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ORIGINAL
ARTICLE
PEDIATRIC ALLERGIC RHINITIS:
FACTORS
AFFECTING TREATMENT CHOICE
Pediatric allergic rhinitis: Factors
affecting treatment choice
Erwin W. Gelfand, MD
Abstract
Allergic rhinitis is the most prevalent chronic allergic disease
in children. Although it is not life-threatening, it can have
a significantly detrimental effect on a child’s quality of life,
and it may exacerbate a number of common comorbidities,
including asthma and sinusitis. The Allergic Rhinitis and
its Impact on Asthma guidelines, an evidence-based algorithm for the treatment of allergic rhinitis, advocate the use
of antihistamines for the treatment of the broad spectrum
of the disease. However, first-generation antihistamines
are associated with a number of adverse events, including
central nervous system impairment and anticholinergic
and cardiovascular effects. Moreover, these agents have
not been rigorously tested in the pediatric population. Nevertheless, first-generation antihistamines remain the most
frequently prescribed agents in this class of drugs. This is
despite the fact that the second-generation antihistamines
are largely free of the undesirable side effects associated
with their predecessors and the fact that they have been
shown to be effective in relieving allergic rhinitis symptoms
in children in a number of large-scale clinical trials. Therefore, when selecting an antihistamine for a child, it would
be prudent to consider the full range of antihistamines and
to base the selection of a particular drug on its efficacy,
onset and duration of action, and safety profile.
Introduction
We have recently seen a rapid increase in the incidence of
allergic disorders, particularly in the pediatric population.
Of these, allergic rhinitis is the most common chronic allergic disease, and recent reports estimate that as many as
40% of children are affected by the condition.1
Allergic rhinitis is clinically defined as an allergeninduced inflammation of the nasal membranes and
surrounding tissues that results in sneezing, rhinorrhea,
conjunctivitis, nasal congestion, and pruritus of the nose,
From the Division of Cell Biology, Department of Pediatrics, National
Jewish Medical and Research Center, Denver.
Reprint requests: Erwin W. Gelfand, MD, Department of Pediatrics,
National Jewish Medical and Research Center, 1400 Jackson St.,
Denver, CO 80206. Phone: (303) 398-1196; fax: (303) 270-2105;
e-mail: [email protected]
The preparation of this article was supported by an educational grant
from Aventis Pharmaceuticals of Bridgewater, N.J.
Volume 84, Number 3
palate, throat, and/or ears. Allergic rhinitis can be classified as either intermittent or persistent; persistent allergic
rhinitis is subclassified as either seasonal or perennial,
depending on the duration and frequency of symptoms.
Allergic rhinitis is most common in children; the mean age
of patients at its onset is approximately 10 years and its
incidence peaks between the ages of 13 and 19 years.2,3
Although allergic rhinitis is not an acute disease, it can
have an important negative impact on the quality of life in
children, impairing their learning performance,4,5 reducing
their ability to concentrate,6,7 and causing disturbed sleep
patterns.7 Moreover, allergic rhinitis may also be associated
with the development of other allergic diseases––the socalled allergic march. Left untreated, allergic rhinitis may
exacerbate asthma, another prevalent childhood chronic
disease with a high burden of morbidity.8 A range of other
disorders has also been linked to pediatric allergic rhinitis,
including sinusitis, sleep apnea, nasal polyposis, nasal collapse, hearing impairment, abnormal craniofacial development, and impaired cognitive functioning.9
Given the high prevalence of allergic rhinitis in children,
its negative impact on quality of life, and its potential to
exacerbate or lead to other disorders, there is little doubt
that the disease warrants effective treatment and management. In this article, the author reviews the efficacy, the
onset and duration of action, and the safety of currently
available treatments.
Overview of treatment options
As is the case with many other allergic disorders, first-line
treatment for allergic rhinitis is allergen avoidance. The
ease with which this can be accomplished depends on the
type of allergen involved. Indoors, a range of measures
can be taken to reduce the allergen load. Aggressive cleaning––particularly of carpets, curtains, and bedding––can
be effective. However, the efficacy of nonallergenic bedcovering products is still questionable; whereas some studies have shown that they are associated with a reduction
in allergic rhinitis symptoms,10 others have found them to
be of little benefit when used alone.11 Ubiquitous aeroallergens such as pollen are harder to avoid, and patients who
are sensitive to them are therefore more likely to require
medication to relieve their symptoms.
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GELFAND
The Allergic Rhinitis and its Impact on Asthma (ARIA)
guidelines were developed by the World Health Organization to establish an evidence-based protocol for the
treatment of allergic rhinitis.8 These guidelines provide
a useful point of reference for physicians who treat both
adults and children with allergic rhinitis. They contain a
stepwise approach to treatment to maximize its beneficial
effects while minimizing its adverse effects. In view of
children’s developmental vulnerability, the guidelines
include a recommendation that physicians pay special
attention to the risk/benefit ratio of any therapeutic intervention in this population.
The ARIA guidelines also include a review of the
therapeutic agents that are indicated for the treatment of
allergic rhinitis, including oral and intranasal antihistamines, intranasal glucocorticosteroids, local chromones,
oral and intranasal decongestants, intranasal anticholinergics, and antileukotrienes.8 The suitability and availability
of these agents in children vary. For example, intranasal
glucocorticosteroids, with their global effects on the
inflammatory response, are indicated only for moderateto-severe or persistent allergic rhinitis. The guidelines’
authors express some concern about the use of intranasal
glucocorticosteroids in children, and they stress the need
for monitoring these children. Very few intranasal glucocorticosteroid therapies have been approved for children,
and none is available for children younger than 3 years of
age. In contrast, antihistamines are indicated for the broad
spectrum of allergic rhinitis severity, and oral formulations of this drug class remain the mainstay of treatment
in children.
Phenbenzamine, the first available antihistamine, was
developed in the 1940s. It was succeeded by a number of
similar agents, including chlorpheniramine, brompheniramine, diphenhydramine, promethazine, and hydroxyzine.
These older, first-generation antihistamines were associated
with a range of adverse effects, including sedation, dry
mucous membranes, and tachycardia. The second-generation agents––fexofenadine, loratadine, cetirizine, and
azelastine––were developed in recent years to reduce these
side effects. A number of first- and second-generation oral
and inhaled antihistamines have been approved for use in
children and are available either as over-the-counter or
prescription-only drugs (table).
Antihistamines are antagonists to the H1 histamine
receptor, and they reduce inflammation by blocking the
histamine-driven inflammatory cascade. However, although all antihistamines mediate their therapeutic effects
via the same primary mechanism, each agent has different
properties, both positive and negative. Therefore, product
selection should be tailored to the needs of each patient. A
range of criteria should be borne in mind when making this
selection, including efficacy, onset and duration of action,
and safety profile because there are important differences
among the antihistamines in each of these areas.
164
Efficacy
The best evidence of the benefits of antihistamine use in the
pediatric population is provided by well-designed clinical
trials. Such data are generally not available for the first-generation agents because they were introduced at a time when
study requirements were less rigid than they are today. The
most recent data on the first-generation agents derive from
their use as active controls in studies of second-generation
agents. This means that although diphenhydramine is the
most widely used antihistamine in the United States,12 its
exact benefits in terms of symptom reduction are unclear,
particularly in the pediatric population. The paucity of data
from well-designed studies coupled with concerns over
tolerability led a recent consensus group to recommend
that the use of first-generation antihistamines should be
limited in all patients with allergic rhinitis.12
The efficacy and safety of some second-generation antihistamines in children have been assessed in a number
of well-designed clinical trials. Four of these agents are
currently available for use in children in the U.S.: fexofenadine is indicated for use in children aged 6 years and
older, loratadine for children 2 years or older, cetirizine for
children 6 months and older, and azelastine for children 5
years and older. (The secondary metabolite of loratadine,
desloratadine, is currently approved only for patients aged
12 years and older.) However, there have been no head-tohead trials among the second-generation agents in children,
so direct comparisons are not possible.
Fexofenadine. In 2000, fexofenadine was approved
in the U.S. for the treatment of seasonal allergic rhinitis
in children aged 6 to 11 years. This antihistamine was
shown to alleviate symptoms in a placebo-controlled,
double-blind study of 935 children aged 6 to 11 years in
15 countries.13 The primary endpoint of this study was the
change from baseline in the mean total symptom score;
these symptoms included sneezing; rhinorrhea; itchy nose,
mouth, throat, and/or ears; and itchy, watery, and/or red
eyes. Nasal congestion was assessed separately. At study’s
end, children who had taken fexofenadine 30 mg twice
daily had a significantly lower mean total symptom score
than did those in the placebo control group ( p ≤ 0.0001).
The mean change from baseline for the fexofenadinetreated group was 1.94 compared with 1.21 for the placebo
group. Moreover, secondary endpoint analyses revealed
that fexofenadine was significantly more effective than
placebo in reducing individual symptom scores, including
those for nasal congestion ( p ≤ 0.05 for each symptom).
The data also suggest that fexofenadine is rapidly effective, as improvement in both individual and total symptom
scores were observed on the first day of treatment and were
maintained throughout the entire 14-day trial.
Loratadine. Loratadine is available over the counter for
the treatment of seasonal and perennial allergic rhinitis
as a tablet (10 mg) for children aged 6 and older and as a
syrup (5 mg/ml) for children aged 2 to 5 years. Trials of
ENT-Ear, Nose & Throat Journal ■ March 2005
PEDIATRIC ALLERGIC RHINITIS: FACTORS AFFECTING TREATMENT CHOICE
Table. Dosing information for selected first- and second-generation antihistamines approved for use in
children with allergic rhinitis
Drug
Indication/age
Dosage
Brompheniramine
SAR: Infants
and older
<3 yr: 0.4 to 1 mg/kg/day in 4 divided doses
3 to 6 yr: 2 mg 3 or 4 times daily
6 to 12 yr: 2 to 4 mg 3 or 4 times daily
Chlorpheniramine
SAR: ≥2 yr
2 to 6 yr: 1 mg 3 times daily
6 to 12 yr: 2 mg 3 times daily
Promethazine
PAR, SAR: ≥2 yr
2 to 5 yr: 5 to 15 mg once daily
5 to 10 yr: 10 to 25 mg once daily
Diphenhydramine
SAR: Infants and
older
>20 lbs: 12 to 25 mg 3 or 4 times daily;
max: 300 mg/day
Fexofenadine
SAR: ≥6 yr
6 to 11 yr: 30 mg twice daily
Loratadine
SAR: ≥2 yr
2 to 5 yr: 5 mg/ml once daily
≥6 yr: 10 mg twice daily
Cetirizine
PAR: ≥6 mo
SAR: ≥2 yr
6 to 24 mo: 2.5* to 5 mg once daily
2 to 5 yr: 2.5* to 5 mg once daily
6 to 11 yr: 5 to 10 mg once daily
Azelastine
SAR: ≥5 yr
5 to 11 yr: 125 µg twice daily
First-generation
Second-generation
* 2.5-mg dose is administered as one-half a teaspoon of syrup.
SAR = seasonal allergic rhinitis; PAR = perennial allergic rhinitis.
loratadine in the pediatric population have included only
relatively small numbers of patients. The initial efficacy data
on loratadine for seasonal allergic rhinitis were obtained
during a 14-day trial of 40 children aged 3 to 6 years.14
A total of 21 patients received loratadine syrup at 0.11 to
0.24 mg/kg ideal body weight once daily, and 19 children
received first-generation dexchlorpheniramine syrup at 0.10
to 0.23 mg/kg every 8 hours. The efficacy data showed that
loratadine was just as effective as dexchlorpheniramine in
terms of alleviating nasal and ocular symptoms.
A randomized, double-blind, parallel-group study of 96
children aged 3 to 6 years with seasonal allergic rhinitis
showed that the therapeutic response at the study’s endpoint
was rated by physicians as good or excellent in 82% of
children who took loratadine syrup at 5 or 10 mg once daily
for 14 days, compared with only 60% of those who took
terfenadine suspension at 15 mg twice daily for 14 days.15
According to physicians’ ratings, treatment outcomes were
similar across groups, except at day 14 when the response
was significantly better in the loratadine group ( p ≤ 0.02).
Volume 84, Number 3
Nasal and nonnasal symptom severities were also rated by
physicians on a 4-point scale at baseline and on treatment
days 3, 7, and 14. Mean nasal and nonnasal scores decreased
significantly from baseline in both groups at each test point
( p < 0.05), with greater nonnasal symptom improvement
found in the loratadine group at day 14 ( p = 0.05).
Cetirizine. Cetirizine is approved for the treatment of
seasonal allergic rhinitis in children aged 2 years and
older and for perennial allergic rhinitis in those aged 6
months and older. Several trials have evaluated cetirizine
in children, but they all differed in scale, controls, and
primary endpoints.16-19 Overall, these studies have shown
that cetirizine is an effective treatment for allergic rhinitis
in children, but there is some variation in outcomes among
these trials.
The largest of these trials was a randomized, doubleblind, placebo-controlled study of cetirizine syrup at 5
and 10 mg once daily in the treatment of seasonal allergic
rhinitis in 209 children aged 6 to 11 years.16 At 4 weeks,
cetirizine 10 mg was significantly better than placebo in
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GELFAND
lowering total symptom scores ( p < 0.05); there was no
significant difference between placebo and the 5-mg dose
of cetirizine.
Another study showed that cetirizine at 5 and 10 mg
was as effective as chlorpheniramine in reducing total
symptom scores in 188 children aged 6 to 11 years with
allergic rhinitis.17 Similar studies have shown that cetirizine is effective in children and in infants as young as 6
months of age.18,19
Azelastine. Azelastine is approved for the treatment
of seasonal allergic rhinitis in children aged 5 years and
older. Unlike the other second-generation agents discussed
here, azelastine is not an oral preparation; it is delivered
as a nasal spray. The efficacy of azelastine in pediatric
allergic rhinitis has not been clinically assessed. Instead,
the efficacy of a 125-µg dose has been extrapolated from
adult studies. This dose was found to be safe and well
tolerated in an initial series of controlled safety studies in
176 children aged 5 to 12 years who were treated over 6
weeks.20 The efficacy of this dose has not yet been established in children.
Onset and duration of action
Given the relatively small variations in efficacy among the
second-generation antihistamines, other factors––including the onset and duration of action and the incidence of
side effects––are important considerations in the selection
of treatment.
Antihistamines are often used intermittently, and as such
they should have a rapid onset of action, which can minimize
disruption of the patient’s daily life. Histamine-induced
wheal-and-flare skin reactivity testing is the gold standard
for measuring the onset and duration of peripheral H1 receptor blockade by an antihistamine.21-25 This assay has been
used widely in adult studies to assess the newer-generation
antihistamines. For example, Simons and Simons used this
technique to compare loratadine 10 mg and fexofenadine
120 mg.26 They found that although both medications were
effective in suppressing histamine-induced wheal and flare
for 24 hours, fexofenadine had a significantly faster onset
of action. In a similar comparative study, Day et al found
that the onset of action of cetirizine 10 mg occurred at 1
hour, versus 3 hours with loratadine 10 mg.27
However, comparable pharmacologic data in children
are limited, as studies of this nature in special populations
have only recently been conducted. In one of the first of
these studies, Simons et al compared the pharmacology
of single doses of fexofenadine 30 mg and cetirizine 10
mg in children with allergies.28 They enrolled 15 children
(mean age: 8.8 ± 0.5 yr) in a randomized, double-blind,
crossover, single-dose study. The authors found that while
both cetirizine and fexofenadine significantly suppressed
the wheal-and-flare reaction over the 24-hour test period,
cetirizine demonstrated greater H1 activity. However, it
should be noted that the single test dose of fexofenadine
166
was 30 mg, which is not the currently recommended daily
dosage for children aged 6 to 11 years (the recommended
dosage is 30 mg twice daily). Furthermore, cetirizine 10 mg
is the larger of two available doses indicated for children
and is equivalent to the adult dose. Children aged 6 to 24
months and 2 to 5 years can be prescribed 2.5 to 5 mg of
cetirizine; the 2.5-mg dose is administered as one-half a
teaspoon of syrup.
Although it is clear that this subject merits further research, it is important to recognize that wheal-and-flare
testing is not a direct substitute for clinical efficacy trials.
Further clinical pharmacologic trials should be conducted
in this population.
Safety profile
First-generation antihistamines have long been associated
with a range of adverse events, including impairment of
the central nervous system (CNS) and anticholinergic and
cardiovascular effects. Many of these adverse effects arise
as a result of the first-generation agents’ lower degree of
specificity for the H1 receptor and their propensity to cross
the blood-brain barrier. Consequences are particularly serious in cases of overcompliance or overdose. More than
14,000 accidental exposures to first-generation antihistamines in children younger than 6 years of age occur every
year in the U.S., and these exposures have resulted in
several fatalities and severe toxic reactions.29 For example,
accidental ingestion of diphenhydramine caused multiple
seizures and the eventual death of a 15-month-old boy.30
Second-generation antihistamines with H1 receptor
specificity are generally not associated with such adverse
effects. Few cases of overdose have been reported, but when
they have occurred, outcomes have been generally satisfactory. For example, an 18-month-old boy who ingested 180
mg of cetirizine remained asymptomatic and exhibited no
electrocardiographic (ECG) abnormalities.31
Learning impairment. Studies have shown that poorly
controlled allergic rhinitis can have a significant impact on
a child’s development and social integration, particularly
with respect to learning performance.4,7 It has been estimated
that more than 1.5 million school days are lost each year
in the U.S. as a direct result of allergic rhinitis.4
Unfortunately, treatment of allergic rhinitis with firstgeneration antihistamines appears to have exacerbated
learning impairment. Vuurman et al compared the effects
of antihistamines on children’s learning ability and found
that diphenhydramine caused significantly more impairment than did loratadine.4 In a subsequent study, these same
researchers found that diphenhydramine compounded the
learning disability associated with allergic rhinitis.32
In contrast, second-generation antihistamines that cause
significantly fewer adverse CNS effects may be less likely
to have a negative impact on academic performance, particularly in children who require medication for prolonged
periods of time. For example, in a large, double-blind study
ENT-Ear, Nose & Throat Journal ■ March 2005
PEDIATRIC ALLERGIC RHINITIS: FACTORS AFFECTING TREATMENT CHOICE
of 574 children, Reilly et al found that fexofenadine therapy
was associated with reduced absenteeism and improved
classroom performance.33
However, Bender et al reported that the intermittent
use of antihistamines by patients with mild symptoms is
unlikely to have any lasting negative effect on learning
performance.34
Sedation. Sedation is the most common adverse effect associated with the first-generation antihistamines.
It occurs secondary to the drugs’ penetration of the
blood-brain barrier. Indeed, a number of first-generation
antihistamines––diphenhydramine, promethazine, and
hydroxyzine––have been used to sedate children prior to
electroencephalography (EEG), and they are still recommended by some physicians for sedation, pain relief, and
as an antinausea medication for infants prior to surgery.7
The authors of the ARIA guidelines recommend avoiding
the “global impairment of psychomotor performance” observed with the older-generation antihistamines.8
Data from clinical trials in adults have established that
some second-generation antihistamines are nonsedating.35,36 Similar observations have been made in the pediatric population.13,37 For example, during a safety study of
fexofenadine in 875 children, the incidence of somnolence
was comparable in those children who received the drug
and in those who received placebo.38 Similarly, Meltzer
et al recently conducted a pooled analysis of three 2-week
placebo-controlled trials of fexofenadine (at 15, 30, and
60 mg twice daily) in children aged 6 to 11 years with
seasonal allergic rhinitis and found that the drug was not
associated with any sedating effects.37
As is the case with their predecessors, however, secondgeneration antihistamines vary in their ability to cause
adverse CNS effects. Some of these agents have been
consistently found to be free of sedative effects, whereas
others have been reported to be mildly sedating in children
according to objective measurements.39 For example, there
is evidence that cetirizine causes sedation in some children
at therapeutic doses, whereas recent meta-analyses have
found that fexofenadine is the only second-generation antihistamine that is consistently not associated with adverse
CNS effects.40,41
The need for objective rather than subjective assessments of sedation in this population was highlighted by
a recent report from Ng et al.39 They found that cetirizine
10 mg and chlorpheniramine 4 mg were associated with
significantly ( p < 0.03) greater degrees of P300 latency
(an objective EEG-based measure of somnolence) than
was placebo; however, when these patients self-rated
their sedation on a visual analog scale, they reported no
significant increase in sedation. Despite the difficulties of
assessing the clinical relevance of the adverse effects of
antihistamines on the CNS in children, further studies are
clearly required in this area.
Anticholinergic effects. The poorer H1 receptor specificVolume 84, Number 3
ity of the older antihistamines has resulted in a range of
anticholinergic effects caused by blockade of muscarinic
receptors. Dry mouth, urinary retention, tachycardia, and
constipation have all been linked to a number of first-generation agents. In comparison, the newer H1 antagonists have
much lower affinities for muscarinic cholinergic receptors.42
In studies of the safety of fexofenadine,43 loratadine,44 and
cetirizine,45 the incidence of anticholinergic adverse effects
was equivalent to that seen with placebo.
Cardiovascular effects. Concerns over cardiotoxicity
with first-generation and some second-generation antihistamines have largely centered on poor receptor selectivity
and the blockade of cardiac potassium ion channels. A
number of cases of QT prolongation as a consequence of
this effect were reported in patients who took astemizole
and terfenadine. However, these agents have subsequently
been withdrawn from the market in most countries.46 In
addition, diphenhydramine has been shown to cause a
moderate but significant increase in QTc interval.47
The potential for fexofenadine, loratadine, and cetirizine
to affect cardiovascular function has been examined, and
none has been shown to have any effect on QT interval
and other ECG parameters in children. In a safety study
of fexofenadine, 14 children with allergic rhinitis received
single doses of fexofenadine 30 or 60 mg.43 Two-lead ECG
measurements were taken before and 2.5 hours after dosing,
and no abnormalities were found in any ECG rhythm strip.
Similar ECG findings have been observed for loratadine44
and cetirizine.45 These findings were supported by in vitro
measurements showing that fexofenadine, loratadine, and
cetirizine have very low affinities for cardiac potassium
ion channels.48
Conclusion
Despite the efficacy and popularity of first-generation
antihistamines for the treatment of allergic rhinitis, these
agents are associated with adverse effects in children. These
effects can be avoided by using the currently available
second-generation antihistamines, which have been shown
to be not only safer, but just as effective. Given the number
of second-generation preparations that are available and
the differences in their specific pharmacologic attributes,
care must be taken to match the particular drug to the needs
of the individual child.
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