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

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Focus of this review

Antihistamines, the first line treatment for conditions such as allergic rhinitis and urticaria, are

amongst the most commonly used medications in the world with more than 40 histamine-1

antagonist agents available. The 18th Expert Committee on the Selection and Use of Essential

Medicines requested an evaluation for the use of chlorphenamine (the systemic first generation

histamine-1-receptor antagonist currently on the EML) versus diphenhydramine.

This review will provide efficacy, safety and cost information on two 1st generation

antihistamines (FGAHs) – chlorphenamine and diphenhydramine. However, considering the

favorable pharmacotherapy and side-effect profile of 2nd generation systemic antihistamines

(SGAHs), this review will also provide an overview of efficacy, safety and cost of three over-the-

counter, SGAHs (cetirizine, loratadine and fexofenadine) and compare them to FGAHs.

This review is intended to answer the following questions.

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

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

3. If so, should this be an addition or replacement to the FGAH currently on the list?

4. Which SGAH should be listed?

Table of Contents List of Tables .................................................................................................................................. 1

Acronyms and Abbreviations: ........................................................................................................ 2

Executive Summary ........................................................................................................................ 3

I. Background and Rationale for this review .............................................................................. 6

II. Public health relevance of allergic conditions ..................................................................... 7

III. Methods.............................................................................................................................. 10

IV. Medications, Clinical Efficacy and Safety Evaluation ...................................................... 10

1. Similarities and differences amongst FGAHs and SGAHs ............................................... 10

2. Pharmacokinetic (PK) and Pharmacodynamic (PD) properties of antihistamines ............ 11

3. Comparing chlorphenamine and diphenhydramine ........................................................... 13

4. Treatment of selected common conditions with FGAH and SGAH.................................. 17

A. Allergic Rhinitis .................................................................................................................... 17

B. Urticaria ................................................................................................................................. 23

C. Anaphylaxis (adjunct) ............................................................................................................ 28

5. Safety Profile of Antihistamines ........................................................................................ 29

V. Use of Antihistamines in special populations .................................................................... 36

1. Elderly ................................................................................................................................... 36

2. Children and Infants .............................................................................................................. 36

VI. Cost, Regulatory and Current NEML Availability Evaluation .......................................... 41

VII. Summary and Recommendations ...................................................................................... 43

Appendix ....................................................................................................................................... 45

Appendix 1 – Drug-Drug Interactions: 1st Generation Antihistamines .................................... 46

Appendix 2 – Drug-Drug Interactions: 2nd

Generation Antihistamines .................................... 48

Appendix 3 – Precautions, Contraindications and Breast Feeding Risk of 1st Generation

Antihistamines ........................................................................................................................... 49

Appendix 4 – Precautions, Contraindications and Breast Feeding Risk of 2nd

Generation

Antihistamines ........................................................................................................................... 50

Appendix 5: Non-allergic conditions treated with Antihistamines ........................................... 51

A. Motion Sickness, Nausea, Emesis ......................................................................................... 51

B. Antitussive uses ..................................................................................................................... 51

C. Insomnia (Night-time sleep aid) ............................................................................................ 52

D. Extrapyramidal Symptoms .................................................................................................... 53

Appendix 6: EML Application Sections ................................................................................... 54

References ..................................................................................................................................... 56

List of Tables

Table 1: Medications under review for safety, efficacy and cost ................................................................................... 7

Table 2: FDA approved and off-label indications for antihistamines and strength of evidence and recommendation . 8

Table 3: PK and PD properties of antihistamines ......................................................................................................... 12

Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria ............................................................. 15

Table 5: Guidelines on Treatment of Allergic Rhinitis .................................................................................................. 18

Table 6: Efficacy and safety of SGAH in Allergic Rhinitis .............................................................................................. 19

Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria ..................................................................... 24

Table 8: Efficacy and Safety of SGAHs in Urticaria ...................................................................................................... 25

Table 9: Comparative side-effect profile of first and second generation antihistamines ............................................ 31

Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment .................................................................... 32

Table 11: Safety in children and breast feeding........................................................................................................... 38

Table 12: Cost comparison of 1st and 2nd generation antihistamines........................................................................ 42

Table 13: Availability of reviewed medications on NEMLs of 15 nations .................................................................... 42

Table 14: Treatment Details for Loratadine................................................................................................................. 44

Table 15: Dose Adjustments for Loratadine................................................................................................................. 44

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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 18

th Expert Committee on the Selection and Use of Essential Medicines (18

th EC)

requested a comparative review for chlorphenamine (systemic antihistamine currently on the

EML) versus diphenhydramine, to update Section 3 of the EML titled “Antiallergics and

Medicines Used in Anaphylaxis.”[1]

Allergic conditions such as allergic rhinitis and urticaria are histamine mediated reactions that

may require management with pharmacological agents.[2-4] Histamine is a naturally occurring

compound produced and present all throughout the human body. Likewise, histamine receptors,

H-1, H-2, H-3, and H-4 are expressed throughout the body and in-conjunction with histamine,

play important roles in regulation of functions ranging from embryo development to wound

healing and regeneration. The primary target of the antihistamines under review is the histamine-

1 (H-1) receptor, which is involved in central nervous system functions such as sleep and waking

cycles (circadian rhythm), energy regulation, cognition, memory and in peripheral body

functions such as allergic inflammation and reactions causing H-1 mediated hypotension,

tachycardia, flushing and headache via its effects on the cardiovascular system.[3-7]

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

The FDA (an SRA) has approved several uses of antihistamines as listed in Table 2 below;

however, this review will focus on three conditions within the purview of section 3 of the EML,

1) allergic rhinitis 2) urticaria and 3) anaphylaxis. There are several other off-label indications

for these medications listed in Table 2 below.[3, 8-19] A discussion on treatment of selected off-

label and non-histamine mediated conditions is available in appendix 5. Table 2 also provides a

detailed look at the level of evidence and recommendation of treatment of FDA approved and

off-label indications.[10] The FDA was selected for this assessment due to its status as

recognized SRA, availability of online FDA databases and due to the availability of the

information in English. UK, Australia and Canada SRAs as well as PubMed databases, Cochrane

library, BNF, Micromedex and Lexi-Comp were also searched for pertinent information and

evidence. [8-10, 20-22]

This review will compare efficacy, safety and cost of two 1st generation antihistamines (FGAHs)

chlorphenamine and diphenhydramine for use as anti-allergics and in anaphylaxis. Considering

the favorable, pharmacotherapy and side-effect profile of the 2nd

generation systemic

antihistamines (SGAHs), this review will also provide an overview of efficacy, safety and cost of

three SGAH (cetirizine, loratadine and fexofenadine) and compare them to FGAHs for use as

anti-allergics and in anaphylaxis.[3, 5, 7, 23-28]

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The two FGAH are reviewed

because they are requested by

the EC and the three SGAH

were selected for review due to

their classification as over-the-

counter (OTC) medications by

the FDA and their off-patent

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 30-

40% of the world’s population suffers from an allergic condition at any given time; within

Europe alone, 87 million people suffer from allergies and 80-90% of asthmatics are also living

with allergic rhinitis, a systemic inflammatory condition that significantly impacts quality of life,

while 10-30% of adults and 40% of children worldwide suffer from non-infectious rhinitis.[4, 29,

32] Worldwide, an estimated 40-50% of schoolchildren are expected to be sensitized to one or

more of the common allergens.[4, 29] Furthermore, the worldwide prevalence of chronic

idiopathic urticaria, characterized by hives, wheals and pruritus, is estimated to be up to 0.5%,

with the average duration of the disease between 3-7 years.[29] However, many chronic allergic

conditions are underdiagnosed and undertreated, possibly due to lack of awareness, therefore,

underestimating the impact of allergic diseases on health and on the quality of life for the

patients.[29] For example, moderate to severe allergic rhinitis has been shown to be consistently

underdiagnosed and undertreated; a condition that has the potential to induce sleep disorders,

sinusitis, acute and serious otitis media, asthma and other medical complications due to its

association with larger inflammatory process affecting other organ systems.[4]

Table 1: Medications under review for safety, efficacy and cost

Com

pari

son

Agent(s) or Class Comparative

Medication or Class

1 Chlorphenamine vs. Diphenhydramine

2 FGAH:

chlorphenamine and

diphenhydramine

vs.

SGAH: cetirizine,

loratadine and

fexofenadine

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Table 2: FDA approved and off-label indications for antihistamines and strength of evidence and recommendation

Medication FDA Approved Indication and Strength of Recommendation and

Evidence (R/E)

Off-Label (Non-FDA approved) Indication and Strength of

Recommendation and Evidence (R/E)

Diphenhydramine

Indication Adults (R/E) Children (R/E) Indication Adults (R/E) Children (R/E)

Allergic rhinitis Yes (Class IIb /

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)


B)

Extrapyramidal disease -

Medication-induced

movement disorder

No (Class IIb /

Category B)

No evidence

Common cold Yes (Class IIb /

Category B)

Yes (>6yr of age) (Class

IIb / Category B)

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)


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)

Chlorphenamine Allergic rhinitis Yes (Class IIa /

Category B)


IIa / Category B)

Contrast media adverse

reaction

No (Class IIb /

Category B)

No (Class IIb /

Category B)

Common cold Yes (Class IIb /

Category B)


IIb / Category B)

Systemic mast cell disease No (Class IIb /

Category B)

No (Class IIb /

Category B)

Loratadine Idiopathic urticaria,

chronic


B)


IIb / Category B)

Asthma No (Class IIb /

Category B)

No (Class IIb /

Category B)

Allergic rhinitis Yes (Class IIa / Category

B)


IIa / Category B)

Eosinophilic non-allergic

rhinitis

No evidence No evidence

Cetirizine Allergic rhinitis

(Perennial)

Yes (Class IIa / Category

B)

Yes (>6months of age)


Asthma, adjunct No (Class IIa /

Category B)

No evidence

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Allergic rhinitis

(Seasonal)


B)


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

Fexofenadine Idiopathic urticaria,

chronic


B)

Yes (>6yr, oral tablets,

orally disintegrating

tablets; 6 months to 11

years, oral suspension


Hymenoptera

immunotherapy,

Pretreatment

No (Class IIb /

Category B)

No evidence

Allergic rhinitis

(Seasonal)


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 Strength of Evidence

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

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. Comparing chlorphenamine and diphenhydramine for safety and efficacy.

2. Providing information on safety and efficacy of FGAH or SGAH as monotherapy

against placebo.

3. Comparing FGAH to SGAH for safety and efficacy.

4. Use of FGAH and SGAH for allergic rhinitis, urticaria and anaphylaxis.

5. Use of FGAH and SGAH in special populations, children and the elderly.

6. Antihistamines used for treatment of extrapyramidal symptoms, motion sickness,

antitussive.

The online databases of four stringent regulatory authorities were also searched for pertinent

information: FDA (United States), TGA (Australia), MHRA (UK) and Health Canada. Other

online databases searched were: British National Formulary, and Micromedex and Lexi-Comp

(clinical pharmacy databases). All SRAs and databases were selected based on their online

availability in English.

The following search terms were used: first generation antihistamines; chlorphenamine; chlor-

trimeton; diphenhydramine; second generation antihistamines; cetirizine; loratadine;

fexofenadine; allegra; zyrtec; claritin; safety and efficacy of medications under review;

pharmacokinetic and pharmacodynamics of medications under review; allergic rhinitis; rhinitis;

urticaria; chronic urticaria; extrapyramidal symptoms; EPS; akathisia; dystonic reactions;

dystonia; pseudoparkinsonism; antipsychotic induced EPS; anaphylaxis; food allergies and

antihistamines; motion sickness and antihistamine; nausea/vomiting/emesis and antihistamine

use; antitussive; cough suppression and antihistamine use. A title review was conducted to

identify relevant results followed by an abstract review.

IV. Medications, Clinical Efficacy and Safety Evaluation

1. Similarities and differences amongst FGAHs and SGAHs

Both FGAHs and SGAHs agents act as antagonists (also known as inverse agonists) to

the H-1 receptor. These agents attach to the H-1 receptor, however, they do not activate

the chemical cascade that histamine activates when attached to the same receptor.[3-5, 8]

Instead, the antihistamines work to keep the receptors in their inactivated form and

compete with histamine from attaching and initiating the cascade, thus shifting the

equilibrium of the H-1 receptors towards the inactive state thus preventing histamine-

mediated allergic reactions.[3, 8] Despite their similar mechanism of action on the H-1

receptors, the overall cumulative effects of FGAHs and SGAHs on the human body tend

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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 side-

effect of sedation. The FGAHs are referred to as ‘sedating’ while the SGAHs as ‘non-

sedating.’[3] This broad distinction is based on two primary differences between these

medicine classes: 1) SGAHs are far more specific to H-1 receptors compared to their

older counterparts that also exhibit an affinity for muscarinic, serotonin and alpha-

adrenergic receptors. [3, 26] And 2) FGAHs are considered lipophilic compounds that are

able to cross the blood brain barrier as opposed to the SGAHs, which lack this ability. [3,

8, 26] These differences in receptor specificity and liphophilicity cause FGAHs to display

significant central nervous system, cardiovascular system, and gastrointestinal system

side-effects discussed below.[3, 8, 26]

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

Table 3 highlights PK and PD factors of FGAH and SGAH, with a focus on

chlorphenamine, diphenhydramine, cetirizine, loratadine and fexofenadine. [3, 8-10, 15,

33, 34] This table presents the comparative pharmacological profile for agents in this

review along with their potential for onset of action, duration of action, drug-drug

interactions, drug-disease interaction (renal and hepatic insufficiencies), and pregnancy

categories.

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Table 3: PK and PD properties of antihistamines

1st generation antihistamines 2

nd generation antihistamines

PK/PD Property Chlorphenamine Diphenhydramine Cetirizine Loratadine Fexofenadine

Duration of Action Up to 24h Less than 12h 24h 24h 24h

Volume of Distribution Children 4-7L/kg;

Adults 6-12L/kg

Children 22L/kg; Adults

17L/kg; Elderly 14L/kg

0.56L/kg Variable Not available

Protein Binding 33% 98.5% 93% 97% 60 to 70%

Metabolism Hepatic, significant first-

pass effect

Hepatic, significant first-

pass effect

Hepatic (limited) Hepatic (extensive) Hepatic (minimal)

Absorption

(Bioavailability)

Good Moderate 42 to 62% Rapid Rapid Rapid

Half-life 27h Children 5h; Adults 9h;

Elderly 13.5h.

8h 12-15h 14h

Time to Peak Onset of action 3h; time

to peak 2-3h

Onset of action 2h; time to

peak 2h

Onset of action 0.7h;

time to peak 1h

Onset of action 2h;

time to peak 1h

Onset of action 1h;

time to peak 2.6h

Excretion Urine Urine Urine (70%) and feces

(10%)

Urine (40%) and

feces (40%)

Feces (80%) and urine

(11%)

Dose adjustment in renal

impairment

Data not available Yes Yes Yes Yes

Dose adjustment in

hepatic impairment

Data not available Yes Yes Yes No

Clinically relevant drug-

drug interactions

Possible Possible Unlikely Possible Unlikely

Pregnancy category

(FDA)

Category B1 Category B

1 Category B

1 Category B

1 Category C

2

Pregnancy category

(TGA)

Category A3 Category A

3 Category B2

4 Category B1

5 Category B2

4

1FDA 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. 3TGA 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 anti-

histamine agents for treatment of allergic rhinitis and urticaria and their safety via side-

effect profile as a class is well established in literature.[25, 37-40] An RCT including 64

Nigerian patients with allergic rhinitis found chlorphenamine to be significantly better

than vitamin C (control) at relieving symptoms.[37] Another RCT with 15 elderly

patients, found both diphenhydramine and chlorphenamine to significantly better than

placebo in suppressing histamine-induced cutaneous allergic reactions.[25] A multicenter

RCT with 188 chronic urticaria participants found hydroxyzine (a FGAH) to be as

effective as cetirizine and more effective than placebo to control urticaria symptoms.[40]

Table 4 below summarizes several RCTs examining efficacy and side-effects of FGAHs

in treatment of allergic rhinitis and urticaria.

Given their status, chlorphenamine and diphenhydramine may appropriately be referred

to as FGAHs and explored as a class rather than individual agents. Both agents have

similar efficacy in treatment of histamine mediated allergic disorders and with similar

side effect profile.[3, 4, 18, 41, 42] However, one recent systematic review concluded

that chlorphenamine is likely to cause greater impairment of cognitive function and

psychomotor performance than diphenhydramine.[4] Section IV- 5 and Table 9 below

discuss the safety profile of these agents in detail.

Mechanism of Action and PK/PD: Section IV- 1 closely examined the mechanism of

action of antihistamines. Table 3 shows the pharmacokinetics and pharmacodynamics

data on diphenhydramine and chlorphenamine. There is less data available on the PK and

PD profile of chlorphenamine compared to diphenhydramine. Data are still lacking for

dosing of chlorphenamine in hepatic and renal insufficiency.

Pregnancy Category: Table 3 above also shows the pregnancy categories assigned to

these agents by the FDA and TGA. FDA categorizes all antihistamines under review as

category B, with the exception of fexofenadine, which is considered category C. TGA

considers the FGAHs as category A, cetirizine and fexofenadine as category B2 and

loratadine as category B1.

Indications: The primary differences between these two FGAHs are best defined in Table

2. Diphenhydramine has been approved by an SRA (FDA) for 7 conditions while

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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.

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Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria

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

Publication Study Design Study Population Medications/Doses Objective(s) Results

Controlled clinical

study of the efficacy

of loratadine in

Nigerian patients

with allergic rhinitis.

Nwawolo, C. C.,

Olusesi, A. D.

(2001)[37]

Randomized

controlled trial

64 Nigerian

patients with

allergic rhinitis

Loratadine + Vitamin

C

Chlorphenamine +

Vitamin C

Vitamin C

To assess

efficacy and

tolerance of

loratadine

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).

Drowsiness was noted in 19.2% of patients on loratadine

compared with 57.1% of patients on chlorpheniramine.

Efficacy and safety

of loratadine

suspension in the

treatment of children


Boner, A.L. (1989)

[38]

Randomized

controlled trial

Twenty-

one children with

allergic rhinitis

Loratadine 0.11-0.24

mg/kg ideal body

weight once daily

Dexchlorpheniramine

0.10-0.23 mg/kg every

8 h

for 14 days

Safety and effica

cy of loratadine

compared to

dexchlorphenira

mine in children.

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.

Drowsiness was present only in the dexchlorpheniramine-

treated group.

Central nervous

system effects of H1-

receptor antagonists

in the elderly.

Simons, F. E., et al.,

(1999) [25]

Rrandomized,

double-blind, single-

dose, placebo-

controlled, 5-way

crossover study

15 healthy elderly

subjects (mean age

71 +/- 5 years)

Cetirizine 10 mg,

Loratadine 10 mg,

Diphenhydramine 50

mg,

Chlorphenamine 8 mg,

or

Placebo

To compare

effects of study

medications on

performance,

somnolence, and

peripheral H1-

blockade.

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.

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)

Terfenadine 60 mg,

Chlorphenamine, 4

mg, or

Placebo

To compare

effects of study

medications on

performance,

somnolence, and

peripheral H1-

blockade

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.

of 63

Simons, F. E., et al.,

(1994) [39]

Terfenadine and placebo did not increase somnolence

compared with baseline, but chlorphenamine did.

Cetirizine versus

hydroxyzine and

placebo in chronic

idiopathic urticaria.

Breneman, D. L.

(1996) [40]

Multicenter,

randomized, double-

blind, double-

dummy, placebo-

controlled

188 patients at least

12 years of age,

with symptomatic

chronic idiopathic

urticaria that had

occurred

episodically for at

least 6 weeks.

Cetirizine 10 mg once

daily,

Hydroxyzine 25 mg

three times daily, 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.

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.

Urticaria: clinical

efficacy of cetirizine

in comparison with

hydroxyzine and

placeb.

Kalivas J, et al. (1990) [44]

Multicenter, double-

blind, placebo-

controlled

Patients with

chronic urticaria

Cetirizine 5 to

20mg/day,

Hydroxyzine 25 to

75mg/day

or Placebo for 4 weeks

To evaluate

safety and

efficacy of

cetirizine

compared to

hydroxyzine in

treatment of

urticaria

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.

of 63

4. Treatment of selected common conditions with FGAH and SGAH

A. Allergic Rhinitis

Allergic rhinitis is a common condition affecting up to 30% of adults and 40% of

children worldwide and complicating asthma management in up to 90% asthmatics who

also suffer from allergic rhinitis.[29, 45] Allergic rhinitis has tremendous effect on a

patient’s quality of life; it can impact social life, sleep, academics and work and

contribute to substantial indirect economic impact.[32] FGAHs are widely used in adults

and children for management of allergic rhinitis.[35] Several classes of medications are

used for the treatment of allergic rhinitis including antihistamines, corticosteroids, mast

cell stabilizers, decongestants, nasal anticholinergics and leukotriene-receptor

agonists.[46] Inhaled glucocorticosteroids are considered to be the most effective

medications for the treatment of allergic rhinitis in both adults and children.[32, 47]

SGAHs are the preferred and recommended medications by multiple guidelines,

including guidelines developed in collaboration with WHO, as the first-line treatment

option for allergic rhinitis; and due to the adverse effects and safety concerns of FGAHs,

guidelines recommend that FGAHs should be avoided.[4, 32, 46, 48-51] The GRADE

recommendation for use of SGAHs in AR is strong.[46] Table 5 below summarizes

guidelines and their recommendations for the use of SGAHs while avoiding use of

FGAH for this indication, limiting their usefulness.

Table 6 below summarizes the RCT data showing efficacy of SGAHs for the treatment of

AR, including as compared to FGAHs. Although there is a lack of data to determine

substantial differences within distinct chemicals in SGAH class, but they appear to be

equally effective and safe.[2, 3] However, a 28-day prospective, randomized, double-

blind, parallel-group studied efficacy of loratadine versus cetirizine in 80 children 2 to 6

years of age, with perennial allergic rhinitis and found that while both treatments were

effective, cetirizine provided significant, greater relief for symptoms of rhinorrhea,

sneezing, nasal obstruction and nasal pruritus compared to loratadine.[52] A post hoc

analysis of a multi-center, randomized, placebo-controlled, double-blind, double-dummy

study comparing loratadine and fexofenadine in 835 seasonal allergic rhinitis patients

between 12 and 60 years old found that loratadine was significantly more effective in

providing relief over fexofenadine by day 2 of treatment period; possibly indicating faster

clinical onset of loratadine.[53]

of 63

Table 5: Guidelines on Treatment of Allergic Rhinitis

Guidelines Treatment of AR Evidence Level and

Recommendation

Allergic Rhinitis and its Impact on Asthma

(ARIA) guidelines: 2010 Revision [46]

First line therapy: 2nd

generation antihistamine

GRADE: strong recommendation with

low-quality evidence

International Primary Care Respiratory

Group (IPCRG) Guidelines: management of

allergic rhinitis. 2006 [51]

2nd

generation

antihistamines preferred

therapy

Strong Evidence for efficacy:

provided by generally consistent

findings on multiple, high quality

scientific studies.

British Society for Allergy and Clinical

Immunology (BSACI) Standards of Care

Committee guideline on the management of

allergic and non-allergic rhinitis (2010) [50]



Recommendation level: A (High)

of 63

Table 6: Efficacy and safety of SGAH in Allergic Rhinitis

Efficacy and safety of SGAH in Allergic Rhinitis


Double-blind,

placebo-controlled

study comparing the

efficacy and safety of

fexofenadine

hydrochloride

(120 and 180 mg onc

e daily) and cetirizine

in seasonal allergic

rhinitis.

Howarth, P. H., et

al. (1999)[54]

Multicenter, double-

blind, parallel-

group, placebo-

controlled trial

722 adults with

seasonal allergic

rhinitis

Fexofenadine 120 mg

once daily,

Fexofenadine 180 mg

once daily, or

Cetirizine 10

mg once daily (active

control)

Placebo, for 14 days

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.

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).

Comparison of the

efficacy, safety and

quality of life

provided by

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]

Multinational,

double-blind,

randomized, placebo

-controlled, parallel

group study

688 adults with

seasonal allergic

rhinitis

Fexofenadine 120 mg

once daily,

Loratadine 10 mg once

daily, or

Placebo, once daily,

for 14 days

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.

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.

Controlled clinical

study of the efficacy

of loratadine in

Nigerian patients


Nwawolo, C. C.,

Olusesi, A. D.

(2001)[37]

Randomized

controlled trial

64 Nigerian

patients with

allergic rhinitis

Loratadine + Vitamin

C

Chlorphenamine +

Vitamin C

Vitamin C

To assess

efficacy and

tolerance of

loratadine

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).

Drowsiness was noted in 19.2% of patients on loratadine

compared with 57.1% of patients on chlorpheniramine.

Loratadine provides Multi-center, 835 patients aged Loratadine 10mg once Evaluate efficacy Significantly greater mean reductions from baseline were

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

of loratadine

versus

fexofenadine and

placebo in

treatment of

allergic rhinitis.

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.

Efficacy and safety

of loratadine

suspension in the



Boner, A.L. (1989)

[38]

Randomized

controlled trial

Twenty-

one children with

allergic rhinitis

Loratadine 0.11-0.24

mg/kg ideal body

weight once daily

Dexchlorpheniramine

0.10-0.23 mg/kg every

8 h

for 14 days

Safety and effica

cy of loratadine c

ompared to

dexchlorphenira

mine in children.

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.

Drowsiness was present only in the dexchlorpheniramine-

treated group.

Comparison of the

effects of loratadine

and astemizole in the


with seasonal

allergic

rhinoconjunctivitis .

Boner AL, et al.

(1992) [56]

Randomized, single-

blind, 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

Astemizole 2 mg/10

kg body weight once

daily for 14 days

Evaluate the

efficacy and

safety of a once-

daily dose of

loratadine and

astemizole

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.

No abnormal changes in lab values were observed in either

group

A comparative study

of the efficacy and

safety of loratadine

syrup and

terfenadine

suspension in the

treatment of 3- to 6-

year-old children

Randomized, third-

party-blind,

placebo-controlled,

parallel-group study

96 children 3- to 6-

year-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

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%.

of 63

with seasonal

allergic rhinitis.

Lutsky BN, et al.

(1993)[57]

days. Adverse events were not significantly different between the

two treatment groups.

There were no reports of sedation or dry mouth in either

group.

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]

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,

Or placebo for 3

weeks.

Evaluate the

effectiveness and

safety of

loratadine syrup

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).

No adverse reactions were recorded in both groups.

Fexofenadine is

efficacious and safe

in children (aged 6-

11 years) with

seasonal allergic

rhinitis. Wahn U, et

al. (2003) [59]

Multinational,

randomized,

placebo-controlled,

parallel-group,

double-blind study

935 children, 6-11

years of age with

seasonal allergic

rhinitis

Fexofenadine 30 mg

twice daily

or placebo twice daily

for 14 days.

Assess the

efficacy and

safety of

fexofenadine in

children with

seasonal allergic

rhinitis.

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.

The efficacy and

safety of 30 mg

fexofenadine HCl bid

in pediatric patients


Ngamphaiboon J, et

al. (2005)[60]

Multi-center, open-

label, non-

comparative study

100 Asian

(Thailand)

children, 6-11

years of age

diagnosed with

seasonal or

perennial allergic

rhinitis.

Fexofenadine 30 mg

twice-daily

Evaluate efficacy

and safety of a

twice-daily oral

dose of

fexofenadine

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 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

107 children of

both sexes between

2 and 6 years of

age with pollen-

induced seasonal

allergic rhinitis

Cetirizine drops 5mg

once daily

or placebo once daily

for 14 days

Evaluate the

safety and

efficacy of

cetirizine

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.

A placebo-controlled

trial of cetirizine in

seasonal allergic

rhino-conjunctivitis

Multi-center,

double-blind,

placebo-controlled,

parallel group study

124 children of

both sexes aged

between 6 and 12

years with pollen-

Cetirizine 5mg twice

daily,

or placebo twice daily

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.

of 63

in children aged 6 to

12 years. Masi M, et

al. (1993)[62]

associated rhino-

conjunctivitis

for 14 days Improvement in individual daily symptoms was greater for

cetirizine than placebo.

Once-daily

cetirizine effective in

the treatment of

seasonal allergic

rhinitis in children

aged 6 to 11 years: a

randomized, double-

blind, placebo-

controlled study.

Pearlman DS, et al.

(1997)[63]

Randomized,

double-blind,

placebo-controlled

trial

209 children, 6 to

11 years of age

with seasonal

allergic rhinitis

Cetirizine syrup (5 or

10 mg daily)

or placebo for 4 weeks

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 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.

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, open-

label, non-

comparative 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)

Cetirizine provided significant improvements in HRQL in all

age groups (6-7, 8-9, 10-11 years) (p < 0.001) during the

treatment period.

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, double-

blind, longitudinal,

parallel-group study

80 children, 2 to 6

years of age, with

perennial allergic

rhinitis

Cetirizine 0.2mg/kg

Loratadine 0.2mg/kg

for 28 days

Evaluate

comparative

efficacy and

safety of

cetirizine and

loratadine.

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

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.

of 63

Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria

Guidelines/Systematic Review Treatment of Urticaria Evidence Level and Recommendation

EAACI/GA2LEN/EDF/WAO

guideline: management of urticaria

(2009)[14]



GRADE: Strong recommendation with low-

quality evidence

Avoid 1st generation

antihistamines

GRADE: Strong recommendation with high

quality evidence

Second-generation H1-antihistamines 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

of 63

Table 8: Efficacy and Safety of SGAHs in Urticaria

Efficacy and Safety of SGAHs in Urticaria


Central nervous

system effects of

H1-receptor

antagonists in the

elderly. Simons,

F. E., et al.,

(1999) [25]

Randomized,

double-blind,

single-dose,

placebo-

controlled, 5-

way crossover

study

15 healthy elderly

subjects (mean

age 71 +/- 5 years)

Cetirizine 10 mg,

Loratadine 10 mg,

Diphenhydramine 50

mg,

Chlorphenamine 8

mg, or

Placebo

To compare effects of study

medications on performance,

somnolence, and peripheral H1-

blockade.

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.

Benefit/risk ratio

of the

antihistamines

(H1-receptor

antagonists)

terfenadine and

chlorpheniramine

in children.

Simons, F. E., et

al., (1994) [39]

Double-blind,

single-dose,

placebo-

controlled,

three-way

crossover study

15 children with

allergic rhinitis

(mean age, 8.5 +/-

1.4 years)

Terfenadine 60 mg,

Chlorphenamine, 4

mg, or

Placebo




blockade


histamine-induced wheal and flare compared with

baseline and with placebo; terfenadine was

significantly more effective (p < 0.05).





Cetirizine versus

hydroxyzine and

placebo in

chronic

idiopathic

urticaria.

Breneman, D. L.

(1996) [40]

Multicenter,

randomized,

double-blind,

double-dummy,

placebo-

controlled

188 patients at

least 12 years of

age, with

symptomatic

chronic idiopathic

urticaria that had

occurred

episodically for at

least 6 weeks.


daily,

Hydroxyzine 25 mg

three times daily, 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.

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).

Both agents showed significant improvement in

urticaria symptoms at the end of 4 weeks compared to

placebo group (p < 0.001).

4 patients in the hydroxyzine group, 1 patient in the

cetirizine group, and 1 patient in the placebo group

discontinued the study because of sedation.

A double-blind,

placebo-

controlled trial of

Multicenter,

placebo-

controlled

439 patients with

moderate to severe

pruritus and

Fexofenadine 20, 60,

120, or 240 mg twice

daily

Evaluate the safety and efficacy of

fexofenadine for the treatment of

chronic urticaria symptoms.

All 4 doses of fexofenadine were statistically superior

to placebo (P ≤ 0.0238) in relieving symptoms of

urticaria.

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 240-

mg groups and were quantitatively better than those

in the 20mg group.

Adverse events were mild and occurred with similar

incidence in all treatment groups.

Doses of 60 mg twice a day or greater are most

effective.

Fexofenadine

HCl is safe and

effective for

treatment of

chronic

idiopathic

urticaria.

Nelson HS, et al.

(2000) [73]

Multi-center,

double-blind,

randomized,

placebo-

controlled

study

418 patients with

urticaria

Fexofenadine 20, 60,

120, or 240 mg twice

daily

or Placebo for 4

weeks

Assess safety and efficacy of

fexofenadine in chronic idiopathic

urticaria.

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.

Fexofenadine, twice-daily doses of 60 mg or greater

were most effective.

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


daily

or Terfenadine 60 mg

twice daily for 20

days

Evaluate the efficacy of cetirizine

and terfenadine in chronic

idiopathic urticaria

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.

of 63

Cetirizine and

astemizole

therapy for

chronic

idiopathic

urticaria: a

double-blind,

placebo-

controlled,

comparative trial.

Breneman D, et

al. (1995)[70]

Multicenter,

randomized,

double-blind

trial

187 total patients

with chronic

idiopathic

urticaria;

180 included in

the safety analysis

and 177 included

in efficacy

analysis

Cetirizine 10mg once

daily

Astemizole 10mg

once daily

or Placebo for 4

weeks

Compare the efficacy of cetirizine

and astemizole in relieving the

symptoms of chronic idiopathic

urticaria

Both cetirizine and astemizole were significantly

superior to placebo in relieving symptoms of chronic

idiopathic urticaria with more rapid clinical benefit

with cetirizine.

Both active treatments were well tolerated, and the

incidence of somnolence did not differ statistically

between cetirizine (14.5%) and astemizole (10.3%).

Urticaria: clinical

efficacy of

cetirizine in

comparison with

hydroxyzine and

placeb.

Kalivas J, et al.

(1990) [44]

Multicenter,

double-blind,

placebo-

controlled

Patients with

chronic urticaria

Cetirizine 5 to

20mg/day,

Hydroxyzine 25 to

75mg/day

or Placebo for 4

weeks

To evaluate safety and efficacy of

cetirizine compared to hydroxyzine

in treatment of urticaria

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.

Randomized

placebo-

controlled 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]

Randomized,

double-blind,

double-dummy,

placebo-

controlled,

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).

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.

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.

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

of 63

an H-1 antagonist is indicated in this setting, an alternative dosing with a less-

sedating, oral SGAH such as cetirizine, may be recommended given its relatively

rapid onset of action.[16]

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

Allergology and Clinical Immunology, recommends that an H-1 antagonist,

ideally in the liquid form and non-sedating, should be administered, but

acknowledges lack of evidence for efficacy in anaphylaxis and supports use of

epinephrine as first line therapy.[81] However, in a community setting, the

Academy recommends the use of an H-1 antagonist syrup at the first signs of an

allergic reaction.[81] All non-sedating SGAHs considered in this discussion have

a syrup formulation. However, only diphenhydramine and chlorphenamine have

parenteral formulations.[81]

The above discussion illustrates not only the lack of evidence and support for use

of H-1 antagonist in anaphylaxis, but also shows that if it is to be used, a non-

sedating SGAH may be used as well unless a parenteral formulation is indicated.

5. Safety Profile of Antihistamines

Table 9 below lists a side-by-side comparison of major side-effects observed with

antihistamine agents by class. Due to the multiple functions of H-1 receptor, the use anti-

histamine agents leads to many desired therapeutic and undesired side-effects.[7, 25, 35,

84] As mentioned above, the FGAHs, such as diphenhydramine and chlorphenamine, are

lipophilic molecules, a chemical property that allows them to cross the blood-brain

barrier resulting in the observed central nervous system side-effects such as drowsiness,

somnolence, reduced mental alertness, and impaired memory and motor performance.

Furthermore, it is important to note that these side effects are present with lowest and

therapeutic doses of FGAHs as recommended by the manufacturers.[35, 85] Positron

emission tomography studies have confirmed that FGAHs can occupy between 45% and

70% of brain H-1 receptors and lead to prolonged effects on performance impacting daily

activities.[86, 87] These agents also lack specificity for the H1 receptor and have

significant anti-muscarinic, anti-alpha-adrenergic and anti-serotonin effects leading to

symptoms such as mydriasis, photophobia, and diplopia, xerostomia, tachycardia,

constipation, urinary retention, agitation, and confusion. Conversely, SGAH have

reduced capacity to cross the blood-brain barrier and exhibit a greater specificity for

the H1 receptor, limiting the frequency and the magnitude of the side-effects observed

with FGAH. Second-generation H1 receptor antagonists such as cetirizine, loratadine and

fexofenadine provide good selective H1 receptor blockade without anticholinergic or

alpha-adrenergic or serotonergic antagonist activity. [3-5, 8, 15, 18, 23-26, 39, 42, 84, 88-

99]

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

of 63

been elucidated with cetirizine and should be avoided. This data further establish the

superior safety profile of SGAHs.

Given this comparison, it is apparent that SGAHs have a better safety and tolerability

profiles, and have at least similar efficacy compared with FGAHs.

Table 9: Comparative side-effect profile of first and second generation antihistamines

Side-effect 1st Generation Antihistamines 2

nd Generation Antihistamines

Central

Nervous

System

With therapeutic doses may cause drowsiness, fatigue,

somnolence, dizziness; impairment of cognitive

function, memory, and psychomotor performance;

headache, dystonia, dyskinesia, agitation, confusion, and

hallucinations.

May cause adverse effects in newborns if taken

by mother immediately before parturition; may cause

irritability, drowsiness, or respiratory depression in

nursing infants

Adverse effects such as drowsiness

may occur at higher doses.

No adverse effects reported in

newborns or nursing infants.

Cardiovascular

System

Dose-related sinus tachycardia; reflex tachycardia and

supraventricular arrhythmias; dose related prolongation

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.

Anti-

Cholinergic

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 anti-

cholinergic side-effects.

Overdose 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

No serious toxic effects or deaths

reported.

Table adapted with modifications from Simons, ER [3]

of 63

Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment

Side-effects: Sedation, drowsiness, psychomotor impairment


Effects of

fexofenadine,

diphenhydramine,

and alcohol on

driving

performance. A

randomized,

placebo-controlled

trial in the Iowa

driving simulator.

Weiler, J.M., et

al., (2000) [100]

Randomized,

double-blind,

double-dummy,

four-treatment,

four-period

crossover trial.

40 licensed drivers

with seasonal

allergic rhinitis

between 25 to 44

years of age.

One dose of

Fexofenadine 60 mg,

Diphenhydramine 50

mg,

Alcohol

(approximately 0.1%

blood alcohol

concentration),

or Placebo

To measure coherence, drowsiness

and other driving measure with

study medications.

Coherence: Participants had significantly better

coherence after taking alcohol or fexofenadine than

after taking diphenhydramine.

Lane keeping (steering instability and crossing the

center line) was impaired after alcohol and

diphenhydramine use compared with fexofenadine

use.

Central nervous

system effects of

H1-receptor

antagonists in the

elderly. Simons,

F. E., et al.,

(1999) [25]

Randomized,

double-blind,

single-dose,

placebo-

controlled, 5-

way crossover

study

15 healthy elderly

subjects (mean

age 71 +/- 5 years)

Cetirizine 10 mg,

Loratadine 10 mg,

Diphenhydramine 50

mg,

Chlorphenamine 8

mg,

or Placebo




blockade.










placebo.

Benefit/risk ratio

of the

antihistamines

(H1-receptor

antagonists)

terfenadine and

chlorpheniramine

in children.

Simons, F. E., et

al., (1994) [39]

Double-blind,

single-dose,

placebo-

controlled,

three-way

crossover study

15 children with

allergic rhinitis

(mean age, 8.5 +/-

1.4 years)

Terfenadine 60 mg,

Chlorphenamine, 4

mg,

or Placebo




blockade


histamine-induced wheal and flare compared with

baseline and with placebo; terfenadine was

significantly more effective (p < 0.05).





Increased risk of

serious injury

following an

initial prescription

for

diphenhydramine.

A retrospective

cohort study

12,106 patients

with initial

antihistamine

prescription for

diphenhydramine

and 24,968

N/A 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.

The rate of all injuries was 308 per 1,000 person-

years 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)

of 63

Finkle, W. D., et

al., (2002) [102]

patients with

initial

antihistamine

prescription for

loratadine.

Prevalence of

chlorpheniramine

in aviation

accident pilot

fatalities, 1991-

1996. Soper, J.

W., et al. (2000)

[103]

Retrospective A postmortem

toxicology

database--

maintained at the

Civil Aeromedical

Institute--was

examined for the

presence of

chlorphenamine in

the fatalities,

occurred during

1991-1996.

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.

Chlorphenamine was present in some aviation

fatalities at levels higher than therapeutic levels.

First-generation

H1 antihistamines

found in pilot

fatalities of civil

aviation accidents,

1990-2005. Sen,

A., et al. (2007)

[104]

Retrospective 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.

First generation anti-

histamines:

brompheniramine,

chlorphenamine,

diphenhydramine,

doxylamine,

pheniramine,

phenyltoloxamine,

promethazine, and

triprolidine.

To detect the presence of one of the

study medications in blood

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.

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.

Differential

cognitive effects

of terfenadine and

chlorpheniramine.

Meador, K. J., et

al. (1989) [88]

Double-blind,

randomized,

three-period

crossover

24 healthy adult

subjects

Terfenadine 60 mg,

Chlorphenamine

maleate 8 mg,

or Placebo

Assess the latency of the P3-

evoked 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

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

of 63

and drug states that adversely

affect the central nervous system

can slow P3 latency.)

much higher P3 latency. Both medications increased

the P3 latency compared to placebo and baseline.

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

or Placebo

Assess sedation and performance

impairment with study

medications.

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.

Ingesting 10 mg of loratadine daily does not appear to

have sedative effects or impair cognitive-motor

performance.

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, double-

blind cross-

over trial

Sixteen healthy

male and female

Cetirizine 10 mg,

Loratadine 10 mg

Alcohol

or Placebo

Assess driving performance with

study medications.

Alcohol significantly affected almost every

performance measure.

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).

The effects of alcohol and cetirizine appeared to be

additive.

Loratadine had no significant effect on any

performance parameter.

It was concluded that cetirizine, but not loratadine,

generally caused mild impairment of performance

after a single 10 mg dose.

Central nervous

system effects of

H1-receptor

antagonists in the

elderly. Simons,

Rrandomized,

double-blind,

single-dose,

placebo-

controlled, 5-

15 healthy elderly

subjects (mean

age 71 +/- 5 years)

Cetirizine 10 mg,

Loratadine 10 mg,

Diphenhydramine 50




blockade.





of 63

F. E., et al.,

(1999) [25]

way crossover

study

mg,

Chlorphenamine 8

mg, or

Placebo






placebo.

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,

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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]

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Table 11: Safety in children and breast feeding

Safety in children and breast feeding


Prospective, long-

term safety evaluatio

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]

Prospective, double-

blind, randomized

placebo controlled

817 children with

atopic dermatitis, 12

to 24 months old

Cetirizine 0.25

mg/kg twice daily

or Placebo twice

daily.

Assess safety of

study medication

(adverse events,

diary cards,

physical

examinations,

developmental

assessments,

electrocardiogra

ms, blood

hematology and

chemistry tests,

and urinalyses.)

Reported symptoms were mild, including respiratory or

gastrointestinal infections, exacerbations of allergic disorders, or age-

related 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.

Prophylactic manage

ment of children at ri

sk for recurrent uppe

r respiratory

infections: the

Preventia I Study.

Grimfeld, A. (2004)

[121]

Multinational,

randomized

placebo-

controlled study

Children, 12–30

months of age

Phase 1: 342

Phase 2: 310

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: double-

blind follow-up

period without study

medication.

Evaluate the

efficacy and

long-term safety

of loratadine in

reducing the

number of

respiratory

infections in

children at 24

months.

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.

Safety of

levocetirizine

treatment in young

atopic children: An

18-month study.

Simons F.E., et al.

(2007) [36]

prospective,

randomized, double-

masked, placebo-

controlled

255 children (with

study drug) and 255

children (placebo);

12-24 months of age

Levocetirizine 0.125

mg/kg twice daily

or placebo twice

daily

for 18 months

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.

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Levocetirizine is safe for long term use in young children.

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

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(0-

12) (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.

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.

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.

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

Review of

evidence

supporting the

safety profiles of

frequently used

oral

antihistamines

for the treatment

allergic diseases,

(allergic rhinitis

and urticaria.)

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.

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

Assessment of

safety of

cetirizine in

The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg

(SD).

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randomized, double-

blind, placebo-

controlled study.

Simons FE, et al.

(2003) [122]

double-blind,

placebo-controlled

study

or Placebo twice

daily orally

for 1 week.

infants,

particularly with

regard to central

nervous system

and cardiac

effects,

inclusive.

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.

Safety of

fexofenadine in

children treated for

seasonal allergic

rhinitis.

Graft DF, et al.

(2001) [123]

Two large, double-

blind, 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.

Evaluate the

safety of

fexofenadine

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.

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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 2

nd 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.

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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$)

Daily

Maximum Dose

(adult)

Monthly cost based on

maximum dosing (US$)

FDA

Approved

TGA

Approved

Chlorphenamine 4mg tab 0.0038 0.114 24mg/daily 0.684 Yes Yes Chlorphenamine

2mg/5mL oral solution

0.0043/mL 0.43 24mg/daily 7.74 Yes Yes

Chlorphenamine

10mg/mL injection

0.1470/mL 1.47 24mg/daily N/A Yes Yes

Diphenhydramine 25mg

cap

0.0161 0.483 200mg/daily 3.864 Yes Yes

Diphenhydramine

50mg/mL injection

3.1264/mL 6.25 400mg/daily N/A Yes Yes

Diphenhydramine

12.5mg/5mL oral solution


Loratadine 10mg tab 0.0225 0.675 10mg/daily 0.675 Yes Yes Loratadine 1mg/1mL

oral solution


Lexi-Comp online (US market price) Cetirizine 5mg 1.000 30 10mg/daily 60 Yes Yes Cetirizine 10mg 0.1899 5.70 10mg/daily 5.70 Yes Yes Cetirizine 1mg/mL oral

solution


Fexofenadine 180mg tab 0.8663 25.99 180mg/daily 25.99 Yes Yes

Fexofenadine 30mg/5mL

solution*

0.1749 17.49 180mg/daily 157.41 Yes Yes

*Originator brand suspension for fexofenadine, all other prices are for generic products

Table 13: Availability of reviewed medications on NEMLs of 15 nations

# Country Chlorphenamine

tab/inj/syrup

Diphenhydramine

cap/inj/solution

Loratadine

tab/syrup

Cetirizine

tab/syrup

Fexofenadine

tab/syrup

1 Bangladesh tab/inj Not present Not present Not present Not present

2 China tab cap/inj Not present Not present Not present

3 Dominican Republic tab cap/inj/solution tab/syrup Not present Not present

4 Ecuador Not present cap/inj/solution tab/syrup Not present Not present

5 Fiji Not present Not present Not present Not present Not present 6 Ghana tab/syrup tab Not present Not present Not present

7 India tab Not present Not present tab/syrup Not present

8 Iran tab/inj/syrup tab/inj/solution tab/syrup tab/syrup tab

9 Kyrgyzstan Not present tab/inj tab/syrup tab/syrup Not present

10 Malta tab/syrup tab/syrup tab/syrup tab/syrup tab

11 Morocco Not present Not present tab/syrup tab/syrup Not present

12 Malaysia tab/inj/syrup Not present Not present Not present Not present 13 Namibia tab/syrup Not present Not present Not present Not present 14 Nigeria tab/inj/syrup Not present Not present Not present Not present 15 Oman tab/inj/syrup Not present tab/syrup tab/syrup Not present

Total # of surveyed countries with

identified medications on the NEML

(any formulation) and (%)

10 7 7 6 2

66% 46% 46% 40% 13%

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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

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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

formulations)

Indication Adult Dosing Pediatric Dosing Monitoring

Loratadine[126]

(Tablet 10mg,

Syrup 1mg/mL)

Allergic

Rhinitis

10mg tab or

syrup, PO

Once Daily

2-5 years: 5 mg tab or syrup,

PO Once Daily

6 years and older: 10 mg tab

or syrup, PO Once Daily

Improvement in

symptoms of rhinitis

Sedation

Chronic

Urticaria

Improvement in

urticaria

Sedation

Anaphylaxis No evidence to support use of antihistamines in anaphylaxis; clinicians may

refer to institutional guidelines or procedures for appropriate use.

Table 15: Dose Adjustments for Loratadine

Impairment Age Group Dose

Renal Impairment

(GFR<30mL/min)

6 years and older 10mg PO every other day

2 to 5 years 5mg every other day

Hepatic Impairment 6 years and older 10mg PO every other day

2 to 5 years 5mg every other day

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Appendix

This page is blank.

of 63

Appendix 1 – Drug-Drug Interactions: 1st Generation Antihistamines

FGAH Interacting drug or class EML(y/n) Severity Documentation Interaction Details

Diphenhy-

dramine

1 Linezolid N Major Fair Concurrent use of DIPHENHYDRAMINE and LINEZOLID may result in increased

anticholinergic toxicity effects.

2 Zolpidem / sedatives N Major Fair Concurrent use of ZOLPIDEM and SEDATIVES may result in an increase in central

nervous system depressant effects.

3 Oxycodone / sedatives N Major Fair Concurrent use of OXYCODONE and SEDATIVES may result in an increase in CNS or

respiratory depression.

4 Tapentadol sedatives N Major Fair Concurrent use of TAPENTADOL and SEDATIVES may result in an increase in central

nervous system and respiratory depression.

5 Hydromorphone /

sedatives

N Major Fair Concurrent use of HYDROMORPHONE and SEDATIVES may result in an increase in

CNS or respiratory depression.

6 Metoprolol Y Moderate Good Concurrent use of DIPHENHYDRAMINE and METOPROLOL may result in increased

metoprolol plasma concentration.

7 Tamoxifen Y Moderate Fair Concurrent use of DIPHENHYDRAMINE and TAMOXIFEN may result in decreased

plasma concentrations of the active metabolites of tamoxifen.

8 Clomipramine Y Moderate Fair Concurrent use of CLOMIPRAMINE and DIPHENHYDRAMINE may result in

increased anticholinergic effects (dry mouth, urinary retention).

9 Amitriptyline Y Moderate Fair Concurrent use of AMITRIPTYLINE and DIPHENHYDRAMINE may result in

increased anticholinergic effects (dry mouth, urinary retention).

10 Triflupromazine N Moderate Fair Concurrent use of TRIFLUPROMAZINE and DIPHENHYDRAMINE may result in

anticholinergic effects (dry mouth, urinary retention, altered mental status).

11 Procarbazine Y Moderate Fair Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS

depression.

12 Amoxapine N Moderate Fair Concurrent use of AMOXAPINE and DIPHENHYDRAMINE may result in increased

anticholinergic effects (dry mouth, urinary retention).

13 Belladonna N Minor Fair Concurrent use of BELLADONNA and DIPHENHYDRAMINE may result in excessive

anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive

sedation, blurred vision).

Chlorphe-

namine

1 Lorcaserin N Major Fair Concurrent use of LORCASERIN and SEROTONERGIC AGENTS may result in

increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,

myoclonus, mental status changes).

2 Bromocriptine N Major Fair Concurrent use of BROMOCRIPTINE and CHLORPHENIRAMINE may result in

increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia,

myoclonus, mental status changes).

3 Phenytoin Y Moderate Fair Concurrent use of PHENYTOIN and CHLORPHENIRAMINE may result in an increased

risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).

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4 Fosphenytoin N Moderate Fair Concurrent use of FOSPHENYTOIN and CHLORPHENIRAMINE may result in an

increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).

5 Procarbazine Y Moderate Fair Concurrent use of ANTIHISTAMINES and PROCARBAZINE may result in CNS

depression.

6 Belladona N Minor Fair Concurrent use of BELLADONNA and CHLORPHENIRAMINE may result in excessive

anticholinergic activity (severe dry mouth, constipation, decreased urination, excessive

sedation, blurred vision).

Definition: Severity Definition: Documentation

Contraindicated - The drugs are contraindicated for concurrent use.

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.

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.

Table created using information from Micromedex online clinical pharmacy database.[10]

of 63

Appendix 2 – Drug-Drug Interactions: 2nd

Generation Antihistamines

SGAH Interacting drug or class EML(y/n) Severity Documentation Interaction Details

Loratadine 1 Amiodarone Y Major Good Concurrent use of AMIODARONE and LORATADINE may result in

increased risk of QT interval prolongation and torsade de pointes.

2 Cimetidine N Minor Good Concurrent use of CIMETIDINE and LORATADINE may result in

increased loratadine serum concentrations; possible loratadine toxicity.

Y

Cetirizine 1 Ritonavir Y Minor Good Concurrent use of CETIRIZINE and RITONAVIR may result in increased

exposure and half-life of cetirizine as well as reduced cetirizine clearance.

Fexofenadine 1 Droperidol N Major Fair Concurrent use of DROPERIDOL and ANTIHISTAMINES may result in

an increased risk of cardiotoxicity (QT prolongation, torsades de pointes,

cardiac arrest).

2 Antacids; interacting compounds

-magnesium carbonate;

magnesium hydroxide;

magnesium trisilicate;

magnesium oxide; aluminum

carbonate, basic; aluminum

hydroxide; aluminum phosphate;

dihydroxyaluminum

aminoacetate;

dihydroxyaluminum sodium

carbonate; magaldrate

N Moderate Good Concurrent use of FEXOFENADINE and ANTACIDS may result in

decreased fexofenadine efficacy.

3 St John’s Wort Extract N Moderate Good Concurrent use of FEXOFENADINE and ST JOHN'S WORT may result in

decreased effectiveness of fexofenadine.

Definition: Severity Definition: Documentation

Contraindicated - The drugs are contraindicated for concurrent use.

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.

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.

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Appendix 3 – Precautions, Contraindications and Breast Feeding Risk of 1st Generation Antihistamines

Chlorphenamine

Precautions Contraindications Breast Feeding Risk

1. Asthma

2. Bladder neck obstruction

3. Hepatic insufficiency

4. Narrow-angle glaucoma

5. Pyloroduodenal obstruction

6. Sedative effects; some patients may be more or less

susceptible

7. Stenosing peptic ulcer

8. Symptomatic prostatic hypertrophy

1. Hypersensitivity to

chlorpheniramine or

dexchlorpheniramine

1. Avoid Breastfeeding.

2. Infant risk cannot be ruled out.

3. Available evidence and/or expert

consensus is inconclusive or is inadequate

for determining infant risk when used

during breastfeeding. Weigh the potential

benefits of medication treatment against

potential risks before prescribing this

medication during breastfeeding.

Diphenhydramine


1. Bladder neck obstruction

2. Concurrent maoi therapy

3. Concurrent use of central nervous system depressants

4. Decreases mental alertness and psychomotor performance

5. Do not use topical form on eyes or eye lids

6. Elderly are more susceptible to the side effects of

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

1. Hypersensitivity to

diphenhydramine

2. Newborns or premature infants

3. Nursing mothers

1. Milk effects are possible.

2. Evidence suggests this medication may

alter milk production or composition. If

an alternative to this medication is not

prescribed, monitor the infant for adverse

effects and/or adequate milk intake.

Table based on clinical information from Micromedex clinical pharmacy database.[10]

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Appendix 4 – Precautions, Contraindications and Breast Feeding Risk of 2nd

Generation Antihistamines

Loratadine


1. Impaired liver function

2. Impaired renal function

3. Pregnancy

1. Hypersensitivity to loratadine or any of its

ingredients

2. Hypersensitivity to desloratadine, an active

metabolite of loratadine

1. Maternal medication usually compatible with

breastfeeding.

2. Infant risk is minimal.

3. The weight of an adequate body of evidence

and/or expert consensus suggests this

medication poses minimal risk to the infant

when used during breastfeeding.

Cetirizine


1. Activities requiring mental alertness

2. Concurrent use of central nervous system

depressants

3. Elderly

4. Hepatic dysfunction

5. Renal insufficiency

1. Hypersensitivity to cetirizine, levocetirizine (R

enantiomer of cetirizine hydrochloride), or

components

2. Hypersensitivity to hydroxyzine

1. Infant risk cannot be ruled out.

2. Available evidence and/or expert consensus

is inconclusive or is inadequate for

determining infant risk when used during

breastfeeding. Weigh the potential benefits of

medication treatment against potential risks

before prescribing this medication during

breastfeeding.

Fexofenadine


1. Concurrent administration of aluminum- and

magnesium-containing antacid within 15

minutes; decrease fexofenadine absorption

2. Concurrent consumption of fruit juices, such

as grapefruit, orange, and apple; decrease

fexofenadine bioavailability and exposure

1. Hypersensitivity to fexofenadine or any of the

ingredients

1. Maternal medication usually compatible with

breastfeeding.

2. Infant risk is minimal.

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.

Table based on clinical information from Micromedex clinical pharmacy database.[10]

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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

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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

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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]

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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)



of 63

10. Summary of comparative effectiveness in a variety of clinical settings:

See the following:

Table 4: Efficacy and side-effects of FGAHs in Allergic Rhinitis and Urticaria on

page 15

Table 5: Guidelines on Treatment of Allergic Rhinitis on page 18

Table 6: Efficacy and safety of SGAH in Allergic Rhinitis on page 19

Table 7: Guidelines and Systematic Reviews on Treatment of Urticaria on page

24

Table 8: Efficacy and Safety of SGAHs in Urticaria on page 25

11. Summary of comparative evidence on safety:

See the following:

Table 9: Comparative side-effect profile of first and second generation

antihistamines on page 31

Table 10: Side-effects: Sedation, drowsiness, psychomotor impairment on

page 32

Table 11: Safety in children and breast feeding on page 38

12. Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group:


41 and Table 12: Cost comparison of 1st and 2nd generation antihistamines on page

42

13. Summary of regulatory status of the medicine (in country of origin, and preferably in

other countries as well)



42

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International

Pharmacopoeia, United States Pharmacopoeia)



42

15. Proposed (new/adapted) text for the WHO Model Formulary



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Section 3: Antiallergics and Medicines Used in Anaphylaxis

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