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Carson S, Lee N, Thakurta S. Drug Class Review: Newer Antihistamines: Final Report Update 2 [Internet]. Portland (OR): Oregon Health & Science University; 2010 May.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Drug Class Review: Newer Antihistamines

Drug Class Review: Newer Antihistamines: Final Report Update 2 [Internet].

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Antihistamines inhibit the effects of histamine at H1 receptors. Histamine is a physiologically active, endogenous substance that binds to and activates histamine H1 and H2 receptors in the respiratory tract (including the nose), the gastrointestinal tract,2 brain, adrenal medulla, skin vasculature, and the heart.3

Antihistamines have a number of clinical indications including allergic conditions (rhinitis, dermatoses, atopic dermatitis, contact dermatitis, allergic conjunctivitis, hypersensitivity reactions to drugs, mild transfusion reactions, and urticaria), chronic idiopathic urticaria, motion sickness, vertigo, and insomnia.

In allergic conditions, histamine and other substances are secreted from mast cells, basophils, and other cell types. Histamine then binds to, and activates, specific receptors, causing smooth muscle constriction, vasodilation, endothelial permeability, and sensory nerve stimulation. These actions of histamine manifest clinically as characteristic allergic signs and symptoms: sneezing, rhinitis, rhinorrhea, erythema, pruritus, and urticaria.2 Oral antihistamines generally provide relief of these symptoms, which are all associated with the early response to histamine. Symptoms of nasal obstruction are characteristic of late allergic reaction and are minimally relieved by antihistamines.4

Antihistamines are classified5 as first generation (sedating, including chlorpheniramine, diphenhydramine, promethazine, and hydroxyzine) and newer. The newer antihistamines are sometimes referred to as second generation (relatively nonsedating, including terfenadine, astemizole, loratadine, cetirizine, and levocetirizine) and third generation (including fexofenadine, norastemizole, and descarboethoxyloratadine). First-generation antihistamines are highly lipophilic and therefore readily cross the blood-brain barrier, contributing to adverse central nervous system effects including sedation, drowsiness, and decreased cognitive processing. First-generation drugs also have relatively short half-lives, necessitating multiple daily doses.6

Newer antihistamines were developed to decrease the adverse effects of first generation drugs. Second-generation antihistamines emerged in the early 1980’s and had higher specificity for binding to H1 receptors, lower affinity for non-histamine receptors, and are lipo-phobic (thus have poor penetration of the blood brain barrier). These drugs are thereby less likely to be sedating than first generation drugs. They also have longer half-lives, permitting once- or twice-daily dosing.6 Third-generation antihistamines are active metabolites of first-generation drugs, developed with the goal of improving clinical efficacy and minimizing side effects.5

The original second-generation agents were terfenadine and astemizole; both were removed from the market after case reports of prolonged QT interval resulting in torsade de pointes. Both of these drugs exhibited K+ blocking properties in cardiac conducting tissues, and had Cytochrome P450 (CP450) isoenzyme CYP3A4-dependent metabolism. Case reports of the use of terfenadine with concomitant ketoconazole were the first link between altered drug metabolism and adverse events. While the QT-prolonging properties of astemizole were not as well defined, its long half-life of 48 hours (up to 12 days for its metabolite) and the presence of active metabolites presented a potential risk for adverse events.

The newer oral antihistamines available in the United States and Canada and addressed in this review are cetirizine, desloratadine, fexofenadine, loratadine (which is now available over-the-counter), levocetirizine, and azelastine, and olopatadine nasal sprays. These drugs and their indications are listed below in Table 1.

Table 1. Included drugs and their labeled indications.

Table 1

Included drugs and their labeled indications.


Rhinitis refers to disease involving inflammation of the nasal membranes.7 Symptoms include nasal discharge, sneezing, and congestion. Rhinitis is considered pathologic when symptoms are severe enough to require therapy. Rhinitis may be infectious or noninfectious. Noninfectious, or allergic, rhinitis (allergic rhinitis) may be seasonal (seasonal allergic rhinitis) or perennial (perennial allergic rhinitis), and is characterized by nasal mucous membrane swelling and blockage, reflex sneezing and hypersecretion, and ocular manifestations including itching, tearing, and conjunctival edema and redness. Non-allergic (vasomotor, “irritant”) rhinitis is also common, and responds better to topical nasal steroids than oral antihistamines (although moderate response can often be seen with topical nasal antihistamines).

Persons with seasonal allergic rhinitis, otherwise known as hay fever or pollinosis, have symptoms primarily in the spring, summer, or fall, during the pollinating season of the plants to which affected persons are sensitive, including trees, grass, or weeds.7 Persons with perennial allergic rhinitis, on the other hand, have year-round symptoms (although there may be some seasonal variation) related to allergens that are largely indoors (house dust mites [D. pteronyssinus], animal dander, and mold spores).7, 8

As it is often difficult to differentiate between seasonal allergic rhinitis and perennial allergic rhinitis, and the World Health Organization’s Allergic Rhinitis and its Impact on Asthma Group has recommended instead that allergic rhinitis be classified as “intermittent” or “persistent”.9

Allergic rhinitis is a very common condition worldwide, with estimates of global prevalence ranging between 10% and 25%,10 and epidemiologic evidence suggests that the prevalence of allergic rhinitis is increasing.11, 12 Approximately 40 million people in the United States experience significant symptoms of allergic rhinitis for all or part of each year.13–15 Allergic rhinitis is even more prevalent in younger populations and is thought to affect up to 40% of children and adolescents.7, 10, 16, 17

Allergic rhinitis has a number of important sequelae. Health-related quality of life is impacted by allergic rhinitis, including effects on physical function, energy, social function, mental health, bodily pain, mood, learning ability, and workplace productivity.18, 19 If left untreated, allergic rhinitis can be associated with serious complications, including asthma, sinusitis, respiratory infections, and otitis media.19, 20 In addition, allergic rhinitis appears to be linked to a number of other conditions. Allergic rhinitis may be considered an independent risk factor for asthma and the 2 diseases often coexist.6, 9 Atopic dermatitis is also linked to both allergic rhinitis and asthma.

Allergic rhinitis among children is particularly problematic, as the condition is often undiagnosed or misdiagnosed. Allergic rhinitis can have a large impact on the health and quality of life of children, including school absenteeism, diminished school performance, and mental health consequences.19, 20 In the United States, it is estimated that children with allergic rhinitis miss 2 million days of school per year.16 Allergic rhinitis and its treatment can affect school performance by causing diminished cognitive function,20 irritability, disrupted sleep patterns and sleep loss, mood disturbances, and impaired social function.6 Children with poorly-controlled allergic rhinitis are at an increased risk for developing asthma, chronic sinusitis, and otitis media, as well as other respiratory complications.

The objective of treatment of allergic rhinitis is to diminish symptoms and decrease progression to other sequelae and complications. Since this is a chronic condition, treatments must be safe, well-tolerated, and effective in the long term. First-line treatments for allergic rhinitis include allergen avoidance and environmental control, however the evidence for the effectiveness of these interventions is limited.3 Pharmacotherapy treatment recommendations depend on symptom severity and may include antihistamines, decongestants, corticosteroids, leukotriene-receptor antagonists, mast cell stabilizers, anticholinergics, and allergen-specific immunotherapy.21


Urticaria, or hives, is a condition characterized by transient, pruritic wheals (swellings) that are primarily the result of histamine release from mast cells. It is estimated that at least 50% of the general population have experienced urticaria at one time or another.2 Chronic urticaria is usually defined as recurring episodes of urticaria lasting 6 weeks or more.2

The etiology of chronic urticaria can be physical stimuli or may be idiopathic. Types of chronic urticaria that occur in response to physical stimuli include dermatographism (urticaria in response to stroking, friction, or rubbing), cholinergic urticaria (where stimuli that raise the core temperature of the body elicit urticaria), cold urticaria (where wheals occur after exposure to cold; this condition is rarely associated with underlying diseases),22 solar urticaria (provoked by ultraviolet light), and aquagenic urticaria (precipitated by contact of the skin with water of any temperature). So-called “idiopathic urticaria” may be due to an autoimmune process in 40% to 50% of patients.23 Chronic idiopathic urticaria is self-limited for most patients; 50% undergo spontaneous remissions within 1 year. Twenty percent, however, have intermittent symptoms for years.22

Acute urticaria is much more common than the chronic form in both adults and children, accounting for 70% of cases.22 Acute urticaria is idiopathic in greater than 50% of cases. It can, however, occur as a hypersensitivity reaction to food, wasp or bee stings, as a response to blood products, infection, or febrile illness, or as a response to various drugs. A variety of drugs can cause acute as well as chronic urticaria, most commonly antimicrobial agents, anti-inflammatory drugs, analgesics, angiotensin-converting enzyme inhibitors, and blood products.22

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid disease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of studies’ results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The goal of this report is to compare the efficacy, effectiveness, and adverse effects of newer antihistamines in both adult and pediatric populations. The Oregon Evidence-based Practice Center wrote preliminary key questions and identified the populations, interventions, and outcomes of interest. Based on these key questions, the eligibility criteria were developed for studies included in this review. The key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians, patients, and policy-makers. The participating organizations approved the following key questions to guide this report:

Key question 1. For outpatients with seasonal or perennial allergic rhinitis or urticaria, do newer antihistamines differ in effectiveness?

Key question 2. For outpatients with seasonal or perennial allergic rhinitis or urticaria, do newer antihistamines differ in harms?

Key Question 3. Are there subgroups of patients based on demographics (age, racial groups, gender), socioeconomic status, other medications (drug-drug interactions), comorbidities (drug-disease interactions), or pregnancy for which one newer antihistamine is more effective or associated with fewer harms?

Copyright © 2010 by Oregon Health & Science University, Portland, Oregon 97239. All rights reserved.
Bookshelf ID: NBK50554


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