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The use of antihistamines in children

Article · April 2016

DOI: 10.1016/j.paed.2016.02.006

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 OCCASIONAL REVIEW
The use of antihistamines
in children
Katherine Anagnostou
Kate E Swan
Helen Brough
Abstract
Antihistamines are commonly used in paediatric medicine mainly for
the treatment of allergic conditions. First generation antihistamines
have been in use for many years, despite limited research studies sup-
porting their use. Second generation antihistamines have been inves-
tigated for both efficacy and safety in paediatrics. An optimal
understanding of their effects and pharmacology are required for
optimal use in each patient. In this review we discuss the indications
for use, as well as efficacy and safety of both old and newer antihista-
mines for the paediatric population.
Keywords allergic rhinitis; antihistamines; asthma; atopic dermatitis;
children; urticaria
Introduction
Antihistamines are widely used in paediatrics for the treatment of
a variety of conditions, including acute allergic reactions, allergic
rhinitis, allergic conjunctivitis, allergic asthma, urticaria and
atopic dermatitis. A study by the Spanish Society of Allergology
and Clinical Immunology has shown that 56.4% of paediatric
patients below the age of 14 years had received some antihista-
mine before seeing an allergist.
First generation antihistamines have been used for over 50
years and still remain popular, despite the fact that they have not
been adequately studied in the paediatric population. In contrast,
newer antihistamines (2nd generation) have been studied
extensively regarding both their efficacy and safety profile in
children. Second generation antihistamines are the treatment of
choice for allergic conditions and appear to be safer and less
sedative than first generation antihistamines. They also have the
added advantage of a longer half-life and less frequent dosing
requirements (Table 1).
Antihistamines available for use in paediatrics
There are four types of histamine receptors (H1eH4), of which
H1 and H2 receptors stimulate both the early-phase (vasodilation
Katherine Anagnostou MD (Hons) MSc PhD is a Consultant in
Paediatric Allergy, Paediatric Allergy Department, St Thomas’
Hospital, London, UK. Conflicts of interest: none declared.
Kate E Swan MSc (Allergy) MA BMBCh MRCPCH is a Paediatric Allergy
Specialist Trainee (ST8) in the Paediatric Allergy Department, St
Thomas’ Hospital, London, UK. Conflicts of interest: none declared.
Helen Brough MA (Hons) MSc (Allergy) PhD MB BS FRCPCH is a Consultant
in Paediatric Allergy, Paediatric Allergy Department, St Thomas’
Hospital, London, UK. Conflicts of interest: none declared.
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Anagnostou K, et al., The use of antihistamines in children, Paediatrics and Child Health (2016), http://
dx.doi.org/10.1016/j.paed.2016.02.006
with erythema, angioedema and hypotension) and late-phase
allergic response (induction of a pro-inflammatory state
through up-regulation of cytokines and cell adhesion molecules).
Antihistamines do not block H1-receptors as previously thought,
but function as reverse agonists. They have a preferential affinity
for the inactive state of the histamine H1-receptors and stabilise
them in this conformation. As a result of this action, there is a
shift in equilibrium towards the inactive state and consequent
down-regulation of acute and chronic allergic inflammation.
First generation (old) antihistamines are well absorbed after
oral administration and reach peak level concentrations in the
serum within 1e3 hours. They can also be administered via the
parenteral route for the treatment of anaphylaxis. They are
rapidly eliminated in children and generally have shorter half-life
and shorter duration of action in the paediatric population
compared with adults. However, it takes approximately 3 days
for skin reactivity to return to baseline after ingestion. First
generation antihistamines are able to cross the bloodebrain
barrier and as a result, they exert significant effects on the ner-
vous system. They also display anticholinergic effects, such as
dry mouth and constipation, via their action through cholinergic
receptors.
Second generation (newer) antihistamines commonly used
include loratadine, desloratadine, cetirizine, levocetirizine and
fexofenadine. Loratadine is rapidly absorbed by the GI tract with
a mean half-life of 7.8e11 hours. It is metabolised by the cyto-
chrome P-450 enzyme system in the liver. In contrast, cetirizine,
levocetirizine and fexofenadine are largely eliminated without
metabolic transformation; subsequently, cetirizine and levoce-
tirizine are excreted in the urine and fexofenadine in the bile. The
mean elimination half-life for fexofenadine is 18 hours in chil-
dren (versus 14 hours in adults), but children attain higher levels
of the drug. Most of the newer generation antihistamines have a
duration of action of at least 24 hours, facilitating daily dosing.
Although plasma clearance of long acting anti-histamine may be
less than 24 hours, the medication remains in the extravascular
space for longer, with a prolonged effect beyond one day. Reg-
ular second generation antihistamines have a more sustained
effect, which is still significant 3 days after stopping the medi-
cation, compared to placebo. Studies have confirmed that 2nd
generation antihistamines also have rapid onset of action, with
Cetirizine resulting in inhibited wheal responses within 90 mi-
nutes of a single dose, in over 40% of patients. Second genera-
tion antihistamines are the treatment of choice for an allergic
response due to their high selectivity for the H1 receptor, high
efficacy and few side effects.
Clinically, patients are advised to stop taking long-acting anti-
histamines 5e7 days before skin prick testing and short-acting
antihistamine 48 hours prior to testing. The H2 antagonist, ra-
nitidine, has been shown to reduce skin reactivity and there are
some suggestions that it should be stopped on the day of testing,
however, the clinical significance is not clear.
Indications for use of antihistamines in paediatrics
Allergic rhinitis and conjunctivitis
Allergic rhinitis (AR) is a common chronic childhood disorder
and its prevalence is increasing, especially in the Western world.
1 Ó 2016 Published by Elsevier Ltd.
 OCCASIONAL REVIEW
Commonly used first and second generation antihistamines and route of administration (in brackets)
First generation
Chlorphenamine (oral, IV)
Hydroxyzine (oral)
Promethazine hydrochloride (oral)
Ketotifen (oral, eye drops)
Table 1
Symptoms can be troublesome for the child causing significant
reduction in quality of life.
Both old and newer generation antihistamines have been used
for the treatment of allergic rhinitis. Clinical studies examining
the use of first generation antihistamines in children are lacking.
However, in 2009, a Global Allergy and Asthma European
Network (GA2LEN) position paper examined the risks of these
antihistamines and determined that they reduce rapid eye
movement (REM)-sleep, impair learning and reduce work effi-
ciency, which can have a significant compounding impact on
paediatric patients who already have reduced quality of sleep and
poor daytime concentration due to their AR symptoms. In 2007, a
case-control analysis of 1834 students in the UK, aged 15 to 17,
revealed that up to 43% suffered from AR and that symptomatic
allergic rhinitis and resultant medication use was associated with
a 70% increased risk of unexpectedly dropping a grade in sum-
mer examinations, compared to a 40% risk in untreated students
with AR. GA2LEN and Allergic Rhinitis and its Impact on Asthma
(ARIA) initiative recommend that older first-generation H1-
antihistamines should no longer be available as over-the-
counter drugs for self-medication of allergic diseases, with the
newer second generation non-sedating H1-antihistamines, which
have fewer side effects, being treatment of choice for AR.
There are a large number of studies supporting the use of
second generation antihistamines in the paediatric population.
Antihistamines are effective in alleviating sneezing, itching and
rhinorrhoea; they appear to be less effective against nasal
blockage. Specifically, the use of Loratadine, at a dose of 2.5e5
mg daily has shown to improve significantly both nasal and
ocular symptoms in a study of 21 children suffering from sea-
sonal allergic rhinitis (hayfever). Several placebo-controlled tri-
als support the use of cetirizine for both seasonal and perennial
allergic rhinitis. Children receiving cetirizine daily at a dose of 5
mg BD (twice daily) or 10 mg OD (once daily), have demon-
strated significant improvement in their allergic symptoms,
compared with the placebo group. In addition, a multi-centre,
prospective, randomised controlled study involving 935 chil-
dren between 6 and 11 years of age has shown Fexofenadine to
be significantly superior to placebo in alleviating seasonal
allergic rhinitis symptoms with a good safety profile. Some evi-
dence exists that regular use of H1 antihistamines is more
effective in controlling symptoms of allergic rhinitis than an ad-
hoc regimen. A continual, long-term treatment may result in
better control of airway symptoms and improved quality of life.
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Anagnostou K, et al., The use of antihistamines in children, Paediatrics and Child Health (2016), http://
dx.doi.org/10.1016/j.paed.2016.02.006
Second generation
Cetirizine (oral)
Levocetirizine (oral)
Loratadine (oral)
Desloratadine (oral)
Fexofenadine (oral)
Azelastine (intranasal)
Olopatadine (eye drops)
Topical nasal antihistamine azelastine is more effective in
treating allergic rhinitis symptoms than oral antihistamines, but
intranasal steroids are far superior to antihistamine monotherapy
for allergic rhinitis. A combination of an intranasal steroid and
antihistamine spray also demonstrates good efficacy, with some
evidence that it is better than either intranasal steroid or topical
nasal antihistamine alone. For allergic conjunctivitis, olopatadine
eye drops have shown good effectiveness and symptom relief.
Allergic asthma (in combination with allergic rhinitis
symptoms)
Most children with asthma, also have allergic rhinitis. The
concept of the “united airway” has been in the literature for
several years and it is known that upper airway disease (rhinitis)
often precedes lower airway disease (asthma). Immunomodula-
tory cytokines, produced as a result of allergic activation of mast
cells in the nasal mucosa, can cause an inflammatory response in
the lower airways. Histamine is an important inflammatory
mediator in the respiratory tract and a rise in plasma levels has
been noted in asthma attacks. Antihistamines have been shown
to improve cough and lung function in children with pollen al-
lergy, during the pollen season, as one would expect with the
concept of the “united airway”. A systematic review has indi-
cated that ketotifen alone or in combination with other drugs
effectively improved asthma and wheezing control in children
with mild to moderate asthma. Generally, in patients with both
upper and lower airway inflammation (concurrent symptoms of
rhinitis and asthma), the use of antihistamines may induce a
significant decrease in symptoms as well as in the use of bron-
chodilators. A population-based, case-control study in patients
with asthma and allergic rhinitis in the USA suggested that
treatment of allergic rhinitis reduces the risk of emergency room
visits and hospitalisations for asthma.
Studies examining the role of regular antihistamine use in
preventing asthma in children sensitised to pollen and house
dust mites, have failed to demonstrate a significant difference in
asthma prevalence; therefore antihistamines are not recom-
mended for this use. According to the current BTS guidelines,
antihistamines should not be used in the management of asthma
per se.
Urticaria
Antihistamines are regularly used for the treatment of both acute
and chronic urticaria in children. Acute urticaria is common and
2 Ó 2016 Published by Elsevier Ltd.
 OCCASIONAL REVIEW
usually occurs as a result of an immediate allergic reaction to
food or other allergen. It can also follow viral infections in young
children. Chronic urticaria (more than6 weeks of daily symp-
toms) is less common in children.
The EPAAC study examined the effect of levocetirizine anti-
histamine in 510 high-risk infants, aged 12e24 months, with
atopic dermatitis, at a dose of 0.125 mg twice daily, for 18
months. The use of levocetirizine resulted in a reduction of the
number of subjects who experienced episodes of urticaria
(27.5% in the treatment versus 41.6% in the placebo group), the
mean number of urticarial episodes (0.71 versus 1.71 days) and
the duration of episodes of urticaria (4.43 versus 5.36 days). The
investigators concluded that regular, long-term treatment with
levocetirizine effectively prevents and treats urticaria in young
children. Cetirizine has also shown similar beneficial effects in a
different study.
In chronic urticaria, which does not respond to the recom-
mended dose of a second generation antihistamine after 1e4
weeks, high doses (up to four-fold the recommended dose) of a
second generation H1 antihistamine or a combination of two
different second generation antihistamines may offer some
advantage. H2 antihistamines may also be used as second line
treatment, although their efficacy is unproven.
Atopic dermatitis
Itchiness causes significant discomfort in children with atopic
dermatitis and affects their quality of life. First generation anti-
histamines have been used for the relief of pruritus for many
years, although their efficacy has been questioned and studies
have shown conflicting results. Cetirizine and fexofenadine have
also been used for the same purpose, but scientific evidence
supporting this practice are lacking. The European Academy of
Allergology and Clinical Immunology/American Academy of
Allergy, Asthma and Immunology/PRACTALL Consensus Report
states that the therapeutic value of antihistamines is primarily
due to their sedative properties, making them useful as a short-
term adjuvant to topical treatment during relapses associated
with severe pruritus. Hydroxyzine, a first generation anti-
histamine, is sometimes used for this purpose.
The NICE guidelines for the treatment of atopic dermatitis
suggest a 1-month trial of a non-sedating antihistamine in chil-
dren with severe itchiness; this treatment needs to be reviewed
every three months and only be continued if there is a positive
response to the medication.
Acute allergic reactions
The use of H1 antihistamines for acute, IgE-mediated allergic
reactions is strongly recommended and forms part of the emer-
gency management plan for allergic children. However, it is
important to note that this refers to non-anaphylactic reactions;
the first line treatment for anaphylaxis is intramuscular admin-
istration of adrenaline. Anti-histamines should only be used after
adrenaline and initial resuscitation because they are unlikely to
be life-saving in anaphylaxis. Chlorphenamine administration is
part of the Resuscitation Council UK guidelines for the manage-
ment of anaphylaxis after adrenaline has been given, but a
Cochrane review by Sheikh et al. found no high quality evidence
for or against the use of antihistamines in the management of
anaphylaxis.
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Anagnostou K, et al., The use of antihistamines in children, Paediatrics and Child Health (2016), http://
dx.doi.org/10.1016/j.paed.2016.02.006
No evidence of efficacy
Otitis media
The use of H1 antihistamines either alone or in combination with
decongesting agents, in the treatment of otitis media with effu-
sion has shown no significant clinical benefit. Despite elevations
in histamine concentration in the middle ear effusions of patients
with otitis media, antihistamine therapy is not recommended.
Cough
Cough is a very common childhood complaint. Two different
meta-analyses, which reviewed the effectiveness of antihista-
mines in treating both acute and prolonged non-specific cough,
have demonstrated no significant clinical benefit of such treat-
ment when compared with placebo. Cough due to postnasal drip,
responds to nasal douching and intranasal steroids.
Respiratory infections
A meta-analysis examining the use of antihistamines for treat-
ment of respiratory infections has shown no clinical benefit.
Specifically, when these drugs were administered as mono-
therapy, they provided no relief of sneezing, nasal congestion or
rhinorrhoea for the common cold.
Safety
Central nervous system
First generation antihistamines cross the bloodebrain barrier and
can cause fatigue, somnolence and lethargy or paradoxically,
irritability, hyperactivity and seizures. They may also induce
respiratory depression and sleep apnoea. Due to their action on
cholinergic receptors, they can also cause blurred vision and dry
mouth.
Sedating antihistamines can also affect learning. Vuurman
et al examined learning performance in 52 primary school chil-
dren with allergic rhinitis who were assigned to receive a
sedating antihistamine or a non-sedating antihistamine or a
placebo (Three groups). All 52 children were matched with
healthy controls (children of the same age with no allergies) and
the performance of both atopic and non-atopic children was
assessed following treatment. It was reported that the atopic
children performed less well than the non-atopic group and
within the atopic group, performance results were worse for
those who had received sedating antihistamine treatment.
Second generation antihistamines have limited access to
central H1 receptors and do not generally cause adverse CNS
effects in children. Cetirizine is less sedating than first generation
antihistamines, but can be more sedating than loratadine or
fexofenadine. Loratadine is non-sedating at the recommended
daily dose of 10 mg, but may cause significant sedation and
performance impairment if used at 2e4 times the recommended
dose. Fexofenadine however, does not appear to have any
sedative effects even at high doses (i.e. 690 mg twice daily in
adults). Headache, tiredness and dizziness are all side effects that
have been reported following fexofenadine use.
Cardiac effects
First generation antihistamines terfenadine and astemizole have
been associated with adverse cardiac events, such as torsade de
pointes. This has resulted in discontinuation of their use.
3 Ó 2016 Published by Elsevier Ltd.
 OCCASIONAL REVIEW
Newer antihistamines, such as cetirizine, are free from cardiac
side effects. Loratadine is non-arrythmogenic as it does not in-
crease the QT interval and no arrythmias have been reported
with its use. In a similar way, fexofenadine has not been shown
to cause any QT interval prolongation.
Overdose
An overdose of first generation antihistamines is potentially le-
thal; cardiorespiratory arrest and death are possible following
intoxication. Due to their effect on cholinergic receptors, they
may also cause anticholinergic syndrome with hot, flushed skin,
hallucinations, seizures, hypertension and fever.
The data on second generation antihistamine overdose are
limited. A small study reported two children with cetirizine
overdose, one displaying a brief period of agitation, following
ingestion of 180 mg and the second suffering from vomiting and
severe drowsiness, following ingestion of 60 mg in a single dose.
Pregnancy and lactation
Some first generation antihistamines have shown teratogenic
effects in animals, but not humans. Withdrawal symptoms
(tremor, irritability) have been reported in babies whose mothers
received large doses of first generation antihistamines prior to
delivery, as well as in nursing babies, since antihistamines are
excreted in the breast milk.
There is no evidence of teratogenic effects with second and
third generation antihistamines, however their use in pregnancy
is only recommended if the benefits to the mother significantly
outweigh any potential risks to the fetus. Both loratadine and
cetirizine are known to be excreted in breast milk; it is not
known whether this is also the case for fexofenadine, so its use in
nursing mothers should be done with caution. Loratadine and
cetirizine are classified as pregnancy category B, whereas fex-
ofenadine is classified as category C. Category B is defined as
animal studies not showing any fetal risk and no human studies
done or animal studies showing fetal risk, but human studies
showing no risk. Category C is defined as fetal risk in animal
studies without adequate human studies or no adequate animal
or human studies.
Conclusions
Antihistamines are frequently used in paediatric patients for the
treatment of allergic conditions. Second generation antihista-
mines have been well investigated with regards to their efficacy
and adverse effects and many studies support their use in chil-
dren. They are the treatment of choice for allergic rhino-
conjunctivitis and chronic urticaria due to their ease in admin-
istration (once daily schedule), better safety profile and reduced
potential for sedation. A J Investig Allergol Clin Immunol 2007; 17(suppl 2): 28e40.
PAEDIATRICS AND CHILD HEALTH --:-
Please cite this article in press as: Anagnostou K, et al., The use of antihistamines in children, Paediatrics and Child Health (2016), http://
dx.doi.org/10.1016/j.paed.2016.02.006
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Learning points
C Various research studies support the use of second generation
antihistamines in children and show good efficacy.
C Newer H1 antihistamines are non-sedative and relatively free from
adverse CNS effects in children.
C Second generation antihistamines represent the treatment of
choice for allergic disorders in children, such as allergic rhino-
conjunctivitis and chronic urticaria.
C A combination of a non-sedating antihistamine and a steroid
nasal spray is recommended for the treatment of allergic rhinitis
in children.
C A 1-month trial of a non-sedative antihistamine can be used for
children with atopic dermatitis who suffer from intense itchiness.
C In chronic urticaria the antihistamine dose can be increased up to
four times the recommended dose. If sedation is a problem then
consider using fexofenadine.
C The use of H1 antihistamines is recommended for the treatment
of mild/moderate allergic reactions and forms part of the emer-
gency management plan.
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4 Ó 2016 Published by Elsevier Ltd.