Download Section 3: Antiallergics and Medicines Used in Anaphylaxis

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-thecounter, 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?
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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.
V.
Safety Profile of Antihistamines ........................................................................................ 29
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
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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
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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.
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Review
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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 histamine1 (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 offlabel 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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Comparison
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
Medication or Class
were selected for review due to
their classification as over-thevs. Diphenhydramine
1 Chlorphenamine
counter (OTC) medications by
FGAH:
SGAH: cetirizine,
2
chlorphenamine and vs. loratadine and
the FDA and their off-patent
diphenhydramine
fexofenadine
status.[9] OTC medications are
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 3040% 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]
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Table 2: FDA approved and off-label indications for antihistamines and strength of evidence and recommendation
Medication
Diphenhydramine
Chlorphenamine
Loratadine
Cetirizine
FDA Approved Indication and Strength of Recommendation and
Evidence (R/E)
Indication
Adults (R/E)
Children (R/E)
Off-Label (Non-FDA approved) Indication and Strength of
Recommendation and Evidence (R/E)
Indication
Adults (R/E)
Children (R/E)
Allergic rhinitis
Yes (Class IIb /
Category B)
Yes (Class IIb / Category
B)
Chemotherapy-induced
nausea and vomiting
No (Class IIb /
Category B)
No evidence
Anaphylaxis;
Adjunct
Yes (Class IIb /
Category B)
Yes (Class IIb / Category
B)
No (Class IIb /
Category B)
No evidence
Common cold
Yes (Class IIb /
Category B)
Yes (>6yr of age) (Class
IIb / Category B)
Extrapyramidal disease Medication-induced
movement disorder
Hyperemesis gravidarum
No (Class IIb /
Category B)
No evidence
Insomnia
Yes (Class IIb /
Category B)
Yes (>12yr of age)
(Class IIb / Category B)
Local anesthesia
No (Class IIb /
Category B)
No evidence
Motion sickness
Yes (Class IIb /
Category B)
Yes (Class IIb / Category
B)
Parkinsonism
Yes (Class IIb /
Category B)
Not FDA approved
Pruritus of skin
Yes (Class IIa /
Category B)
Yes topical formulation
only, 2 y and older
(Class IIa / Category B)
Allergic rhinitis
Yes (Class IIa /
Category B)
Yes (>6yr of age) (Class
IIa / Category B)
Contrast media adverse
reaction
No (Class IIb /
Category B)
No (Class IIb /
Category B)
Common cold
Yes (Class IIb /
Category B)
Yes (>6yr of age) (Class
IIb / Category B)
Systemic mast cell disease
No (Class IIb /
Category B)
No (Class IIb /
Category B)
Idiopathic urticaria,
chronic
Yes (Class IIb / Category
B)
Yes (>2yr of age) (Class
IIb / Category B)
Asthma
No (Class IIb /
Category B)
No (Class IIb /
Category B)
Allergic rhinitis
Yes (Class IIa / Category
B)
Yes (>2yr of age) (Class
IIa / Category B)
Eosinophilic non-allergic
rhinitis
No evidence
No evidence
Allergic rhinitis
(Perennial)
Yes (Class IIa / Category
B)
Yes (>6months of age)
(Class IIa / Category B)
Asthma, adjunct
No (Class IIa /
Category B)
No evidence
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Fexofenadine
Allergic rhinitis
(Seasonal)
Yes (Class IIa / Category
B)
Yes (>2yr of age) (Class
IIa / Category B)
Atopic dermatitis
No (Class IIb /
Category B)
No (Class IIb /
Category B)
Urticaria, chronic
Yes (Class IIa / Category
B)
Yes (>6months) (Class
IIa / Category B)
Urticaria, acute
No (Class IIb /
Category B)
No evidence
Idiopathic urticaria,
chronic
Yes (Class IIa / Category
B)
Yes (>6yr, oral tablets,
orally disintegrating
tablets; 6 months to 11
years, oral suspension
(Class IIa / Category B)
Hymenoptera
immunotherapy,
Pretreatment
No (Class IIb /
Category B)
No evidence
Allergic rhinitis
(Seasonal)
Yes (Class IIa / Category
B)
Yes 6yr and older, oral
tablets, orally
disintegrating tablets; 2
to 11 years, oral
suspension (Class IIa /
Category B)
Allergic rhinitis (Perennial)
No (Class IIb /
Category B)
No evidence
Strength of Recommendation
Class I - Recommended
 The given test or treatment has been proven to be useful, and should be
performed or administered.
Class IIa - Recommended, In Most Cases
 The given test, or treatment is generally considered to be useful, and is
indicated in most cases.
Class IIb - Recommended, In Some Cases
 The given test, or treatment may be useful, and is indicated in some, but not
most, cases.
Class III - Not Recommended
 The given test, or treatment is not useful, and should be avoided.
Class Indeterminate - Evidence Inconclusive
Strength of Evidence
Category A
 Category A evidence is based on data derived from: Meta-analyses of randomized
controlled trials with homogeneity with regard to the directions and degrees of results
between individual studies. Multiple, well-done randomized clinical trials involving large
numbers of patients.
Category B
 Category B evidence is based on data derived from: Meta-analyses of randomized
controlled trials with conflicting conclusions with regard to the directions and degrees of
results between individual studies. Randomized controlled trials that involved small
numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate,
flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies,
observational studies).
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]
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III.
Methods
A search was conducted using all PubMed databases and Cochrane databases for reviews,
observational studies and RCTs:
1.
2.
3.
4.
5.
6.
Comparing chlorphenamine and diphenhydramine for safety and efficacy.
Providing information on safety and efficacy of FGAH or SGAH as monotherapy
against placebo.
Comparing FGAH to SGAH for safety and efficacy.
Use of FGAH and SGAH for allergic rhinitis, urticaria and anaphylaxis.
Use of FGAH and SGAH in special populations, children and the elderly.
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; chlortrimeton; 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 histaminemediated 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
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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 sideeffect of sedation. The FGAHs are referred to as ‘sedating’ while the SGAHs as ‘nonsedating.’[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 alphaadrenergic 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.
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Table 3: PK and PD properties of antihistamines
PK/PD Property
Duration of Action
Volume of Distribution
Protein Binding
Metabolism
Absorption
(Bioavailability)
Half-life
Time to Peak
Excretion
Dose adjustment in renal
impairment
Dose adjustment in
hepatic impairment
Clinically relevant drugdrug interactions
Pregnancy category
(FDA)
Pregnancy category
(TGA)
1st generation antihistamines
Chlorphenamine
Diphenhydramine
Up to 24h
Less than 12h
Children 4-7L/kg;
Children 22L/kg; Adults
Adults 6-12L/kg
17L/kg; Elderly 14L/kg
33%
98.5%
Hepatic, significant first- Hepatic, significant firstpass effect
pass effect
Good
Moderate 42 to 62%
2nd generation antihistamines
Cetirizine
Loratadine
24h
24h
0.56L/kg
Variable
Fexofenadine
24h
Not available
93%
Hepatic (limited)
97%
Hepatic (extensive)
60 to 70%
Hepatic (minimal)
Rapid
Rapid
Rapid
27h
8h
12-15h
14h
Onset of action 2h;
time to peak 1h
Urine (40%) and
feces (40%)
Yes
Onset of action 1h;
time to peak 2.6h
Feces (80%) and urine
(11%)
Yes
Onset of action 3h; time
to peak 2-3h
Urine
Children 5h; Adults 9h;
Elderly 13.5h.
Onset of action 2h; time to
peak 2h
Urine
Data not available
Yes
Onset of action 0.7h;
time to peak 1h
Urine (70%) and feces
(10%)
Yes
Data not available
Yes
Yes
Yes
No
Possible
Possible
Unlikely
Possible
Unlikely
Category B1
Category B1
Category B1
Category B1
Category C2
Category A3
Category A3
Category B24
Category B15
Category B24
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.
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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 antihistamine agents for treatment of allergic rhinitis and urticaria and their safety via sideeffect 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
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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
Study Design
Study Population
Medications/Doses
Publication
Randomized
64
Nigerian
Loratadine + Vitamin
Controlled clinical
controlled trial
patients with
C
study of the efficacy
allergic rhinitis
of loratadine in
Chlorphenamine +
Nigerian patients
Vitamin C
with allergic rhinitis.
Nwawolo, C. C.,
Vitamin C
Olusesi, A. D.
(2001)[37]
Efficacy and safety
of loratadine
suspension in the
treatment of children
with allergic rhinitis.
Boner, A.L. (1989)
[38]
Randomized
controlled trial
Twentyone children with
allergic rhinitis
Loratadine 0.11-0.24
mg/kg ideal body
weight once daily
Dexchlorpheniramine
0.10-0.23 mg/kg every
8h
Objective(s)
To assess
efficacy and
tolerance of
loratadine
Results
Loratadine was significantly better than Vit. C. alone (P =
0.0002).
Chlorpheniramine was also significantly better than Vit. C.
alone (P = 0.039).
Loratadine was significantly better than chlorpheniramine (P
= 0.046).
Safety and effica
cy of loratadine
compared to
dexchlorphenira
mine in children.
Drowsiness was noted in 19.2% of patients on loratadine
compared with 57.1% of patients on chlorpheniramine.
Both loratadine and dexchlorpheniramine were effective in
reducing nasal and ocular symptoms in allergic children.
Substantial improvement in allergy symptoms was observed at
the first evaluation (day 3 of treatment) and was maintained
for the study duration.
No abnormality in lab parameters was observed.
for 14 days
Central nervous
system effects of H1receptor antagonists
in the elderly.
Simons, F. E., et al.,
(1999) [25]
Rrandomized,
double-blind, singledose, placebocontrolled, 5-way
crossover study
15 healthy elderly
subjects (mean age
71 +/- 5 years)
Cetirizine 10 mg,
Loratadine 10 mg,
Diphenhydramine 50
mg,
To compare
effects of study
medications on
performance,
somnolence, and
peripheral H1blockade.
Chlorphenamine 8 mg,
or
Benefit/risk ratio of
the antihistamines
(H1-receptor
antagonists)
terfenadine and
chlorpheniramine in
children.
Double-blind,
single-dose,
placebo-controlled,
three-way crossover
study
15 children with
allergic rhinitis
(mean age, 8.5 +/1.4 years)
Placebo
Terfenadine 60 mg,
Chlorphenamine, 4
mg, or
Placebo
Drowsiness was present only in the dexchlorpheniraminetreated group.
Performance was affected by FGAH more than SGAH in
increasing to decreasing order as follow: chlorphenamine >
diphenhydramine > loratadine > placebo > cetirizine.
Somnolence ranked from more to less with medications as
follows: diphenhydramine > chlorphenamine > cetirizine >
loratadine > placebo.
All H1-receptor antagonists suppressed the histamine-induced
wheal and flare significantly compared to placebo.
To compare
effects of study
medications on
performance,
somnolence, and
peripheral H1blockade
Both terfenadine and chlorphenamine suppressed the
histamine-induced wheal and flare compared with baseline
and with placebo; terfenadine was significantly more effective
(p < 0.05).
Terfenadine did not impact performance in contrast to
chlorphenamine and placebo.
Page 15 of 63
Simons, F. E., et al.,
(1994) [39]
Cetirizine versus
hydroxyzine and
placebo in chronic
idiopathic urticaria.
Breneman, D. L.
(1996) [40]
Urticaria: clinical
efficacy of cetirizine
in comparison with
hydroxyzine and
placeb.
Kalivas J, et al.
(1990) [44]
Multicenter,
randomized, doubleblind, doubledummy, placebocontrolled
Multicenter, doubleblind, placebocontrolled
188 patients at least
12 years of age,
with symptomatic
chronic idiopathic
urticaria that had
occurred
episodically for at
least 6 weeks.
Patients with
chronic urticaria
Cetirizine 10 mg once
daily,
Hydroxyzine 25 mg
three times daily, or
Placebo for 4 weeks
Cetirizine 5 to
20mg/day,
Hydroxyzine 25 to
75mg/day
or Placebo for 4 weeks
To compare the
safety and
efficacy of
cetirizine with
that of
hydroxyzine and
placebo in the
treatment of
chronic
idiopathic
urticaria.
To evaluate
safety and
efficacy of
cetirizine
compared to
hydroxyzine in
treatment of
urticaria
Terfenadine and placebo did not increase somnolence
compared with baseline, but chlorphenamine did.
Cetirizine and hydroxyzine had a significant reduction in
urticaria symptoms of lesions and pruritus at weeks 1, 2, and 3
compared to placebo (p<0.04).
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.
Cetirizine was equivalent in efficacy to hydroxyzine.
The incidence of somnolence in the cetirizine group was not
significantly different from that of the placebo group.
In the hydroxyzine group, the incidence of somnolence was
significantly higher than that in the placebo group (p = 0.001).
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, doubleblind, 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
Allergic Rhinitis and its Impact on Asthma
(ARIA) guidelines: 2010 Revision [46]
International Primary Care Respiratory
Group (IPCRG) Guidelines: management of
allergic rhinitis. 2006 [51]
First line therapy: 2nd
generation antihistamine
2nd generation
antihistamines preferred
therapy
British Society for Allergy and Clinical
Immunology (BSACI) Standards of Care
Committee guideline on the management of
allergic and non-allergic rhinitis (2010) [50]
First line therapy: 2nd
generation antihistamine
Evidence Level and
Recommendation
GRADE: strong recommendation with
low-quality evidence
Strong Evidence for efficacy:
provided by generally consistent
findings on multiple, high quality
scientific studies.
Recommendation level: A (High)
Page 18 of 63
Table 6: Efficacy and safety of SGAH in Allergic Rhinitis
Efficacy and safety of SGAH in Allergic Rhinitis
Study Design
Study Population
Publication
Multicenter,
double722 adults with
Double-blind,
blind, parallelseasonal allergic
placebo-controlled
group, placeborhinitis
study comparing the
efficacy and safety of controlled trial
fexofenadine
hydrochloride
(120 and 180 mg onc
e daily) and cetirizine
in seasonal allergic
rhinitis.
Howarth, P. H., et
al. (1999)[54]
Multinational,
688 adults with
Comparison of the
double-blind,
seasonal allergic
efficacy, safety and
randomized, placebo rhinitis
quality of life
-controlled, parallel
provided by
group study
fexofenadine
hydrochloride 120
mg, loratadine 10 mg
and placebo
administered once
daily for the
treatment of seasonal
allergic rhinitis.
Van Cauwenberge,
P., Juniper E. R.
(2000)[55]
Controlled clinical
study of the efficacy
of loratadine in
Nigerian patients
with allergic rhinitis.
Nwawolo, C. C.,
Olusesi, A. D.
(2001)[37]
Loratadine provides
Randomized
controlled trial
64 Nigerian
patients with
allergic rhinitis
Medications/Doses
Fexofenadine 120 mg
once daily,
Fexofenadine 180 mg
once daily, or
Cetirizine 10
mg once daily (active
control)
Objective(s)
Compared
the efficacy and
safety of fexofen
adine (120 and 1
80mg once daily)
and cetirizine (10
mg once daily)
in the treatment
of seasonal
allergic rhinitis.
Placebo, for 14 days
Fexofenadine 120 mg
once daily,
Loratadine 10 mg once
daily, or
Placebo, once daily,
for 14 days
Loratadine + Vitamin
C
Chlorphenamine +
Vitamin C
Compared
efficacy, safety a
nd impact
on quality of
life (QoL)
in seasonal
allergic rhinitis
patients (SAR)
of fexofenadine a
nd loratadine (wi
th placebo),
when administer
ed once daily.
To assess
efficacy and
tolerance of
loratadine
Vitamin C
Multi-center,
835 patients aged
Loratadine 10mg once
Results
Both doses of fexofenadine were superior to placebo in
reducing the total symptom score.
Efficacy was maintained for 24 hours.
There were no differences in efficacy between the 2 doses
of fexofenadine or between either dose of fexofenadine
and cetirizine.
There was no major side effect, but the combined incidence of
drowsiness or fatigue was greater with cetirizine (9%) than
with placebo (4%) (P =.07) or fexofenadine (4%) (P =.02).
Both fexofenadine (both P ≤ 0.0001) and loratadine (P ≤ 0.001
and P ≤ 0.005, reduced symptoms of seasonal allergic rhinitis
compared with placebo (n = 639).
Fexofenadine was found to better than loratadine in improving
24-h reflective itchy, watery, red eyes, as well as relieving
nasal congestion (P ≤ 0.05). Fexofenadine was also
significantly better than loratadine (P ≤ 0.03) and placebo (P ≤
0.005) in improving QoL, and the differences were of a
magnitude considered to be clinically relevant.
Loratadine did not have statistically significant effect on QoL
compared with placebo.
The incidence of adverse events was low and similar across
all treatment groups.
Loratadine was significantly better than Vit. C. alone (P =
0.0002).
Chlorpheniramine was also significantly better than Vit. C.
alone (P = 0.039).
Loratadine was significantly better than chlorpheniramine (P
= 0.046).
Evaluate efficacy
Drowsiness was noted in 19.2% of patients on loratadine
compared with 57.1% of patients on chlorpheniramine.
Significantly greater mean reductions from baseline were
Page 19 of 63
early symptom
control in seasonal
allergic rhinitis.
Kaiser HB, et al.
(2008) [53]
randomized,
placebo-controlled,
double-blind, double
dummy study (Post
hoc analysis)
12-60 years with a
2 years or longer
history of seasonal
allergic rhinitis
daily
Fexofenadine 60mg
twice daily
or Placebo for 7 days
Efficacy and safety
of loratadine
suspension in the
treatment of children
with allergic rhinitis.
Boner, A.L. (1989)
[38]
Randomized
controlled trial
Twentyone children with
allergic rhinitis
Loratadine 0.11-0.24
mg/kg ideal body
weight once daily
Dexchlorpheniramine
0.10-0.23 mg/kg every
8h
of loratadine
versus
fexofenadine and
placebo in
treatment of
allergic rhinitis.
Safety and effica
cy of loratadine c
ompared to
dexchlorphenira
mine in children.
shown with loratadine compared with fexofenadine in average
daily, total symptom score on days 2 (-3.51 versus -2.84,
respectively; p < 0.002).
Loratadine was significantly more effective than placebo for
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.
Both loratadine and dexchlorpheniramine were effective in
reducing nasal and ocular symptoms in allergic children.
Substantial improvement in allergy symptoms was observed at
the first evaluation (day 3 of treatment) and was maintained
for the study duration.
No abnormality in lab parameters was observed.
for 14 days
Comparison of the
effects of loratadine
and astemizole in the
treatment of children
with seasonal
allergic
rhinoconjunctivitis .
Boner AL, et al.
(1992) [56]
Randomized, singleblind, parallel-group
study
41 children (30
boys and 11 girls,
aged 6-14 years)
with seasonal
allergic
rhinoconjunctivitis.
Loratadine 10 mg (5
mg in patients with
body weight less than
or equal to 30 kg) once
daily
Evaluate the
efficacy and
safety of a oncedaily dose of
loratadine and
astemizole
Astemizole 2 mg/10
kg body weight once
daily for 14 days
Drowsiness was present only in the dexchlorpheniraminetreated group.
A significant improvement (p<0.01) in allergy symptoms was
observed from the third day for both medications;
There was no significant difference between medications,
although loratadine led to a greater reduction in symptoms.
Therapeutic response in loratadine group was 83.3% and in
astemizole group was 58.8%.
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.
A comparative study
of the efficacy and
safety of loratadine
syrup and
terfenadine
suspension in the
treatment of 3- to 6year-old children
Randomized, thirdparty-blind,
placebo-controlled,
parallel-group study
96 children 3- to 6year-old children
Loratadine 5mg once
daily,
Loratadine 10mg once
daily,
Terfenadine 15mg,
twice daily, for 14
Evaluate the
efficacy and
safety of
loratadine and
terfenadine
No abnormal changes in lab values were observed in either
group
Both treatments were effective in relieving individual nasal
and nonnasal symptoms. There were no statistically
significant differences between the two groups in the total
symptom scores at any point during the study.
Therapeutic response to loratadine 82% and to terfenadine
was 60%.
Page 20 of 63
days.
with seasonal
allergic rhinitis.
Lutsky BN, et al.
(1993)[57]
A double-blind,
placebo controlled,
and randomized
study of loratadine
(Clarityne) syrup for
the treatment of
allergic rhinitis in
children aged 3to 12
years. Yang YH, et
al. (2001)[58]
Fexofenadine is
efficacious and safe
in children (aged 611 years) with
seasonal allergic
rhinitis. Wahn U, et
al. (2003) [59]
The aim of this
double-blind,
placebo-controlled,
parallel, randomized
study
60 children 3 to 12
years old with
allergic rhinitis
Loratadine syrup 5 mg
Loratadine syrup 10
mg daily,
Adverse events were not significantly different between the
two treatment groups.
Evaluate the
effectiveness and
safety of
loratadine syrup
Or placebo for 3
weeks.
Multinational,
randomized,
placebo-controlled,
parallel-group,
double-blind study
The efficacy and
safety of 30 mg
fexofenadine HCl bid
in pediatric patients
with allergic rhinitis.
Ngamphaiboon J, et
al. (2005)[60]
Multi-center, openlabel, noncomparative study
Cetirizine for
seasonal allergic
rhinitis in children
aged 2-6 years.
Allegra L, et al.
(1993)[61]
Multi-center,
double-blind,
placebo-controlled,
parallel group study
A placebo-controlled
trial of cetirizine in
seasonal allergic
rhino-conjunctivitis
Multi-center,
double-blind,
placebo-controlled,
parallel group study
935 children, 6-11
years of age with
seasonal allergic
rhinitis
Fexofenadine 30 mg
twice daily
or placebo twice daily
for 14 days.
No adverse reactions were recorded in both groups.
Assess the
efficacy and
safety of
fexofenadine in
children with
seasonal allergic
rhinitis.
100 Asian
(Thailand)
children, 6-11
years of age
diagnosed with
seasonal or
perennial allergic
rhinitis.
107 children of
both sexes between
2 and 6 years of
age with polleninduced seasonal
allergic rhinitis
Fexofenadine 30 mg
twice-daily
Evaluate efficacy
and safety of a
twice-daily oral
dose of
fexofenadine
Cetirizine drops 5mg
once daily
Evaluate the
safety and
efficacy of
cetirizine
124 children of
both sexes aged
between 6 and 12
years with pollen-
Cetirizine 5mg twice
daily,
or placebo once daily
for 14 days
There were no reports of sedation or dry mouth in either
group.
The total symptom score (TSS) (comprising of sneezing,
rhinorrhea, nasal congestion, nasal itching and ocular
symptoms) of the loratadine syrup group at day 7 and day 21
was lower than those of the placebo group (p = 0.003, p =
0.06).
Fexofenadine was significantly superior to placebo to reduce
symptoms of allergic rhinitis (p ≤0.0001).
Reduction is individual symptom scores was superior
compared with placebo (p <.05), including nasal congestion (p
<.05).
There was no significant difference in adverse events between
fexofenadine and placebo.
With fexofenadine, there was a statistically significant
improvement for the total symptom score with or without
blocked nose and for each symptom score such as blocked
nose, sneezing, rhinorrhea, itchy nose/palate and/or throat, and
itchy/watery/red eyes from baseline to week 1 and week 2. (p
< 0.01)
Cetirizine was more effective than placebo for each symptom
evaluated (p=0.04) Cetirizine provided more symptom free
days than did placebo (p = 0.002).
Both treatments were tolerated well. 3 patients on cetirizine
and none on placebo experienced mild somnolence.
Assessment of
efficacy of
cetirizine
Cetirizine provided more mean symptom free days than did
placebo, 56.2% and 29.7%, respectively. This 26.5%
difference was considered clinically significant.
or placebo twice daily
Page 21 of 63
in children aged 6 to
12 years. Masi M, et
al. (1993)[62]
Once-daily
cetirizine effective in
the treatment of
seasonal allergic
rhinitis in children
aged 6 to 11 years: a
randomized, doubleblind, placebocontrolled study.
Pearlman DS, et al.
(1997)[63]
Randomized,
double-blind,
placebo-controlled
trial
associated rhinoconjunctivitis
for 14 days
209 children, 6 to
11 years of age
with seasonal
allergic rhinitis
Cetirizine syrup (5 or
10 mg daily)
or placebo for 4 weeks
Improvement in individual daily symptoms was greater for
cetirizine than placebo.
Evaluate the
safety and
efficacy of
cetirizine syrup
Cetirizine 10 mg produced a significantly greater mean total
symptom severity (TSS) reduction than placebo (P < 0.05)
over the treatment period.
Cetirizine 5 mg once daily produced mean reductions in
weekly TSS, however, this did not differ statistically from
placebo.
The health related
quality of life effects
of once-daily
cetirizine HCl syrup
in children with
seasonal allergic
rhinitis. Gillman SA,
et al. (2002)[64]
Multicenter, openlabel, noncomparative study
544 children, 6 to
11 years of age
with seasonal
allergic rhinitis
Cetirizine syrup 10 mg
once daily for 4 weeks
Assessment of
health-related
quality of life
(HRQL)
Double-blind
comparison of
cetirizine and
loratadine in
children ages 2 to 6
years with perennial
allergic rhinitis.
Sienra-Monge, J.J.,
et al. (1999)[52]
prospective,
randomized, doubleblind, longitudinal,
parallel-group study
80 children, 2 to 6
years of age, with
perennial allergic
rhinitis
Cetirizine 0.2mg/kg
Evaluate
comparative
efficacy and
safety of
cetirizine and
loratadine.
Loratadine 0.2mg/kg
for 28 days
The most commonly reported adverse reactions to both
cetirizine and placebo were headache, pharyngitis, and
abdominal pain; these incidences were not statistically
between treatment and placebo.
Cetirizine provided significant improvements in HRQL in all
age groups (6-7, 8-9, 10-11 years) (p < 0.001) during the
treatment period.
Cetirizine produced significantly greater inhibition of the
wheal response compared with loratadine (P <.0001)
Cetirizine and loratadine produced comparable improvements
in symptoms
Cetirizine was more effective than loratadine in relieving the
symptoms of rhinorrhea, sneezing, nasal obstruction, and
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
EAACI/GA2LEN/EDF/WAO
guideline: management of urticaria
(2009)[14]
Treatment of Urticaria
First line therapy: 2nd
generation antihistamine
Evidence Level and Recommendation
GRADE: Strong recommendation with lowquality evidence
Avoid 1st generation
antihistamines
GRADE: Strong recommendation with high
quality evidence
Second-generation H1antihistamines in chronic urticaria:
an evidence-based review.
Kavosh, E. R. and Khan, D. A.
(2011) [2]
2nd generation
antihistamines
GRADE: Strong recommendation with high
quality evidence
Page 24 of 63
Table 8: Efficacy and Safety of SGAHs in Urticaria
Efficacy and Safety of SGAHs in Urticaria
Study Design
Study Population
Publication
Randomized,
15 healthy elderly
Central nervous
double-blind,
subjects (mean
system effects of
single-dose,
age 71 +/- 5 years)
H1-receptor
antagonists in the placebocontrolled, 5elderly. Simons,
way crossover
F. E., et al.,
study
(1999) [25]
Medications/Doses
Cetirizine 10 mg,
Loratadine 10 mg,
Objective(s)
To compare effects of study
medications on performance,
somnolence, and peripheral H1blockade.
Diphenhydramine 50
mg,
Somnolence ranked from more to less with
medications as follows: diphenhydramine >
chlorphenamine > cetirizine > loratadine > placebo.
Chlorphenamine 8
mg, or
Placebo
Benefit/risk ratio
of the
antihistamines
(H1-receptor
antagonists)
terfenadine and
chlorpheniramine
in children.
Simons, F. E., et
al., (1994) [39]
Cetirizine versus
hydroxyzine and
placebo in
chronic
idiopathic
urticaria.
Breneman, D. L.
(1996) [40]
A double-blind,
placebocontrolled trial of
Double-blind,
single-dose,
placebocontrolled,
three-way
crossover study
Multicenter,
randomized,
double-blind,
double-dummy,
placebocontrolled
Multicenter,
placebocontrolled
15 children with
allergic rhinitis
(mean age, 8.5 +/1.4 years)
Terfenadine 60 mg,
Chlorphenamine, 4
mg, or
To compare effects of study
medications on performance,
somnolence, and peripheral H1blockade
Placebo
188 patients at
least 12 years of
age, with
symptomatic
chronic idiopathic
urticaria that had
occurred
episodically for at
least 6 weeks.
439 patients with
moderate to severe
pruritus and
Cetirizine 10 mg once
daily,
Hydroxyzine 25 mg
three times daily, or
Results
Performance was affected by FGAH more than
SGAH in increasing to decreasing order as follow:
chlorphenamine > diphenhydramine > loratadine >
placebo > cetirizine.
All H1-receptor antagonists suppressed the histamineinduced wheal and flare significantly compared to
placebo.
Both terfenadine and chlorphenamine suppressed the
histamine-induced wheal and flare compared with
baseline and with placebo; terfenadine was
significantly more effective (p < 0.05).
Terfenadine did not impact performance in contrast to
chlorphenamine and placebo.
To compare the safety and efficacy
of cetirizine with that of
hydroxyzine and placebo in the
treatment of chronic idiopathic
urticaria.
Terfenadine and placebo did not increase somnolence
compared with baseline, but chlorphenamine did.
Cetirizine and hydroxyzine had a significant
reduction in urticaria symptoms of lesions and
pruritus at weeks 1, 2, and 3 compared to placebo
(p<0.04).
Cetirizine reduced symptoms of urticaria after one
day of treatment over hydroxyzine. (p=0.002).
Placebo for 4 weeks
Both agents showed significant improvement in
urticaria symptoms at the end of 4 weeks compared to
placebo group (p < 0.001).
Fexofenadine 20, 60,
120, or 240 mg twice
daily
Evaluate the safety and efficacy of
fexofenadine for the treatment of
chronic urticaria symptoms.
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.
All 4 doses of fexofenadine were statistically superior
to placebo (P ≤ 0.0238) in relieving symptoms of
urticaria.
Page 25 of 63
fexofenadine HCl
in the treatment
of chronic
idiopathic
urticaria.
Finn AF Jr, et al.
(1999) [72]
study
urticaria
or Placebo for 4
weeks
Less interference with sleep and daily activities was
observed with fexofenadine over placebo (P
≤0.0001).
Efficacy results were similar in the 60, 120, and 240mg groups and were quantitatively better than those
in the 20mg group.
Adverse events were mild and occurred with similar
incidence in all treatment groups.
Fexofenadine
HCl is safe and
effective for
treatment of
chronic
idiopathic
urticaria.
Nelson HS, et al.
(2000) [73]
Multi-center,
double-blind,
randomized,
placebocontrolled
study
418 patients with
urticaria
Fexofenadine 20, 60,
120, or 240 mg twice
daily
Assess safety and efficacy of
fexofenadine in chronic idiopathic
urticaria.
or Placebo for 4
weeks
Doses of 60 mg twice a day or greater are most
effective.
All four fexofenadine doses were statistically superior
to placebo (P ≤ 0.0115) for reducing pruritus and
number of wheals scores over the 4-week treatment
period.
Greater reductions in urticaria symptoms occurred
with 60, 120 and 240 mg fexofenadine groups than in
the 20 mg group.
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.
A comparison of
the efficacy of
cetirizine and
terfenadine: a
double-blind,
controlled study
of chronic
idiopathic
urticaria
Andri L, et al.
(1993)[69]
Double-blind,
randomized,
parallel study
30 patients with
chronic idiopathic
urticaria
Cetirizine 10 mg once
daily
or Terfenadine 60 mg
twice daily for 20
days
Evaluate the efficacy of cetirizine
and terfenadine in chronic
idiopathic urticaria
Fexofenadine, twice-daily doses of 60 mg or greater
were most effective.
Cetirizine was more effective than terfenadine in
controlling urticaria symptoms. Symptoms assessed
on a 4-point scale showed a better improvement in the
cetirizine group.
The number and severity of side-effects were similar
in both treatment groups.
Page 26 of 63
Cetirizine and
astemizole
therapy for
chronic
idiopathic
urticaria: a
double-blind,
placebocontrolled,
comparative trial.
Breneman D, et
al. (1995)[70]
Urticaria: clinical
efficacy of
cetirizine in
comparison with
hydroxyzine and
placeb.
Kalivas J, et al.
(1990) [44]
Randomized
placebocontrolled trial
comparing
desloratadine and
montelukast in
monotherapy and
desloratadine
plus montelukast
in combined
therapy for
chronic
idiopathic
urticaria.
Di Lorenzo G, et
al. (2004) [71]
Multicenter,
randomized,
double-blind
trial
187 total patients
with chronic
idiopathic
urticaria;
180 included in
the safety analysis
and 177 included
in efficacy
analysis
Multicenter,
double-blind,
placebocontrolled
Patients with
chronic urticaria
Cetirizine 10mg once
daily
Astemizole 10mg
once daily
Compare the efficacy of cetirizine
and astemizole in relieving the
symptoms of chronic idiopathic
urticaria
Both active treatments were well tolerated, and the
incidence of somnolence did not differ statistically
between cetirizine (14.5%) and astemizole (10.3%).
or Placebo for 4
weeks
Cetirizine 5 to
20mg/day,
To evaluate safety and efficacy of
cetirizine compared to hydroxyzine
in treatment of urticaria
Hydroxyzine 25 to
75mg/day
or Placebo for 4
weeks
Randomized,
double-blind,
double-dummy,
placebocontrolled,
parallel-group
study
160 patients aged
18 to 69 years
(mean +/- SD,
43.9 +/- 13.4
years) with a
history of
moderate chronic
idiopathic urticaria
Desloratadine 5mg
once daily (n = 40),
Montelukast 10mg
once daily (n = 40),
Desloratadine 5mg (n
= 40) in the morning
plus montelukast in
the evening,
or matched placebo (n
= 40).
Both cetirizine and astemizole were significantly
superior to placebo in relieving symptoms of chronic
idiopathic urticaria with more rapid clinical benefit
with cetirizine.
Cetirizine was equivalent in efficacy to hydroxyzine.
The incidence of somnolence in the cetirizine group
was not significantly different from that of the
placebo group.
In the hydroxyzine group, the incidence of
somnolence was significantly higher than that in the
placebo group (p = 0.001).
Evaluate the efficacy of 5 mg of
desloratadine administered once
daily either as monotherapy or
combined with a leukotriene
antagonist, 10 mg of montelukast
daily, and 10 mg of montelukast
administered daily as monotherapy
for the treatment of patients
affected by CIU with placebo.
Cetirizine has a greater safety margin over
hydroxyzine.
Treatment groups significantly reduced number of
hives and size of largest hive compared to placebo.
Only groups receiving desloratadine significantly
reduced pruritus.
There were no significant differences between the
group treated with montelukast alone and the placebo
group for pruritus and size of largest hive.
27 of the 40 patients in the montelukast group and 35
of the 40 patients in the placebo group discontinued
the treatment. No patients in the desloratadine study
discontinued the study.
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 lesssedating, 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 nonsedating 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 antihistamine 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, 8899]
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
Central
Nervous
System
1st Generation Antihistamines
With therapeutic doses may cause drowsiness, fatigue,
somnolence, dizziness; impairment of cognitive
function, memory, and psychomotor performance;
headache, dystonia, dyskinesia, agitation, confusion, and
hallucinations.
2nd Generation Antihistamines
Adverse effects such as drowsiness
may occur at higher doses.
No adverse effects reported in
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
supraventricular arrhythmias; dose related prolongation
System
of the QT interval and ventricular arrhythmias reported
for diphenhydramine other 1st generation agents.
No major concern in the United
States since regulatory approval
was withdrawn for astemizole and
terfenadine.
After therapeutic doses, may cause pupillary dilatation,
dry eyes, dry mouth, urinary retention and hesitancy,
gastrointestinal motility, constipation, erectile
dysfunction, memory deficits; peripheral vasodilatation,
postural hypotension, dizziness; contraindicated in
patients with glaucoma or prostatic hypertrophy.
Rare, no major concerns for anticholinergic side-effects.
Central nervous system effects — extreme drowsiness,
lethargy, confusion, delirium, and coma in adults;
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]
No serious toxic effects or deaths
reported.
AntiCholinergic
Overdose
Page 31 of 63
Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment
Side-effects: Sedation, drowsiness, psychomotor impairment
Study Design
Study Population
Medications/Doses
Publication
Randomized,
40
licensed
drivers
One dose of
Effects of
double-blind,
with seasonal
Fexofenadine 60 mg,
fexofenadine,
diphenhydramine, double-dummy, allergic rhinitis
four-treatment, between 25 to 44
Diphenhydramine 50
and alcohol on
four-period
years of age.
mg,
driving
crossover trial.
performance. A
Alcohol
randomized,
(approximately 0.1%
placebo-controlled
blood alcohol
trial in the Iowa
concentration),
driving simulator.
Weiler, J.M., et
or Placebo
al., (2000) [100]
Randomized,
15 healthy elderly Cetirizine 10 mg,
Central nervous
double-blind,
subjects (mean
system effects of
single-dose,
age 71 +/- 5 years) Loratadine 10 mg,
H1-receptor
antagonists in the placebocontrolled, 5Diphenhydramine 50
elderly. Simons,
way crossover
mg,
F. E., et al.,
study
(1999) [25]
Chlorphenamine 8
mg,
Objective(s)
To measure coherence, drowsiness
and other driving measure with
study medications.
Lane keeping (steering instability and crossing the
center line) was impaired after alcohol and
diphenhydramine use compared with fexofenadine
use.
To compare effects of study
medications on performance,
somnolence, and peripheral H1blockade.
Double-blind,
single-dose,
placebocontrolled,
three-way
crossover study
A retrospective
cohort study
15 children with
allergic rhinitis
(mean age, 8.5 +/1.4 years)
Terfenadine 60 mg,
Chlorphenamine, 4
mg,
To compare effects of study
medications on performance,
somnolence, and peripheral H1blockade
or Placebo
12,106 patients
with initial
antihistamine
prescription for
diphenhydramine
and 24,968
N/A
Performance was affected by FGAH more than
SGAH in increasing to decreasing order as follow:
chlorphenamine > diphenhydramine > loratadine >
placebo > cetirizine.
Somnolence ranked from more to less with
medications as follows: diphenhydramine >
chlorphenamine > cetirizine > loratadine > placebo.
or Placebo
Benefit/risk ratio
of the
antihistamines
(H1-receptor
antagonists)
terfenadine and
chlorpheniramine
in children.
Simons, F. E., et
al., (1994) [39]
Increased risk of
serious injury
following an
initial prescription
for
diphenhydramine.
Results
Coherence: Participants had significantly better
coherence after taking alcohol or fexofenadine than
after taking diphenhydramine.
All H1-receptor antagonists suppressed the histamineinduced wheal and flare significantly compared to
placebo.
Both terfenadine and chlorphenamine suppressed the
histamine-induced wheal and flare compared with
baseline and with placebo; terfenadine was
significantly more effective (p < 0.05).
Terfenadine did not impact performance in contrast to
chlorphenamine and placebo.
Rates of serious injuries in the
diphenhydramine cohort after and
before the first prescription
compared to the rates of injuries in
the loratadine cohort after and
before the first prescription.
Terfenadine and placebo did not increase somnolence
compared with baseline, but chlorphenamine did.
The rate of all injuries was 308 per 1,000 personyears in the diphenhydramine cohort versus 137 per
1,000 person-years in the loratadine cohort.
The percentage of the injuries attributable to
diphenhydramine was 55% (CL 41, 65)
Page 32 of 63
Finkle, W. D., et
al., (2002) [102]
Prevalence of
chlorpheniramine
in aviation
accident pilot
fatalities, 19911996. Soper, J.
W., et al. (2000)
[103]
First-generation
H1 antihistamines
found in pilot
fatalities of civil
aviation accidents,
1990-2005. Sen,
A., et al. (2007)
[104]
Differential
cognitive effects
of terfenadine and
chlorpheniramine.
Meador, K. J., et
al. (1989) [88]
Retrospective
Retrospective
Double-blind,
randomized,
three-period
crossover
patients with
initial
antihistamine
prescription for
loratadine.
A postmortem
toxicology
database-maintained at the
Civil Aeromedical
Institute--was
examined for the
presence of
chlorphenamine in
the fatalities,
occurred during
1991-1996.
The Civil
Aerospace
Medical Institute's
(CAMI's)
Toxicology
Database was
examined for the
presence of the
first-generation
antihistamines in
pilot fatalities of
civil aircraft
accidents that
occurred during a
16-yr (1990-2005)
period.
24 healthy adult
subjects
Chlorphenamine
To detect the presence of
chlorphenamine in blood and liver
There were 47 (2.2%) accidents involving
chlorphenamine. Of these, 16 had only
chlorphenamine at 109 ng.ml-1 (n = 4) in blood and
1412 ng.g-1 (n = 12) in liver. Other medications were
also present in the remaining 31 cases, but
chlorphenamine concentrations were 93 ng.ml-1 (n =
18) in blood and 747 ng.g-1 (n = 12) in liver.
95% of all quantitated blood values were at or above
the therapeutic level. The average blood value was
approximately 10 times higher than the therapeutic
value.
First generation antihistamines:
brompheniramine,
chlorphenamine,
diphenhydramine,
doxylamine,
pheniramine,
phenyltoloxamine,
promethazine, and
triprolidine.
Terfenadine 60 mg,
Chlorphenamine
maleate 8 mg,
or Placebo
To detect the presence of one of the
study medications in blood
Chlorphenamine was present in some aviation
fatalities at levels higher than therapeutic levels.
Of 5383 fatal aviation accidents reviewed, there were
338 accidents wherein pilot fatalities (cases) were
found to contain one of the study medications.
Antihistamines were detected alone in 103 fatalities
(1 antihistamine in 94 and 2 antihistamines in 9),
while other drug(s) and/or ethanol were also present
in an additional 235 fatalities.
The antihistamines were found in approximately 4
and 11% of the fatalities/accidents in 1990 and in
2004, respectively.
Assess the latency of the P3evoked potential with the study
medications. (The P3 is a
cognitively evoked
electroencephalographic response
that is an objective and sensitive
measure of sustained attention and
cerebral processing speed. Disease
The use of antihistamine(s) was determined by the
National Transportation Safety Board to be the cause
of 13 and a factor in 50 of the 338 accidents.
Baseline P3 latency (millisecond) means (+/- mean
standard error) pretreatment was 310 (+/- 1.7).
Post treatment the P3 latencies were for placebo, 313
(+/- 3); for terfenadine, 320 (+/- 3); and for
chlorphenamine, 333 (+/- 3).
Compared to terfenadine, chlorphenamine caused
Page 33 of 63
Loratadine in the
high performance
aerospace
environment.
Hansen, G.R.
(1999) [106]
Systematic
Review
Pooled:
Adult subjects:
517 treated with
loratadine and 510
given placebo
Various doses:
Loratadine 10mg,
20mg and 40mg
and drug states that adversely
affect the central nervous system
can slow P3 latency.)
Assess sedation and performance
impairment with study
medications.
or Placebo
much higher P3 latency. Both medications increased
the P3 latency compared to placebo and baseline.
Pooled data showed sedation in 25 of 517 patients
given 10 mg of loratadine, and 24 of 510 patients
given placebo, with a relative risk of 1.03.
Patients treated with 10 mg of loratadine did not have
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.
Effects of
loratadine and
cetirizine on
actual driving and
psychometric test
performance, and
EEG during
driving.
Ramaekers, J. G.,
et al. (1992) [107]
6-way, doubleblind crossover trial
Sixteen healthy
male and female
Cetirizine 10 mg,
Assess driving performance with
study medications.
Ingesting 10 mg of loratadine daily does not appear to
have sedative effects or impair cognitive-motor
performance.
Alcohol significantly affected almost every
performance measure.
Loratadine 10 mg
Cetirizine effects on driving performance resembled
those of alcohol. It caused the subjects to operate with
significantly greater variability in speed and lateral
position ('weaving' motion).
Alcohol
or Placebo
The effects of alcohol and cetirizine appeared to be
additive.
Loratadine had no significant effect on any
performance parameter.
Central nervous
system effects of
H1-receptor
antagonists in the
elderly. Simons,
Rrandomized,
double-blind,
single-dose,
placebocontrolled, 5-
15 healthy elderly
subjects (mean
age 71 +/- 5 years)
Cetirizine 10 mg,
Loratadine 10 mg,
To compare effects of study
medications on performance,
somnolence, and peripheral H1blockade.
It was concluded that cetirizine, but not loratadine,
generally caused mild impairment of performance
after a single 10 mg dose.
Performance was affected by FGAH more than
SGAH in increasing to decreasing order as follow:
chlorphenamine > diphenhydramine > loratadine >
placebo > cetirizine.
Diphenhydramine 50
Page 34 of 63
F. E., et al.,
(1999) [25]
way crossover
study
mg,
Chlorphenamine 8
mg, or
Placebo
Somnolence ranked from more to less with
medications as follows: diphenhydramine >
chlorphenamine > cetirizine > loratadine > placebo.
All H1-receptor antagonists suppressed the histamineinduced 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
Study Design
Publication
Prospective, doubleProspective, longterm safety evaluatio blind, randomized
placebo controlled
n of the H1-receptor
antagonist cetirizine i
n very young
children with atopic
dermatitis. ETAC
Study Group. Early
Treatment of
the Atopic Child.
Simons FE. (1999)
[120]
Prophylactic manage
ment of children at ri
sk for recurrent uppe
r respiratory
infections: the
Preventia I Study.
Grimfeld, A. (2004)
[121]
Multinational,
randomized
placebocontrolled study
Safety of
levocetirizine
treatment in young
atopic children: An
18-month study.
Simons F.E., et al.
(2007) [36]
prospective,
randomized, doublemasked, placebocontrolled
Study Population
817 children with
atopic dermatitis, 12
to 24 months old
Medications/Doses
Cetirizine 0.25
mg/kg twice daily
or Placebo twice
daily.
Children, 12–30
months of age
Loratadine 5 mg/day
(2.5 mg/day
for children</=24
months of age)
or Placebo
Phase I: 12-month
double-blind period
for treatment with
loratadine or
placebo.
Phase II: doubleblind follow-up
period without study
medication.
Levocetirizine 0.125
mg/kg twice daily
or placebo twice
daily
for 18 months
Phase 1: 342
Phase 2: 310
255 children (with
study drug) and 255
children (placebo);
12-24 months of age
Objective(s)
Assess safety of
study medication
(adverse events,
diary cards,
physical
examinations,
developmental
assessments,
electrocardiogra
ms, blood
hematology and
chemistry tests,
and urinalyses.)
Evaluate the
efficacy and
long-term safety
of loratadine in
reducing the
number of
respiratory
infections in
children at 24
months.
Results
Reported symptoms were mild, including respiratory or
gastrointestinal infections, exacerbations of allergic disorders, or agerelated concerns; they were determined to be not medication-related
adverse effects.
No clinically relevant differences between the groups for neurologic
or cardiovascular symptoms or events, growth, behavioral or
developmental assessments, laboratory test results, or
electrocardiograms, and no child receiving cetirizine therapy had
prolongation of the QTc interval.
Drop-outs and serious events, including hospitalizations, were less
common in cetirizine group versus placebo; the differences were not
statistically significant.
Cetirizine is safe for long term use in young children.
No difference in reduction of respiratory infections was observed
between the loratadine and placebo group.
Loratadine was shown to reduce the number of respiratory
exacerbations during the treatment phase.
None of the 204 children who received loratadine discontinued the
study because of drug-related events.
Loratadine treatment was not more sedating than placebo and was not
associated with cardiovascular events.
Loratadine is safe for long term use in young children.
Assess safety of
levocetirizine in
young atopic
children.
One or more adverse events with levocetirizine: 96.9% and placebo:
95.7%.
Serious adverse events with levocetirizine: 12.2% and placebo: 14.5%
Medication-attributed adverse events with levocetirizine: 5.1% and
placebo: 6.3%
Permanent discontinuation of study medication due to adverse events
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
Terfenadine pharma
cokinetics in breast
milk in lactating wo
men.
Lucas, B. D., et al.
(1995)[119]
Pharmacokinetic
study
4, adult, healthy
lactating women
Terfendadine 60mg
(primary metabolite
is fexofenadine)
Pharmacokinetic
study for
Terfendadine
and its primary
active
metabolite,
fexofenadine
levels in breast
milk and venous
blood
Excretion of loratadi
ne in human breast
milk.
Hilbert, J., et al.
(1988) [118]
Pharmacokinetic
study
6, adult, healthy
lactating women
40-mg loratadine
Pharmacokinetic
study for
loratadine to
determine
plasma and milk
concentrations of
study
medication.
Safety considerations
in the management
of allergic diseases:
focus on
antihistamines.
Yanai, K., et al.
(2012) [4]
Systematic review
Adults and children
First and Second
generation
antihistamines
Safety of cetirizine in
infants 6 to 11
months of age: a
Prospective,
randomized,
parallel-group,
Infants age 6 to 11
months
0.25 mg/kg
cetirizine orally
Review of
evidence
supporting the
safety profiles of
frequently used
oral
antihistamines
for the treatment
allergic diseases,
(allergic rhinitis
and urticaria.)
Assessment of
safety of
cetirizine in
Levocetirizine is safe for long term use in young children.
Mean +/- SD active metabolite data for milk and plasma are as
follows: Cmax (ng/ml), 41.0 +/- 16.4 for milk, 309.0 +/- 120.5 for
plasma; tmax (hours), 4.3 +/- 2.4 for milk, 3.9 +/- 3.0 for plasma; t1/2
beta (hours), 14.2 +/- 5.4 for milk, 11.7 +/- 6.4 for plasma; AUC(012) (ng.hr/ml) 320.4 +/- 99.8 for milk, 1590.0 +/- 300.4 for plasma.
Metabolite milk/plasma AUC(0-12) ratios ranged from 0.12 to 0.28
(mean, 0.21 +/- 0.07).
Newborn dosage estimates based on the highest measured
concentration of terfenadine metabolite in milk suggests the
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.
For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after
dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour
collection interval.
Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and
4.2 micrograms of loratadine was excreted in breast milk, which was
0.010% of the administered dose.
For descarboethoxyloratadine, a metabolite of loratadine, the
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.
Second-generation oral antihistamines (SGAHs) have proven better
safety and tolerability profiles over first-generation antihistamines
(FGAHs).
SGAHs have much lower proportional impairment ratios than
FGAHs.
SGAHs have at least similar, if not better efficacy, than FGAHs.
Only SGAHs, and especially those with a proven long-term clinical
safety, should be prescribed for young children.
The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg
(SD).
Page 39 of 63
randomized, doubleblind, placebocontrolled study.
Simons FE, et al.
(2003) [122]
Safety of
fexofenadine in
children treated for
seasonal allergic
rhinitis.
Graft DF, et al.
(2001) [123]
double-blind,
placebo-controlled
study
or Placebo twice
daily orally
for 1 week.
Two large, doubleblind, randomized,
placebo-controlled,
parallel studies
875 children ages 6
through 11 years with
seasonal allergic
rhinitis.
Fexofenadine 15,
Fexofenadine 30,
Fexofenadine 60 mg
or placebo twice
daily for 2 weeks
after a 1-week
placebo lead-in.
infants,
particularly with
regard to central
nervous system
and cardiac
effects,
inclusive.
Evaluate the
safety of
fexofenadine
No differences in all-cause or treatment-related adverse events were
observed between the cetirizine- and placebo-treated groups.
A trend was observed toward fewer adverse events and sleep-related
disturbances in the cetirizine group compared with the placebo group.
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.
5 patients on placebo and 5 on fexofenadine dropped from the studies
due to adverse events not caused by study medication.
Incidence of adverse events was similar in active and placebo groups,
and did not increase with increasing fexofenadine dose: 36.2% (83 of
229) in the placebo group versus 35.3% (79 of 224), 36.8% (77 of
209), and 34.7% (74 of 213) in the 15, 30, and 60 mg twice-daily
fexofenadine groups, respectively.
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
Strength)
Cost per
unit (US$)
Cost/30 tabs or
100mL solution or
100mg inj (US$)
0.114
0.43
Daily
Maximum Dose
(adult)
24mg/daily
24mg/daily
Monthly cost based on
maximum dosing (US$)
0.684
Chlorphenamine 4mg tab 0.0038
0.0043/mL
7.74
Chlorphenamine
2mg/5mL oral solution
0.1470/mL 1.47
24mg/daily
N/A
Chlorphenamine
10mg/mL injection
0.0161
0.483
200mg/daily
3.864
Diphenhydramine 25mg
cap
3.1264/mL 6.25
400mg/daily
N/A
Diphenhydramine
50mg/mL injection
0.1016/mL 10.16
200mg/daily
8.128
Diphenhydramine
12.5mg/5mL oral solution
0.0225
0.675
10mg/daily
0.675
Loratadine 10mg tab
0.0055/mL 0.55
10mg/daily
1.65
Loratadine 1mg/1mL
oral solution
Lexi-Comp online (US market price)
1.000
30
10mg/daily
60
Cetirizine 5mg
0.1899
5.70
10mg/daily
5.70
Cetirizine 10mg
0.1355/mL 13.55
10mg/daily
40.65
Cetirizine 1mg/mL oral
solution
0.8663
25.99
180mg/daily
25.99
Fexofenadine 180mg tab
0.1749
17.49
180mg/daily
157.41
Fexofenadine 30mg/5mL
solution*
*Originator brand suspension for fexofenadine, all other prices are for generic products
FDA
Approved
TGA
Approved
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Table 13: Availability of reviewed medications on NEMLs of 15 nations
#
Country
Bangladesh
1
China
2
Dominican Republic
3
Ecuador
4
Fiji
5
Ghana
6
India
7
Iran
8
Kyrgyzstan
9
10 Malta
11 Morocco
12 Malaysia
13 Namibia
14 Nigeria
15 Oman
Total # of surveyed countries with
identified medications on the NEML
(any formulation) and (%)
Chlorphenamine
tab/inj/syrup
tab/inj
tab
tab
Not present
Not present
tab/syrup
tab
tab/inj/syrup
Not present
tab/syrup
Not present
tab/inj/syrup
tab/syrup
tab/inj/syrup
tab/inj/syrup
10
66%
Diphenhydramine
cap/inj/solution
Not present
cap/inj
cap/inj/solution
cap/inj/solution
Not present
tab
Not present
tab/inj/solution
tab/inj
tab/syrup
Not present
Not present
Not present
Not present
Not present
7
46%
Loratadine
tab/syrup
Not present
Not present
tab/syrup
tab/syrup
Not present
Not present
Not present
tab/syrup
tab/syrup
tab/syrup
tab/syrup
Not present
Not present
Not present
tab/syrup
7
46%
Cetirizine
tab/syrup
Not present
Not present
Not present
Not present
Not present
Not present
tab/syrup
tab/syrup
tab/syrup
tab/syrup
tab/syrup
Not present
Not present
Not present
tab/syrup
6
40%
Fexofenadine
tab/syrup
Not present
Not present
Not present
Not present
Not present
Not present
Not present
tab
Not present
tab
Not present
Not present
Not present
Not present
Not present
2
13%
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
formulations)
Allergic
Loratadine[126]
Rhinitis
(Tablet 10mg,
Syrup 1mg/mL)
Chronic
Urticaria
Anaphylaxis
Adult Dosing
Pediatric Dosing
Monitoring
Improvement in
symptoms of rhinitis
Sedation
6 years and older: 10 mg tab
Improvement in
or syrup, PO Once Daily
urticaria
Sedation
No evidence to support use of antihistamines in anaphylaxis; clinicians may
refer to institutional guidelines or procedures for appropriate use.
10mg tab or
syrup, PO
Once Daily
2-5 years: 5 mg tab or syrup,
PO Once Daily
Table 15: Dose Adjustments for Loratadine
Impairment
Renal Impairment
(GFR<30mL/min)
Hepatic Impairment
Age Group
6 years and older
2 to 5 years
6 years and older
2 to 5 years
Dose
10mg PO every other day
5mg every other day
10mg PO every other day
5mg every other day
Page 44 of 63
Appendix
This page is blank.
Page 45 of 63
Appendix 1 – Drug-Drug Interactions: 1st Generation Antihistamines
FGAH
Diphenhydramine
Chlorphenamine
Interacting drug or class
1
Linezolid
EML(y/n)
N
Severity
Major
Documentation
Fair
2
Zolpidem / sedatives
N
Major
Fair
3
Oxycodone / sedatives
N
Major
Fair
4
Tapentadol sedatives
N
Major
Fair
5
N
Major
Fair
6
Hydromorphone /
sedatives
Metoprolol
Y
Moderate
Good
7
Tamoxifen
Y
Moderate
Fair
8
Clomipramine
Y
Moderate
Fair
9
Amitriptyline
Y
Moderate
Fair
10
Triflupromazine
N
Moderate
Fair
11
Procarbazine
Y
Moderate
Fair
12
Amoxapine
N
Moderate
Fair
13
Belladonna
N
Minor
Fair
1
Lorcaserin
N
Major
Fair
2
Bromocriptine
N
Major
Fair
3
Phenytoin
Y
Moderate
Fair
Interaction Details
Concurrent use of DIPHENHYDRAMINE and LINEZOLID may result in increased
anticholinergic toxicity effects.
Concurrent use of ZOLPIDEM and SEDATIVES may result in an increase in central
nervous system depressant effects.
Concurrent use of OXYCODONE and SEDATIVES may result in an increase in CNS or
respiratory depression.
Concurrent use of TAPENTADOL and SEDATIVES may result in an increase in central
nervous system and respiratory depression.
Concurrent use of HYDROMORPHONE and SEDATIVES may result in an increase in
CNS or respiratory depression.
Concurrent use of DIPHENHYDRAMINE and METOPROLOL may result in increased
metoprolol plasma concentration.
Concurrent use of DIPHENHYDRAMINE and TAMOXIFEN may result in decreased
plasma concentrations of the active metabolites of tamoxifen.
Concurrent use of CLOMIPRAMINE and DIPHENHYDRAMINE may result in
increased anticholinergic effects (dry mouth, urinary retention).
Concurrent use of AMITRIPTYLINE and DIPHENHYDRAMINE may result in
increased anticholinergic effects (dry mouth, urinary retention).
Concurrent use of TRIFLUPROMAZINE and DIPHENHYDRAMINE may result in
anticholinergic effects (dry mouth, urinary retention, altered mental status).
Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS
depression.
Concurrent use of AMOXAPINE and DIPHENHYDRAMINE may result in increased
anticholinergic effects (dry mouth, urinary retention).
Concurrent use of BELLADONNA and DIPHENHYDRAMINE may result in excessive
anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive
sedation, blurred vision).
Concurrent use of LORCASERIN and SEROTONERGIC AGENTS may result in
increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,
myoclonus, mental status changes).
Concurrent use of BROMOCRIPTINE and CHLORPHENIRAMINE may result in
increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,
myoclonus, mental status changes).
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
5
Procarbazine
Y
Moderate
Fair
6
Belladona
N
Minor
Fair
Definition: Severity
Contraindicated - The drugs are contraindicated for concurrent use.
Concurrent use of FOSPHENYTOIN and CHLORPHENIRAMINE may result in an
increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).
Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS
depression.
Concurrent use of BELLADONNA and CHLORPHENIRAMINE may result in excessive
anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive
sedation, blurred vision).
Definition: Documentation
Excellent
Controlled studies have clearly established the existence of the
interaction.
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 require an alteration in therapy.
Fair
Minor - The interaction would have limited clinical effects. Manifestations
may include an increase in the frequency or severity of the side effects but
generally would not require a Major alteration in therapy.
Available documentation is poor, but pharmacologic
considerations lead clinicians to suspect the interaction exists;
or, documentation is good for a pharmacologically similar drug.
Unknown
Unknown.
Major - The interaction may be life-threatening and/or require medical
intervention to minimize or prevent serious adverse effects.
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
Loratadine
Interacting drug or class
1 Amiodarone
EML(y/n)
Y
Severity
Major
Documentation
Good
2
Cimetidine
N
Minor
Good
Cetirizine
1
Ritonavir
Y
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
2
Antacids; interacting compounds
-magnesium carbonate;
magnesium hydroxide;
magnesium trisilicate;
magnesium oxide; aluminum
carbonate, basic; aluminum
hydroxide; aluminum phosphate;
dihydroxyaluminum
aminoacetate;
dihydroxyaluminum sodium
carbonate; magaldrate
St John’s Wort Extract
N
Moderate
Good
Concurrent use of DROPERIDOL and ANTIHISTAMINES may result in
an increased risk of cardiotoxicity (QT prolongation, torsades de pointes,
cardiac arrest).
Concurrent use of FEXOFENADINE and ANTACIDS may result in
decreased fexofenadine efficacy.
N
Moderate
Good
3
Definition: Severity
Contraindicated - The drugs are contraindicated for concurrent use.
Major - The interaction may be life-threatening and/or require medical intervention to
minimize or prevent serious adverse effects.
Moderate - The interaction may result in exacerbation of the patient's condition and/or
require an alteration in therapy.
Minor - The interaction would have limited clinical effects. Manifestations may include
an increase in the frequency or severity of the side effects but generally would not
require a Major alteration in therapy.
Unknown - Unknown.
Interaction Details
Concurrent use of AMIODARONE and LORATADINE may result in
increased risk of QT interval prolongation and torsade de pointes.
Concurrent use of CIMETIDINE and LORATADINE may result in
increased loratadine serum concentrations; possible loratadine toxicity.
Concurrent use of FEXOFENADINE and ST JOHN'S WORT may result in
decreased effectiveness of fexofenadine.
Definition: Documentation
Excellent
Controlled studies have clearly established the existence of
the interaction.
Good
Documentation strongly suggests the interaction exists,
but well-controlled studies are lacking.
Fair
Available documentation is poor, but pharmacologic
considerations lead clinicians to suspect the interaction
exists; or, documentation is good for a pharmacologically
similar drug.
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
Precautions
Contraindications
Breast Feeding Risk
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
Precautions
Contraindications
Breast Feeding Risk
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
Precautions
Contraindications
Breast Feeding Risk
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
Precautions
Contraindications
Breast Feeding Risk
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)
 See section: ‎VII Summary and Recommendations on page 43 and Table 14:
Treatment Details for Loratadine on page 44.
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:
 See section ‎VI Cost, Regulatory and Current NEML Availability Evaluation on page
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)
 See section ‎VI Cost, Regulatory and Current NEML Availability Evaluation on page
41 and Table 12: Cost comparison of 1st and 2nd generation antihistamines on page
42
14. Availability of pharmacopoeial standards (British Pharmacopoeia, International
Pharmacopoeia, United States Pharmacopoeia)
 See section ‎VI Cost, Regulatory and Current NEML Availability Evaluation on page
41 and Table 12: Cost comparison of 1st and 2nd generation antihistamines on page
42
15. Proposed (new/adapted) text for the WHO Model Formulary
 See section: ‎VII Summary and Recommendations on page 43 and Table 14:
Treatment Details for Loratadine on page 44.
Page 55 of 63
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