebo position ('weaving' motion).
driving.
Ramaekers, J. G., The effects of alcohol and cetirizine appeared to be
et al. (1992) [107] additive.
Loratadine had no significant effect on any

performance parameter.
It was concluded that cetirizine, but not loratadine,

generally caused mild impairment of performance
after a single 10 mg dose.
Central nervous Rrandomized, 15 healthy elderly Cetirizine 10 mg, To compare effects of study Performance was affected by FGAH more than
Page 34 of 63
mg, or
Placebo induced wheal and flare significantly compared to
placebo.
Page 35 of 63
V. Use of Antihistamines in special populations
1. Elderly
Use of FGAHs in the elderly is not generally recommended due to the side effects
associated with this class of medications.[24, 25, 84, 111, 112] According to the Beers
criteria, a project aimed at using comprehensive, systematic review and grading of the
evidence on drug-related problems and adverse drug events (ADEs) to promote safe use
of medications in older adults, both chlorphenamine and diphenhydramine should be
avoided in the elderly. The warning is issued based on the highly anticholinergic effects
of these agents, combined with reduced clearance with advanced age, leading to a greater
risk of confusion, dry mouth, constipation and toxicity. However, the use of
diphenhydramine in special situations such as acute treatment of severe allergic reaction
can be considered appropriate. Level of evidence for this Beers recommendation is
moderate and the strength of recommendation is high.[112] Furthermore, these agents
should be avoided in patients with chronic constipation unless no other alternatives are
available as it can worsen constipation. Also, these agents should not be used by men
with lower urinary tract symptoms or benign prostatic hyperplasia as it may decrease
urinary flow and cause urinary retention. The strength of recommendation for this is
weak while the quality of evidence is moderate to low.[10, 112]
As discussed above, the SGAHs bypass many of the side effects associated with FGAHs
due to their pharmacology. Therefore, given appropriate indication, education and
directions, SGAHs can be the preferred alternative to FGAHs in the elderly.
2. Children and Infants

FGAHs, in addition to their narrow therapeutic index leading to toxicity and implications
in infant deaths (via accidental overdose and via homicides by caregivers) and suicides in
teenagers and adults, are also responsible for cognitive impairment and disrupted sleep in
children and adults.[4, 35, 109, 113-115] Contraindication for use in children less than
six years of age is particularly important given the warning for such use issued by United
Kingdom’s Medicines and Healthcare products Regulatory Agency following reports of
27 deaths with diphenhydramine and 11 deaths with chlorphenamine.[35, 116] The TGA
has also recommended against the use of diphenhydramine and chlorphenamine in
children under the age of 6 and for children between the years of 6 and 11 should only be
treated with these agents under the guidance of a prescribing clinician.[20] Health
Canada has provided a similar recommendation for “Do not give to children under
6.”[21] WHO guidelines on Breastfeeding and Maternal Medications advise avoiding use
of chlorphenamine due to risk of drowsiness and sedation and possible inhibition of
lactation.[117] Appendices 3 and 4 provide detailed information on breast feeding safety
of these medications. Although detailed data on SGAHs in breastfeeding is limited,
Page 36 of 63
however, pharmacokinetic studies loratadine and terfenadine (active metabolite of
terfenadine is fexofenadine) conducted in lactating women indicate that only minimal
amounts SGAHs is secreted in breast milk.[118, 119] Therefore, use of standard doses of
SGAHs in not likely to produce adverse effects in nursing infants.[4, 118, 119]
The safety of cetirizine in an 18-month long, double-blind, placebo controlled study in

817 children 12 to 24 months of age, has been well established.[120] The study found no
significant differences in the treatment groups for behavior, cognition or physical
development (e.g. did not influence height, body mass, gross and fine motor skills,
speech and language skills) during or after the study duration.[120] Similarly, another
double-blind, placebo controlled 18-month study in children, established safety of
levocetirizine, a SGAH, available by prescription.[36] Another long term, randomized,
placebo controlled study evaluated the efficacy and safety of loratadine for prophylactic
use in respiratory infections. In terms of safety, the 12-month long study confirmed that
compared to placebo, loratadine did not cause sedation and was not associated with
cardiovascular events.[121] Table 11 below summarizes several studies providing
evidence for safety of SGAH use in children and breastfed infants. Table 6 above
provides additional efficacy and safety data for use of SGAHs in children.
SGAHs, specifically loratadine and fexofenadine, are preferred over FGAHs. Citing
proven safety and effectiveness in children, WHO-collaborated guidelines, recommend
use of SGAHs for treatment of allergic rhinitis in children and recommends against the
use of FGAHs due to safety concerns, unless SGAHs are not available.[32] The same is
true for urticaria, where the use of SGAH should be primary option in children.[113] An
advantage, in addition to the low side effect profile, in the treatment of chronic urticaria
SGAHs dose may be escalated up to four times in select patients if the standard dose is
deemed ineffective; this cannot be done with FGAHs due to the possibility of fatal side
effects.[14, 113]
Despite the evidence for harm, child-friendly, flavored liquid formulations of FGAHs
continue to be marketed and promoted for use in countries such as the US.[35] However,
given the numerous adverse effects presented in this review and well established in
literature, including a recent 2012 systematic review, FGAHs should be generally
deferred in lieu of SGAHs, in children for most, if not all common indications that
require treatment with an antihistamine agent.[4, 23, 35]
Page 37 of 63
Table 11: Safety in children and breast feeding
Safety in children and breast feeding

Prospective, long- Prospective, double- 817 children with Cetirizine 0.25 Assess safety of Reported symptoms were mild, including respiratory or
term safety evaluatio blind, randomized atopic dermatitis, 12 mg/kg twice daily study medication gastrointestinal infections, exacerbations of allergic disorders, or age-
n of the H1-receptor placebo controlled to 24 months old or Placebo twice (adverse events, related concerns; they were determined to be not medication-related
antagonist cetirizine i daily. diary cards, adverse effects.
n very young physical No clinically relevant differences between the groups for neurologic
children with atopic examinations, or cardiovascular symptoms or events, growth, behavioral or
dermatitis. ETAC developmental developmental assessments, laboratory test results, or
Study Group. Early assessments, electrocardiograms, and no child receiving cetirizine therapy had
Treatment of electrocardiogra prolongation of the QTc interval.
the Atopic Child. ms, blood Drop-outs and serious events, including hospitalizations, were less
Simons FE. (1999) hematology and common in cetirizine group versus placebo; the differences were not
[120] chemistry tests, statistically significant.
and urinalyses.) Cetirizine is safe for long term use in young children.
Prophylactic manage Multinational, Children, 12–30 Loratadine 5 mg/day Evaluate the No difference in reduction of respiratory infections was observed
ment of children at ri randomized months of age (2.5 mg/day efficacy and between the loratadine and placebo group.
sk for recurrent uppe placebo- for children</=24 long-term safety Loratadine was shown to reduce the number of respiratory
r respiratory controlled study Phase 1: 342 months of age) of loratadine in exacerbations during the treatment phase.
infections: the or Placebo reducing the None of the 204 children who received loratadine discontinued the
Preventia I Study. Phase 2: 310 Phase I: 12-month number of study because of drug-related events.
Grimfeld, A. (2004) double-blind period respiratory Loratadine treatment was not more sedating than placebo and was not
[121] for treatment with infections in associated with cardiovascular events.
loratadine or children at 24 Loratadine is safe for long term use in young children.
placebo. months.
Phase II: double-
blind follow-up
period without study
medication.
Safety of prospective, 255 children (with Levocetirizine 0.125 Assess safety of One or more adverse events with levocetirizine: 96.9% and placebo:
levocetirizine randomized, double- study drug) and 255 mg/kg twice daily levocetirizine in 95.7%.
treatment in young masked, placebo- children (placebo); or placebo twice young atopic Serious adverse events with levocetirizine: 12.2% and placebo: 14.5%
atopic children: An controlled 12-24 months of age daily children. Medication-attributed adverse events with levocetirizine: 5.1% and
18-month study. for 18 months placebo: 6.3%
Simons F.E., et al. Permanent discontinuation of study medication due to adverse events
(2007) [36] with levocetirizine: 2.0% and placebo: 1.2%
The most frequent adverse events related to: upper respiratory tract
infections, transient gastroenteritis symptoms, or exacerbations of
allergic diseases.
There were no significant differences between the treatment groups in
height, mass, developmental milestones, and hematology and
biochemistry tests.
Page 38 of 63
Levocetirizine is safe for long term use in young children.
Terfenadine pharma Pharmacokinetic 4, adult, healthy Terfendadine 60mg Pharmacokinetic Mean +/- SD active metabolite data for milk and plasma are as
cokinetics in breast study lactating women (primary metabolite study for follows: Cmax (ng/ml), 41.0 +/- 16.4 for milk, 309.0 +/- 120.5 for
milk in lactating wo is fexofenadine) Terfendadine plasma; tmax (hours), 4.3 +/- 2.4 for milk, 3.9 +/- 3.0 for plasma; t1/2
men. and its primary beta (hours), 14.2 +/- 5.4 for milk, 11.7 +/- 6.4 for plasma; AUC(0-
Lucas, B. D., et al. active 12) (ng.hr/ml) 320.4 +/- 99.8 for milk, 1590.0 +/- 300.4 for plasma.
(1995)[119] metabolite, Metabolite milk/plasma AUC(0-12) ratios ranged from 0.12 to 0.28
fexofenadine (mean, 0.21 +/- 0.07).
levels in breast Newborn dosage estimates based on the highest measured
milk and venous concentration of terfenadine metabolite in milk suggests the
blood maximum level of newborn exposure would not exceed 0.45% of the
recommended maternal weight-corrected dose.
Estimated amounts of fexofenadine consumed by the neonate in
breast milk are not likely to cause harm.
Excretion of loratadi Pharmacokinetic 6, adult, healthy 40-mg loratadine Pharmacokinetic For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after
ne in human breast study lactating women study for dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour
milk. loratadine to collection interval.
Hilbert, J., et al. determine Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and
(1988) [118] plasma and milk 4.2 micrograms of loratadine was excreted in breast milk, which was
concentrations of 0.010% of the administered dose.
study For descarboethoxyloratadine, a metabolite of loratadine, the
medication. concentration in the breast milk was 0.019% of the
administered loratadine dose.
Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of
the administered dose were excreted as loratadine and its active
metabolite.
The maximum estimated exposure of loratadine and metabolite to the
infant was calculated to be 1.1% of the adult dose on a mg/kg basis.
The adult dose is unlikely to present a hazard to infants.
Safety considerations Systematic review Adults and children First and Second Review of Second-generation oral antihistamines (SGAHs) have proven better
in the management generation evidence safety and tolerability profiles over first-generation antihistamines
of allergic diseases: antihistamines supporting the (FGAHs).
focus on safety profiles of SGAHs have much lower proportional impairment ratios than
antihistamines. frequently used FGAHs.
Yanai, K., et al. oral SGAHs have at least similar, if not better efficacy, than FGAHs.
(2012) [4] antihistamines Only SGAHs, and especially those with a proven long-term clinical
for the treatment safety, should be prescribed for young children.
allergic diseases,
(allergic rhinitis
and urticaria.)
Safety of cetirizine in Prospective, Infants age 6 to 11 0.25 mg/kg Assessment of The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg
infants 6 to 11 randomized, months cetirizine orally safety of (SD).
months of age: a parallel-group, cetirizine in
Page 39 of 63
randomized, double- double-blind, or Placebo twice infants, No differences in all-cause or treatment-related adverse events were
blind, placebo- placebo-controlled daily orally particularly with observed between the cetirizine- and placebo-treated groups.
controlled study. study regard to central
Simons FE, et al. for 1 week. nervous system A trend was observed toward fewer adverse events and sleep-related
(2003) [122] and cardiac disturbances in the cetirizine group compared with the placebo group.
effects,
inclusive. No prolongation in the linear corrected QT interval was observed in
cetirizine-treated infants compared with either baseline values or with
values in placebo-treated infants.
Safety of Two large, double- 875 children ages 6 Fexofenadine 15, Evaluate the 5 patients on placebo and 5 on fexofenadine dropped from the studies
fexofenadine in blind, randomized, through 11 years with safety of due to adverse events not caused by study medication.
children treated for placebo-controlled, seasonal allergic Fexofenadine 30, fexofenadine
seasonal allergic parallel studies rhinitis. Incidence of adverse events was similar in active and placebo groups,
rhinitis. Fexofenadine 60 mg and did not increase with increasing fexofenadine dose: 36.2% (83 of
Graft DF, et al. 229) in the placebo group versus 35.3% (79 of 224), 36.8% (77 of
(2001) [123] or placebo twice 209), and 34.7% (74 of 213) in the 15, 30, and 60 mg twice-daily
daily for 2 weeks fexofenadine groups, respectively.
after a 1-week
placebo lead-in. Headache was the most commonly reported adverse event (6.6% in
the placebo group and 8.0%, 7.2%, and 9.4% in the 15, 30, 60 mg
twice-daily fexofenadine groups, respectively.
Clinical, vital sign, electrocardiogram, and laboratory measures were

similar in active and placebo groups. There was no statistically
significant mean change from baseline in any electrocardiogram
parameter after fexofenadine treatment.
Page 40 of 63
VI. Cost, Regulatory and Current NEML Availability Evaluation
Table 12 below summarizes the monthly comparative costs of FGAHs and SGAHs based on
FDA approved maximum daily doses for adults for general allergic reactions. The costs for
chlorphenamine, diphenhydramine and loratadine were collected from MSH 2010 medicine
pricing reference guide for the median buyer unit price.[124] However, the costs for cetirizine,
fexofenadine and diphenhydramine oral solution were collected form Lexicomp online database,
therefore, there costs reflect US market price.[8] Monthly costs for potential tablet and solution
based treatment were calculated; no monthly costs for injection based treatment were calculated
as injections may be used only once or for acute, hospital based treatment. A literature review
looked at publications reporting costs and consequences of using FGAHs and SGAHs for the
treatment of allergic rhinitis; the review compared costs of using diphenhydramine,
chlorphenamine, cetirizine and fexofenadine.[27] The review concluded that due to the PK, PD
and resulting clinical benefits of SGAHs, their use may pose an overall economic benefit.[27]
Furthermore, given the association of lost productivity with the use of FGAHs, use of SGAHs
may prevent negative economic effects in the workplace.[101]
Table 13 below provides an overview of availability of agents under review in 15 countries with
established NEMLs retrieved from the WHO site.[125] The primary formulations of focus were
tablets (tab), injection (inj) and syrup or oral solution. Other chemicals in the 1st or 2nd generation
antihistamine class or other formulations such combination products, topical, suppositories or
extended release formulations were not considered for this survey, however, whenever possible
they were identified as follows: Fiji has promethazine, another FGAH in the injection, tablet and
suspension formulations on the formulary. India has dexchlorpheniramine suryp, pheniramine
injection and promethazine tablets and syrup on the EML; all agents are FGAHs. Kyrgyzstan has
ketotifen tab and syrup, a SGAH on NEML. Morocco has dexchlorpheniramine tablets on
NEML. Malaysia has diphenhydramine as a combination medicine for antitussive use. Nigeria
and Oman also have promethazine tablet, injection and syrup on their respective NEMLs.
Ten of the fifteen countries surveyed had at least one formulation of chlorphenamine on the
NEML; this is expected as many NEMLs are modeled after the WHO EML. Seven of the fifteen
countries had at least one formulation of diphenhydramine on the NEML. Seven countries had
both syrup and tablet formulations of loratadine and six countries had both syrup and tablet
formulations of cetirizine, and two countries had fexofenadine tablets on the NEML, for a total
of 8 countries with a SGAH on the NEML. 53% of the surveyed nations have included a SGAH
on their respective NEMLs, indicating a growing trend and necessity for these agents for patient
care, despite lack of WHO EML listing of these agents or class. However, not having an SGAH
on the EML could be a disadvantage for many nations who primarily use WHO EML to establish
their NEMLs.
Page 41 of 63
Table 12: Cost comparison of 1st and 2nd generation antihistamines
Medication (Name and Cost per Cost/30 tabs or Daily Monthly cost based on FDA TGA
Strength) unit (US$) 100mL solution or Maximum Dose maximum dosing (US$) Approved Approved
100mg inj (US$) (adult)
Chlorphenamine 4mg tab 0.0038 0.114 24mg/daily 0.684 Yes Yes
Chlorphenamine 0.0043/mL 0.43 24mg/daily 7.74 Yes Yes
2mg/5mL oral solution
Chlorphenamine 0.1470/mL 1.47 24mg/daily N/A Yes Yes
10mg/mL injection
Diphenhydramine 25mg 0.0161 0.483 200mg/daily 3.864 Yes Yes
cap
Diphenhydramine 3.1264/mL 6.25 400mg/daily N/A Yes Yes
50mg/mL injection
Diphenhydramine 0.1016/mL 10.16 200mg/daily 8.128 Yes Yes
12.5mg/5mL oral solution
Loratadine 10mg tab 0.0225 0.675 10mg/daily 0.675 Yes Yes
Loratadine 1mg/1mL 0.0055/mL 0.55 10mg/daily 1.65 Yes Yes
oral solution
Lexi-Comp online (US market price)
Cetirizine 5mg 1.000 30 10mg/daily 60 Yes Yes
Cetirizine 10mg 0.1899 5.70 10mg/daily 5.70 Yes Yes
Cetirizine 1mg/mL oral 0.1355/mL 13.55 10mg/daily 40.65 Yes Yes
solution
Fexofenadine 180mg tab 0.8663 25.99 180mg/daily 25.99 Yes Yes
Fexofenadine 30mg/5mL 0.1749 17.49 180mg/daily 157.41 Yes Yes
solution*
*Originator brand suspension for fexofenadine, all other prices are for generic products
Table 13: Availability of reviewed medications on NEMLs of 15 nations
# Country Chlorphenamine Diphenhydramine Loratadine Cetirizine Fexofenadine

tab/inj/syrup cap/inj/solution tab/syrup tab/syrup tab/syrup
1 Bangladesh tab/inj Not present Not present Not present Not present
2 China tab cap/inj Not present Not present Not present
3 Dominican Republic tab cap/inj/solution tab/syrup Not present Not present
4 Ecuador Not present cap/inj/solution tab/syrup Not present Not present
5 Fiji Not present Not present Not present Not present Not present
6 Ghana tab/syrup tab Not present Not present Not present
7 India tab Not present Not present tab/syrup Not present
8 Iran tab/inj/syrup tab/inj/solution tab/syrup tab/syrup tab
9 Kyrgyzstan Not present tab/inj tab/syrup tab/syrup Not present
10 Malta tab/syrup tab/syrup tab/syrup tab/syrup tab
11 Morocco Not present Not present tab/syrup tab/syrup Not present
12 Malaysia tab/inj/syrup Not present Not present Not present Not present
13 Namibia tab/syrup Not present Not present Not present Not present
14 Nigeria tab/inj/syrup Not present Not present Not present Not present
15 Oman tab/inj/syrup Not present tab/syrup tab/syrup Not present
Total # of surveyed countries with 10 7 7 6 2
identified medications on the NEML 66% 46% 46% 40% 13%
(any formulation) and (%)
Page 42 of 63
VII. Summary and Recommendations
This evaluation of histamine-1 receptor antagonists has illustrated in detail the evidence for
treatment of common allergic conditions with FGAH and SGAH agents as well their associated
side effect profiles. Table 2 shows the regulated and unregulated uses of antihistamine agents. In
terms of efficacy and safety, both FGAH agents are in similar standing. This evaluation has also
presented evidence of harm for all populations using FGAHs including the young and the elderly
and loss of productivity and alertness in the working groups that may result in serious, fatal
errors. The PK, PD data as well as the RCT, guidelines and the systematic review evidence
presented for FGAHs and SGAHs shows that SGAHs result in far less side effects and have
equal, if not better, efficacy than FGAHs. However, despite major safety concerns, FGAHs
mistakenly continue to be thought of as safe medications by the general population and
healthcare providers and are still used widely for a range of conditions.[35]
Economic data presented in Table 12 above indicates that the unit prices (mg and mL) for
chlorphenamine are lower than loratadine. However, according to the median buyer price from
the MSH International Drug Price Guide, the monthly cost, based on maximum doses, of
loratadine tablets and syrup are more economical than chlorphenamine.
The availability survey of 15 nations indicates that the SGAHs are already available in many
countries and the benefit of these agents should be extended to patients worldwide by listing
them on the WHO EML and EMLc.
In summary, the recommendations are as follow:
1. Chlorphenamine may be left on the EML; there is not enough evidence to recommend a
change to diphenhydramine. Both agents appear to be equal in efficacy and safety.
a. Chlorphenamine may be retained with square box designation.
b. A change in the age restriction is recommended. Currently, chlorphenamine
recommended age is greater than 1 year. However, as the discussion above has
shown, SRAs strongly recommend against the use of FGAHs in children 6 years
of age. The age restriction of chlorphenamine should be raised to for use in
children older than 6 years only.
2. To add to the EML: Loratadine, tablet and syrup formulations. A square box designation
is recommended for loratadine, to indicate other medications in the second generation
anti-histamine class are acceptable alternatives to loratadine. Table 14 below provides the
standard FDA approved indications and doses for loratadine. Table 15 below provides
information on dose adjustments for loratadine in renal and hepatic impairments.
3. To delete from the EMLc: Chlorphenamine should be deleted from the EMLc.
Discussion above has shown that SGAHs are the preferred agents for children. And given
Page 43 of 63
the recommendation for increase in age restriction to 6 years as well as the safety
concerns regarding FGAH use in children, chlorphenamine should not be on the EMLc.
4. To add to the EMLc: Loratadine, tablet and syrup formulations. A square box designation
is recommended. Age restriction for loratadine is recommended for use against in
children younger than 2 years of age. Table 14 below provides the standard FDA
approved indications and doses for loratadine. Table 15 below provides information on
dose adjustments for loratadine in renal and hepatic impairments.
Table 14: Treatment Details for Loratadine
Medication (Dosage Indication Adult Dosing Pediatric Dosing Monitoring

formulations)
Loratadine[126] Allergic 10mg tab or 2-5 years: 5 mg tab or syrup, Improvement in
Rhinitis syrup, PO PO Once Daily symptoms of rhinitis
(Tablet 10mg, Once Daily Sedation
Syrup 1mg/mL) Chronic 6 years and older: 10 mg tab Improvement in
Urticaria or syrup, PO Once Daily urticaria
Sedation
Anaphylaxis No evidence to support use of antihistamines in anaphylaxis; clinicians may
refer to institutional guidelines or procedures for appropriate use.
Table 15: Dose Adjustments for Loratadine
Impairment Age Group Dose

Renal Impairment 6 years and older 10mg PO every other day
(GFR<30mL/min) 2 to 5 years 5mg every other day
Hepatic Impairment 6 years and older 10mg PO every other day
2 to 5 years 5mg every other day
Page 44 of 63
Appendix
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Page 45 of 63
Appendix 1 – Drug-Drug Interactions: 1st Generation Antihistamines
FGAH Interacting drug or class EML(y/n) Severity Documentation Interaction Details
Diphenhy- 1 Linezolid N Major Fair Concurrent use of DIPHENHYDRAMINE and LINEZOLID may result in increased
dramine anticholinergic toxicity effects.
2 Zolpidem / sedatives N Major Fair Concurrent use of ZOLPIDEM and SEDATIVES may result in an increase in central
nervous system depressant effects.
3 Oxycodone / sedatives N Major Fair Concurrent use of OXYCODONE and SEDATIVES may result in an increase in CNS or
respiratory depression.
4 Tapentadol sedatives N Major Fair Concurrent use of TAPENTADOL and SEDATIVES may result in an increase in central
nervous system and respiratory depression.
5 Hydromorphone / N Major Fair Concurrent use of HYDROMORPHONE and SEDATIVES may result in an increase in
sedatives CNS or respiratory depression.
6 Metoprolol Y Moderate Good Concurrent use of DIPHENHYDRAMINE and METOPROLOL may result in increased
metoprolol plasma concentration.
7 Tamoxifen Y Moderate Fair Concurrent use of DIPHENHYDRAMINE and TAMOXIFEN may result in decreased
plasma concentrations of the active metabolites of tamoxifen.
8 Clomipramine Y Moderate Fair Concurrent use of CLOMIPRAMINE and DIPHENHYDRAMINE may result in
increased anticholinergic effects (dry mouth, urinary retention).
9 Amitriptyline Y Moderate Fair Concurrent use of AMITRIPTYLINE and DIPHENHYDRAMINE may result in
increased anticholinergic effects (dry mouth, urinary retention).
10 Triflupromazine N Moderate Fair Concurrent use of TRIFLUPROMAZINE and DIPHENHYDRAMINE may result in
anticholinergic effects (dry mouth, urinary retention, altered mental status).
11 Procarbazine Y Moderate Fair Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS
depression.
12 Amoxapine N Moderate Fair Concurrent use of AMOXAPINE and DIPHENHYDRAMINE may result in increased
anticholinergic effects (dry mouth, urinary retention).
13 Belladonna N Minor Fair Concurrent use of BELLADONNA and DIPHENHYDRAMINE may result in excessive
anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive
sedation, blurred vision).
Chlorphe- 1 Lorcaserin N Major Fair Concurrent use of LORCASERIN and SEROTONERGIC AGENTS may result in
namine increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,
myoclonus, mental status changes).
2 Bromocriptine N Major Fair Concurrent use of BROMOCRIPTINE and CHLORPHENIRAMINE may result in
increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,
myoclonus, mental status changes).
3 Phenytoin Y Moderate Fair Concurrent use of PHENYTOIN and CHLORPHENIRAMINE may result in an increased
risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).
Page 46 of 63
4 Fosphenytoin N Moderate Fair Concurrent use of FOSPHENYTOIN and CHLORPHENIRAMINE may result in an
increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).
5 Procarbazine Y Moderate Fair Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS
depression.
6 Belladona N Minor Fair Concurrent use of BELLADONNA and CHLORPHENIRAMINE may result in excessive
anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive
sedation, blurred vision).
Definition: Severity Definition: Documentation
Contraindicated - The drugs are contraindicated for concurrent use.
Excellent Controlled studies have clearly established the existence of the
interaction.
Major - The interaction may be life-threatening and/or require medical
intervention to minimize or prevent serious adverse effects. Good Documentation strongly suggests the interaction exists,
but well-controlled studies are lacking.
Moderate - The interaction may result in exacerbation of the patient's
Fair Available documentation is poor, but pharmacologic
condition and/or require an alteration in therapy.
considerations lead clinicians to suspect the interaction exists;
or, documentation is good for a pharmacologically similar drug.
Minor - The interaction would have limited clinical effects. Manifestations
may include an increase in the frequency or severity of the side effects but Unknown Unknown.
generally would not require a Major alteration in therapy.
Unknown - Unknown.
Table created using information from Micromedex online clinical pharmacy database.[10]
Page 47 of 63
Appendix 2 – Drug-Drug Interactions: 2nd Generation Antihistamines
SGAH Interacting drug or class EML(y/n) Severity Documentation Interaction Details
Loratadine 1 Amiodarone Y Major Good Concurrent use of AMIODARONE and LORATADINE may result in
increased risk of QT interval prolongation and torsade de pointes.
2 Cimetidine N Minor Good Concurrent use of CIMETIDINE and LORATADINE may result in
increased loratadine serum concentrations; possible loratadine toxicity.
Y
Cetirizine 1 Ritonavir Y Minor Good Concurrent use of CETIRIZINE and RITONAVIR may result in increased
exposure and half-life of cetirizine as well as reduced cetirizine clearance.
Fexofenadine 1 Droperidol N Major Fair Concurrent use of DROPERIDOL and ANTIHISTAMINES may result in
an increased risk of cardiotoxicity (QT prolongation, torsades de pointes,
cardiac arrest).
2 Antacids; interacting compounds N Moderate Good Concurrent use of FEXOFENADINE and ANTACIDS may result in
-magnesium carbonate; decreased fexofenadine efficacy.
magnesium hydroxide;
magnesium trisilicate;
magnesium oxide; aluminum
carbonate, basic; aluminum
hydroxide; aluminum phosphate;
dihydroxyaluminum
aminoacetate;
dihydroxyaluminum sodium
carbonate; magaldrate
3 St John’s Wort Extract N Moderate Good Concurrent use of FEXOFENADINE and ST JOHN'S WORT may result in
decreased effectiveness of fexofenadine.
Definition: Severity Definition: Documentation
Contraindicated - The drugs are contraindicated for concurrent use.
Excellent Controlled studies have clearly established the existence of
the interaction.
Major - The interaction may be life-threatening and/or require medical intervention to
minimize or prevent serious adverse effects. Good Documentation strongly suggests the interaction exists,
but well-controlled studies are lacking.
Moderate - The interaction may result in exacerbation of the patient's condition and/or
Fair Available documentation is poor, but pharmacologic
require an alteration in therapy.
considerations lead clinicians to suspect the interaction
exists; or, documentation is good for a pharmacologically
Minor - The interaction would have limited clinical effects. Manifestations may include
similar drug.
an increase in the frequency or severity of the side effects but generally would not
require a Major alteration in therapy. Unknown Unknown.
Unknown - Unknown.
Page 48 of 63
Appendix 3 – Precautions, Contraindications and Breast Feeding Risk of 1st Generation Antihistamines
Chlorphenamine
Precautions Contraindications Breast Feeding Risk
1. Asthma 1. Hypersensitivity to 1. Avoid Breastfeeding.
2. Bladder neck obstruction chlorpheniramine or 2. Infant risk cannot be ruled out.
3. Hepatic insufficiency dexchlorpheniramine 3. Available evidence and/or expert
4. Narrow-angle glaucoma consensus is inconclusive or is inadequate
5. Pyloroduodenal obstruction for determining infant risk when used
6. Sedative effects; some patients may be more or less during breastfeeding. Weigh the potential
susceptible benefits of medication treatment against
7. Stenosing peptic ulcer potential risks before prescribing this
8. Symptomatic prostatic hypertrophy medication during breastfeeding.
Diphenhydramine
1. Bladder neck obstruction 1. Hypersensitivity to 1. Milk effects are possible.
2. Concurrent maoi therapy diphenhydramine 2. Evidence suggests this medication may
3. Concurrent use of central nervous system depressants 2. Newborns or premature infants alter milk production or composition. If
4. Decreases mental alertness and psychomotor performance 3. Nursing mothers an alternative to this medication is not
5. Do not use topical form on eyes or eye lids prescribed, monitor the infant for adverse
6. Elderly are more susceptible to the side effects of effects and/or adequate milk intake.
diphenhydramine
7. History of bronchial asthma, increased intraocular pressure,
hyperthyroidism, cardiovascular disease or hypertension
8. May cause excitation in young children
9. Narrow angle glaucoma
10. Pyloroduodenal obstruction
11. Stenosing peptic ulcer
12. Symptomatic prostatic hypertrophy
13. Use of the topical form on patients with chicken pox,
measles, blisters, or large areas of skin unless directed by a
physician
Table based on clinical information from Micromedex clinical pharmacy database.[10]
Page 49 of 63
Appendix 4 – Precautions, Contraindications and Breast Feeding Risk of 2nd Generation Antihistamines
Loratadine
1. Impaired liver function 1. Hypersensitivity to loratadine or any of its 1. Maternal medication usually compatible with
2. Impaired renal function ingredients breastfeeding.
3. Pregnancy 2. Hypersensitivity to desloratadine, an active 2. Infant risk is minimal.
metabolite of loratadine 3. The weight of an adequate body of evidence
and/or expert consensus suggests this
medication poses minimal risk to the infant
when used during breastfeeding.
Cetirizine
1. Activities requiring mental alertness 1. Hypersensitivity to cetirizine, levocetirizine (R 1. Infant risk cannot be ruled out.
2. Concurrent use of central nervous system enantiomer of cetirizine hydrochloride), or 2. Available evidence and/or expert consensus
depressants components is inconclusive or is inadequate for
3. Elderly 2. Hypersensitivity to hydroxyzine determining infant risk when used during
4. Hepatic dysfunction breastfeeding. Weigh the potential benefits of
5. Renal insufficiency medication treatment against potential risks
before prescribing this medication during
breastfeeding.
Fexofenadine
1. Concurrent administration of aluminum- and 1. Hypersensitivity to fexofenadine or any of the 1. Maternal medication usually compatible with
magnesium-containing antacid within 15 ingredients breastfeeding.
minutes; decrease fexofenadine absorption 2. Infant risk is minimal.
2. Concurrent consumption of fruit juices, such 3. The weight of an adequate body of evidence
as grapefruit, orange, and apple; decrease and/or expert consensus suggests this
fexofenadine bioavailability and exposure medication poses minimal risk to the infant
when used during breastfeeding.
Table based on clinical information from Micromedex clinical pharmacy database.[10]
Page 50 of 63
Appendix 5: Non-allergic conditions treated with Antihistamines
A. Motion Sickness, Nausea, Emesis

Motion sickness is a common event amongst approximately 28% of passengers using a
motorized means of transportation, particularly when travelling rapidly in winding or up and
down motion.[127, 128] The feelings of nausea/vomiting originating in the central nervous
system result due to the mismatch of the movements sensed and seen by the vestibular
system and the eyes, respectively.[10, 129] FGAH agents, due to their anticholinergic
activities are commonly used to prevent and combat the nausea/vomiting associated with
motion sickness.[10] While, diphenhydramine may also be used as an adjunctive antiemetic
therapy in chemotherapy induced nauseas/vomiting, however, it is not effective and should
not be used as monotherapy.[130] Furthermore, alternative agents exist and are proven to be
effective for their anti-emetic and anti-nausea use for motion sickness. Metoclopramide was
shown to be more effective than diphenhydramine in treatment of motion sickness in patients
during ambulance transport.[127] According to a Cochrane review, another agent,
scopolamine, is effective in preventing motion sickness compared to placebo; and while there
is mixed evidence when comparing scopolamine to antihistamine agents, low-powered
studies do indicate at least equal efficacy to antihistamine agents.[131]
Since motion sickness is a centrally mediated event, requiring anti-cholinergic activity of the
antihistamines, SGAH are not effective in this respect.[129]
B. Antitussive uses
Diphenhydramine is commonly used as an antitussive agent, although the exact mechanism
for cough suppression has yet to be elucidated.[10, 132] However, it is believed that the
antitussive effect is likely due to action in the central nervous system on the medullary cough
center.[10] While mechanisms peripherally in the body may also be involved, there is not
enough data to firmly make this determination.[10] Studies in animals indicate efficacy for
antitussive activity of diphenhydramine, however, there is lack of supporting data in
humans.[10] In a double-blind study, 13 adults with chronic bronchitis were treated with 25
or 50 mg of diphenhydramine every 4 hours for four doses indicating statistically and
clinically significant reduction in the frequency of coughs with both doses when compared to
placebo.[10, 132] However, half of the participants in the study continued to cough
frequently, with the most frequent side effect of drowsiness, particularly with the 50 mg dose
of diphenhydramine.[10] It should be noted that diphenhydramine is an anti-cholinergic
agent that may lead to thickening of bronchial secretions complicating care of asthmatic
patients since the anticholinergic effects may make secretions more difficult to
expectorate.[10] However, FDA advisory review panel considers diphenhydramine, like
codeine and dextromethorphan, as a safe and effective antitussive agent but with higher
incidence of side-effects.[10] Furthermore, both dextromethorphan and codeine are
considered to be effective medications to alleviate cough; while dextromethorphan profile
Page 51 of 63
indicates it is not likely for the user to become dependent on it or cause respiratory
depression, both of which are concerns for codeine.[10, 133] Moreover, given its wide safety
and toxicity index, dextromethorphan is considered to be the safest antitussive available,
leaving little use for FGAHs in this respect.[10]
A non-blind, randomized clinical trial for 139 children aged 24-60 months, suffering from
cough due to upper respiratory airway infections (URI), compared cough suppressant effects
of 2.5mLs of honey, dextromethorphan and diphenhydramine.[134] The study found that
honey was significantly more effective at suppressing URI-associated cough than
dextromethorphan or diphenhydramine.[134] However, a Cochrane review found that honey
may be better at cough suppression than ‘no treatment’ or diphenhydramine, but not better
than dextromethorphan.[133] Furthermore, if the URI is due to a viral cause, the cough
would not be histamine mediated; therefore, FGAHs may not be effective in alleviating the
cough.[135]
SGAHs do not cross the blood-brain-barrier readily, therefore, their effect on the medullary
cough centers of the brain would be limited, possibly non-existent, providing no indication
for antitussive use.[3, 5, 23]
Given that honey may be more effective at cough suppression than diphenhydramine, with
none of the FGAH associated side-effects and dextromethorphan as the most effective
treatment – it can be argued that antihistamine should not be considered for antitussive use if
alternatives are available.
C. Insomnia (Night-time sleep aid)

Insomnia is the most common of the sleep disorders, affecting 10% of the adults
worldwide.[87] A multi-centered centered study by National Institute of Aging in United
States, surveyed over 9,000 participants aged 65 and older and found prevalence of insomnia
to range between 23 and 34% in this population.[136] With as many as 15% reporting they
never or rarely felt rested in the morning.[136] Furthermore, there is a correlation between
individuals with nocturnal symptoms of allergic conditions such as rhinitis and poor
sleep.[48, 137] Given such a high level of public health presence of insomnia and disturbed
sleep, it is understandable that FGAHs, such as diphenhydramine are commonly used as
prescribed and self-administered sleep aids for patients suffering from insomnia.[87, 138]
Given the pharmacology, FGAHs are capable of inducing drowsiness and somnolence very
effectively, as a side effect.[3, 4, 7, 35] However, there are considerable drawbacks to the use
of this class of medications for the treatment of insomnia or even as an occasional night-time
sleep aid for patients suffering from allergies or other limiting conditions. The FGAHs
interfere with the natural circadian sleep-wake cycle leading to daytime adverse effects of the
medication and are determined to be inappropriate for use as sleep-aids.[4] Studies have
shown that there is a significant “next-day residual sedative effect” or “hangover” effect of
Page 52 of 63
FGAHs including with the use of positron emission tomography (PET scans).[35, 87, 138]
This hangover effect directly leads to subjective reporting of sleepiness, objectively observed
sleepiness and decline in psychomotor performance the day after administration of
diphenhydramine as a sleeping aid.[138] However, no similar side-effects were observed
with another sleep-aid, zolpidem.[138] Furthermore, the use of diphenhydramine has not
been shown to result in improved sleep.[139, 140] And there are conflicting reports on the
ability of habitual users of FGAHs to develop tolerance to daytime sedation and psychomotor
impairment.[35, 141, 142]
Given the poor efficacy and safety profile of FGAHs for this indication, it is concluded that,
when available, other agents, such as zolpidem should be considered for patients suffering
from insomnia.
SGAHs are not as capable of crossing the blood-brain-barrier as FGAHs, therefore, their use
in insomnia would not be indicated.[3, 5, 23]
D. Extrapyramidal Symptoms
Extrapyramidal symptoms (EPS) consist of a constellation of symptoms known as dystonic
reactions, akathisia, and pseudoparkinsonism thought to be the result of antagonism of
central dopamine receptors.[10, 143, 144] These symptoms of EPS are commonly associated
with use of antipsychotic agents and the severity and development of EPS is generally dose
related, however, dystonias may also be of idiopathic origin.[10, 143-147] EPS symptoms,
such as dystonias from use of antipsychotic medications or idiopathic origin can be managed
with anticholinergic agents including intramuscular or oral diphenhydramine.[10, 17, 144,
146-149] However, there are many other treatment options for dystonias such as benztropine,
biperiden, ethopropazine, orphenadrine, procyclidine, trihexyphenidyl, amantadine, or
benzodiazepines.[10, 148] Treatment of akathisia with anticholinergic, on the other hand, is
generally not successful.[10] A change in the antipsychotic dose is considered to be the most
effective treatment in alleviating this symptom of EPS; conversely switching the patient to a
lower-potency antipsychotic agent may also resolve the symptoms.[10] Pseudoparkinsonism
is associated particularly with use of high-potency antipsychotic agents, increasing age and
female patients, is effectively treated with anticholinergic agents such as diphenhydramine,
benztropine, trihexyphenidyl, and biperiden.[10, 148, 150] Benztropine is the preferred
anticholinergic agent due to its long half-life allowing for once or twice daily dosing while
diphenhydramine would need to be administered three times a day.[10]
Given the availability of alternative, effective treatments for EPS, FGAHs should not be
considered first line therapy for management of EPS. Due to the inability of SGAHs to cross
the blood-brain-barrier, their effectiveness in treatment of EPS is limited.[3, 5, 23]
Page 53 of 63
Appendix 6: EML Application Sections
1. Summary statement of the proposal for inclusion, change or deletion
 See section: ‎VII-Summary and Recommendations on page 43.
2. Name of the focal point in WHO submitting or supporting the application (where
relevant)
 Department of Essential Medicines and Pharmaceutical Policy
3. Name of the organization(s) consulted and/or supporting the application
 None
4. International Nonproprietary Name (INN, generic name) of the medicine

 Chlorphenamine
 Loratadine
5. Formulation proposed for inclusion; including adult and pediatric (if appropriate)
 See section: ‎VII Summary and Recommendations on page 43 and Table 14:
Treatment Details for Loratadine on page 44.
6. International availability - sources, if possible manufacturers and trade names
 See section ‎VI Cost, Regulatory and Current NEML Availability Evaluation on page
41 and Table 12: Cost comparison of 1st and 2nd generation antihistamines and Table
13: Availability of reviewed medications on NEMLs of 15 nations on page 42.
7. Whether listing is requested as an individual medicine or as an example of a therapeutic

group
 See section ‎VII Summary and Recommendations on page 43
8. Information supporting the public health relevance (epidemiological information on

disease burden, assessment of current use, target population)
 See section ‎I Background and Rationale for this review on page 6.
9. Treatment details (dosage regimen, duration; reference to existing WHO and other
clinical guidelines; need for special diagnostics, treatment or monitoring facilities and
skills)
Page 54 of 63
10. Summary of comparative effectiveness in a variety of clinical settings:
 See the following:
 Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria on
page 15
 Table 5: Guidelines on Treatment of Allergic Rhinitis on page 18
 Table 6: Efficacy and safety of SGAH in Allergic Rhinitis on page 19
 Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria on page
24
 Table 8: Efficacy and Safety of SGAHs in Urticaria on page 25
11. Summary of comparative evidence on safety:

 See the following:
 Table 9: Comparative side-effect profile of first and second generation
antihistamines on page 31
 Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment on
page 32
 Table 11: Safety in children and breast feeding on page 38
12. Summary of available data on comparative cost and cost-effectiveness within the
pharmacological class or therapeutic group:
41 and Table 12: Cost comparison of 1st and 2nd generation antihistamines on page
42
13. Summary of regulatory status of the medicine (in country of origin, and preferably in
other countries as well)
42
14. Availability of pharmacopoeial standards (British Pharmacopoeia, International

Pharmacopoeia, United States Pharmacopoeia)
42
15. Proposed (new/adapted) text for the WHO Model Formulary
Page 55 of 63
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Ref 2. WHO Histamine-1 Receptor Antagonists

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Section 3: Antiallergics and Medicines Used in Anaphylaxis

Histamine-1 receptor antagonists – A critical evaluation to update Section 3

Developed by Harinder Chahal

For WHO Secretariat

This review is intended to answer the following questions.

1. Should Diphenhydramine replace Chlorphenamine on the Essential Medicines List?

2. Should a SGAH be on the WHO Essential Medicines List?

4. Which SGAH should be listed?

BID – Twice daily

BNF – British National Formulary

DDI – Drug-Drug Interactions

EML – Essential Medicines List

FDA – Food and Drug Administration

FGAH – First (1st) generation antihistamine

GRADE – Grading of Recommendations Assessment, Development and Evaluation

LMICs – Low– and Middle–Income Countries

MHRA – Medicines and Healthcare products Regulatory Agency

NEML – National Essential Medicines List

RCT – Randomized Controlled Trial

SGAH – Second (2nd) generation antihistamine

SRA - Stringent Regulatory Authority

TGA – Therapeutics Goods Administration

WHO – World Health Organization

More than 40 histamine-1 antagonist antihistamine agents are available worldwide.[3, 5, 8, 9]

II. Public health relevance of allergic conditions

Strength of Recommendation Strength of Evidence

1. Comparing chlorphenamine and diphenhydramine for safety and efficacy.

IV. Medications, Clinical Efficacy and Safety Evaluation

2. Pharmacokinetic (PK) and Pharmacodynamic (PD) properties of antihistamines

1st generation antihistamines 2nd generation antihistamines

Given their status, chlorphenamine and diphenhydramine may appropriately be referred

Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria

Drowsiness was noted in 19.2% of patients on loratadine

Guidelines Treatment of AR Evidence Level and

Efficacy and safety of SGAH in Allergic Rhinitis

Drowsiness was noted in 19.2% of patients on loratadine

Early, sustained symptom relief was seen with loratadine,

No abnormal changes in lab values were observed in either

Both treatments were well tolerated; 2 patients in cetirizine

Table 7 below summarizes guidelines recommendations and Table 8 below provides

Guidelines/Systematic Review Treatment of Urticaria Evidence Level and Recommendation

Efficacy and Safety of SGAHs in Urticaria

4 patients in the hydroxyzine group, 1 patient in the

Adverse events were mild and occurred with similar

Doses of 60 mg twice a day or greater are most

Adverse events occurred with similar incidence in all

Fexofenadine, twice-daily doses of 60 mg or greater

Cetirizine has a greater safety margin over

“In anaphylaxis, H1-antihistamines relieve itching, flushing, urticaria,

In the management of anaphylaxis in children, the European Academy of

5. Safety Profile of Antihistamines

Furthermore, chlorphenamine and diphenhydramine are capable of increasing dopamine

Side-effect 1st Generation Antihistamines 2nd Generation Antihistamines

May cause adverse effects in newborns if taken

Side-effects: Sedation, drowsiness, psychomotor impairment

Chlorphenamine was present in some aviation

Using 10 different methods, 20 studies did not find

Two performance studies, digit substitution and

Ingesting 10 mg of loratadine daily does not appear to

Loratadine had no significant effect on any

It was concluded that cetirizine, but not loratadine,

2. Children and Infants

The safety of cetirizine in an 18-month long, double-blind, placebo controlled study in