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Original article
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
archdischild-2015-310416).
1 prescribing can also cause health issues. In this paper,
Department of Paediatrics and
Medical Genetics, Faculty of
Medicine and Health Sciences,
Ghent University, Ghent,
Belgium
2 the evidence base (or lack thereof ) for each indication,
Department of Family
Medicine and Primary Health
Care, Ghent University, Ghent,
Belgium
3
Faculty of Medicine and
Health Sciences, Heymans
Institute of Pharmacology,
Ghent University, Ghent,
Belgium
4
Pharmaceutical Care Unit,
Faculty of Pharmaceutical
Sciences, Ghent University,
Ghent, Belgium
Drug therapy
Correspondence to
Pauline De Bruyne, Department
of Paediatrics and Medical
Genetics, Faculty of Medicine
and Health Sciences, Ghent
University Hospital, 3K12D,
De Pintelaan 185, Ghent
9000, Belgium; pauline.
debruyne@ugent.be
Received 31 December 2015
Revised 25 May 2016
Accepted 30 May 2016
Published Online First
22 June 2016
▸ http://dx.doi.org/10.1136/
archdischild-2016-311527
To cite: De Bruyne P,
Christiaens T, Boussery K,
et al. Arch Dis Child
2017;102:56–60.
56
Are antihistamines effective in children? A review of
the evidence
Pauline De Bruyne,1 Thierry Christiaens,2,3 Koen Boussery,4 Els Mehuys,4
Myriam Van Winckel1
ABSTRACT
Background and aims During the last decades, much
attention has been paid to off-label and unlicensed
prescriptions in paediatrics. However, on-label
the case of first-generation H1-antihistamines is
investigated, notably the range of indications for which
products are licensed in different European countries and
as well as reported adverse drug reactions.
Methods Review of the Summary of Product
Characteristics of first-generation H1-antihistamines with
a focus on paediatric use. This is plotted against the
evidence available in the literature.
Results This investigation shows a large variability in
labelled indications and licensing ages when compared
in five different European countries. Moreover, most of
the indications are not based on clinical trials evaluating
efficacy and safety of these drugs in children.
Conclusions Many of the licensed indications of
first-generation antihistamines do not appear to be
evidence based.
INTRODUCTION
Over the past two decades, there has been an
increase in attention surrounding drug use in chil-
dren. Most of the attention is directed towards
unlicensed and off-label drug use in this popula-
tion. Justifiably, as percentages of unlicensed and
off-label drug prescriptions reach 66% in the hos-
pital and 39% in the ambulatory setting.1 The
paediatric population is a heterogeneous group,
ranging from preterm neonates to postpubertal
adolescents. They have complex physiological,
developmental and psychological characteristics
that differ from adults and these features vary
across the neonate to adolescent age range. The
simple extrapolation of efficacy and safety from
adults to children is insufficient for correct pharma-
cotherapy in children as it can result in suboptimal
therapy, unexpected responses and adverse drug
reactions (ADRs).2 The development of effective
and safe child-specific treatments therefore requires
high-quality trials in children.2–4
On-label use of drugs in children might also con-
front healthcare professionals and consumers with
potential risks. Although it is generally assumed
that drugs are considered for labelling only if they
have been proven efficacious and safe, many medi-
cations, in particular those introduced before 1985
have not been optimally studied in randomised,
controlled trials.5 In their day, they received author-
isation out of lack of regulation of the required spe-
cifications and they remain on the market because
De Bruyne P, et al. Arch Dis Child 2017;102:56–60. doi:10.1136/archdischild-2015-310416
What is already known on this topic?
▸ Off-label use in children has been associated
with an increased risk of adverse drug
reactions.
▸ Side effects are common with first-generation
—‘sedating’—H1-antihistamines in children.
What this study adds?
▸ There is a large variability in labelled
indications and licensed ages for
first-generation H1-antihistamines when
compared in five different European countries.
▸ Many first-generation H1-antihistamines have
not been adequately evaluated in children.
▸ Most of the labelled indications of
first-generation H1-antihistamines are not based
on clinical trials in children.
the pharmacovigilance systems have not detected
enough ADRs requiring their withdrawal.6 A good
example of this is the case of the first-generation
antihistamines such as alimemazine, cyprohepta-
dine, diphenhydramine and dimenhydrinate. There
is widespread use of first-generation H1-antihistamines
in children; they have been on the market for a
long time and many of them have received
over-the-counter (OTC) status,6 though these first-
generation H1-antihistamines are known to have
the most major side effects. They have poor recep-
tor selectivity for the H1 receptor, occupying
muscarinic cholinergic, α-adrenergic, serotonin
receptors and ion channels.5 Additionally, first-
generation H1-antihistamines are lipophilic, facili-
tating crossing of the blood–brain barrier into the
central nervous system with drowsiness, cholinergic
effects and impairment as a consequence.5
The aim of this analysis paper is to compare
registered indications of marketed first-generation
H1-antihistaminic drugs for children in several
European countries and to look for the evidence
supporting these indications. Additionally, reported
ADRs of these drugs involving children will be
evaluated.
METHODS
For this review, we focused on the first-generation
H1-antihistamines with WHO Anatomical
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Original article

Therapeutic Chemical (ATC) classification -code R06, which are

Table 1 Differences in licensed indications and accessibility of
available in an oral single-drug preparation in five selected
alimemazine tartrate (trimeprazine tartrate), cyproheptadine and
European countries (Belgium, France, Germany, the Netherlands
dimethindene maleate in children in the investigated countries
and the UK). Country-specific drug databases and national formu-
laries were searched for first-generation antihistamines.7–13 They Alimemazine Dimethindene
were listed using their International Nonproprietary Names tartrate Cyproheptadine maleate
(INNs). Second, for each formulation, available on the market, Licensed indication
the Summary of Product Characteristics (SPCs) was examined in Allergic conditions B, F and N F, N and UK N
detail. Their licensed indications, the accessibility on the market Allergic rhinitis B
(OTC or prescription-only medication, POM) and the age limit Itch B B
for paediatric use in the respective countries were listed and Itch in chickenpox UK
compared. Finally, these labelled indications were compared Urticaria UK
with the available evidence of efficacy and safety of oral first- Anaphylaxis N
generation H1-antihistamines in children. A literature review of Migraine and vascular UK
clinical trials, case series and case reports of first-generation headache
H1-antihistamines involving children was conducted. Four Insomnia F
major databases, namely Medline, Embase, PubMed and Web of Premedication F and UK
Science were searched. Medline and Embase were searched elec- Asthma bronchiale F and N
tronically via Ovid. Ovid’s age group classification was used to Accessibility
limit the results to the paediatric age groups. PubMed and Web POM B, N and UK N N
of Science were searched via their specific websites. Abstracts OTC F F and UK B
were read and evaluated; if relevant, full papers were obtained. The selected cases are not available in Germany.
Information regarding formulation, route of administration and B, Belgium; F, France; N, The Netherlands; OTC, over-the-counter; POM, prescription-
comparison was gathered. As for safety, we evaluated the only medication; UK, The United Kingdom.
reported ADRs in the obtained papers and consulted the data-
base of The Netherlands Pharmacovigilance Centre Lareb, one
of the best organised pharmacovigilance offices in Europe, for Case 2: cyproheptadine
reports of ADRs of first-generation H1-antihistamines in Cyproheptadine is an antihistamine of the piperidine chemical
children.14 class with antiserotoninergic characteristics. Small prospective

RESULTS
Variability in indications
Sixteen different first-generation H1-antihistamines are mar-
keted in single-drug preparation in the five evaluated countries
(see online supplementary table A). When comparing the differ-
ent INNs, the huge variability in registered indications, accessi-
bility (OTC or POM) and licensing ages for paediatric use is
striking. To demonstrate this variability and the (lack of ) existing
evidence more extensively, three examples will be discussed in
the following paragraphs: the case of alimemazine, cyprohepta-
dine and dimethindene maleate.
Case 1: alimemazine
Alimemazine, also known as trimeprazine, is a first-generation
H1-antihistamine in the phenothiazine chemical class. There is a
broad range of licensed indications and licensing ages for this
drug in the different evaluated countries (table 1). The efficacy
of alimemazine for children with sleep problems has been inves-
tigated in four small randomised controlled trials (table 2).
These trials found conflicting results with some reporting short-
term improvement while on alimemazine.15–19 Alimemazine has
been shown to have the sedative effect, necessary for the use as
a premedicant in children.20 21 In addition, in a randomised
placebo-controlled trial with 15 children, alimemazine caused
relief of retching after Nissen fundoplication.22 In some coun-
tries, alimemazine is indicated for itch, allergic diseases, urti-
caria, cough and asthma bronchiale. However, the clinical trials
supporting these specific indications could not be located. Case
reports described significant morbidity15 23–25 in children of
4 years and younger after alimemazine use and intoxication. All
case reports were published more than 10 years ago. Three out
of eight ADRs after intake of alimemazine in the Lareb database
were in children. Two of them were 2 years or younger.14
De Bruyne P, et al. Arch Dis Child 2017;102:56–60. doi:10.1136/archdischild-2015-310416
Drug therapy
studies evaluated cyproheptadine in children with allergic
conditions, including primary acquired cold urticaria26 and
mite-induced allergic rhinitis.27 In each of these trials, the active
comparator (ketotifen and loratadine, respectively) showed
similar or better results when compared with cyproheptadine
(table 3). The lack of a placebo control group in both
above-mentioned studies makes it difficult to determine if
cyproheptadine had a positive therapeutic effect. In the UK,
cyproheptadine is indicated for prophylaxis of paediatric
migraines (table 1). However, clinical data concerning its effi-
cacy were limited to a retrospective chart review in 30 chil-
dren.28 No trials supporting the use of cyproheptadine in itch
(caused by chickenpox) and anaphylaxis could be located. An
important side effect of cyproheptadine is increased appetite.
This side effect is the reason for the frequent off-label use of
cyproheptadine as an appetite stimulant. We could locate two
chart reviews evaluating this effect: in children aged 7 months–
6 years29 and in children aged 9 months–20 years.30 Reported
(side) effects in these chart reviews were—next to increased
appetite—somnolence, irritability and abdominal pain. Three
out of five side effects of cyproheptadine at Lareb were reported
in children; each in a different age group.14
Case 3: dimethindene maleate
The third example is the case of dimethindene maleate, a
first-generation antihistamine of the alkylamine chemical class.
This drug is indicated for a wide variety of pruritic conditions
(table 1). In some countries, it is used in the treatment of itch in
the context of a varicella infection. In Belgium, it is available
OTC with an approved use in infants 1 month and older. In the
neighbouring country The Netherlands, it is a POM, indicated
for children aged 1 year and older. Only one trial31 examined
the use of this antihistamine in alleviating the pruritus in vari-
cella infection. A randomised placebo-controlled trial in 126
57
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Original article

Table 2 Summarising the available studies with oral alimemazine in children

Investigational
Citation Study group Study type product Comparator Primary outcome Key result

France 45 patients (age 7–27 months) Double-blind, Alimemazine Extinction alone or Daily sleep diary Abrupt reduction in sleep
et al16 with sleep problems randomised +extinction* extinction–plus-placebo (duration and time) disturbance with alimemazine
controlled trial
France 12 patients (age 6–27 months) Double-blind, Alimemazine, two Placebo Daily sleep diary No clinically significant effects of
et al17 with sleep problems randomised different doses (duration and time) the low dose detected, whereas
controlled trial the effects of the high dose were
not consistently replicated across
nor within patients
Richman18 22 patients with severe Double-blind, Alimemazine Placebo Sleep Moderate improvement, no
awaking problems (mean age randomised questionnaires: permanent effect on sleep
22 months) controlled trial composite score
Simonoff 18 patients (age 7–37 months) Double-blind, Alimemazine Placebo Parental sleep diary Significantly fewer awakenings,
and with night waking randomised (duration and time) less awake at night and more
Stores19 controlled trial night-time sleep
Patel 90 patients (age 2–12 years) Double-blind, Midazolam Diazepam-droperidol Anxiolysis on arrival Anxiolysis was significantly
et al21 scheduled for anaesthesia randomised and alimemazine in the anaesthetic greater in the midazolam group
controlled trial room compared with the alimemazine
group
Mitchell 85 children scheduled to Double-blind, Midazolam Alimemazine and Anxiety, crying and More patients were calm and
et al20 undergo anaesthesia for randomised placebo distress on arrival in quiet following midazolam than
adenoidectomy and/or controlled trial the anaesthetic following alimemazine, with both
tonsillectomy, older than room premedicant agents comparing
6 months favourably with placebo
Antao 12 patients (age 8 months– Double-blind, Oral alimemazine Placebo Number of retching Significant decrease in the
et al22 15 years) with retching after randomised episodes number of retching episodes with
Nissen fundoplication controlled trial alimemazine compared with
placebo
*Behavioural extinction by withdrawal of parental attention.
Drug therapy

Table 3 Summarising the available studies with oral cyproheptadine in children

Investigational Primary
Citation Study group Study type product Comparator outcome Key result

Visitsunthorn 6 patients (age 4–9 years) Double-blind Cyproheptadine Ketotifen Clinical No significant difference
et al26 with cold urticaria cross-over study symptoms
Wu et al27 49 patients (age 2–12 years) Open-label, Loratadine Cyproheptadine Total symptom Significantly greater reduction in
with perennial allergic randomised controlled score symptom scores in the loratadine
rhinitis trial group
Lewis et al28 30 patients (age 3–18 years) Chart review Cyproheptadine No comparator Headache Overall positive response rate for
diagnosed with migraine frequency cyproheptadine was 83%
Rodriguez 80 patients (age 9 months– Chart review Cyproheptadine No comparator Resolved Response to therapy was reported
et al30 20 years) with dyspeptic dyspeptic in 55% of patients
symptoms symptoms
Sant’Anna 127 patients (age Chart review Cyproheptadine No comparator Weight change A significant improvement in weight
et al29 7 months–6 years) with was observed compared with
poor weight gain baseline

patients showed improvement in severity of itching in the treat-
ment group. However, neither the method of randomisation
nor the blinding process was described in this paper (table 4).32
Although there were no published case reports of safety issues
in children with this drug, seven out of nine reports of ADRs in
the Lareb were in children, all of them <4 years of age.14
DISCUSSION
Licensed indications may lead to the misconception that these
indications are evidence based, even more if they have an OTC
status. However, our review shows that the on-label indications
for first-generation H1-antihistamines are often not supported
by clinical trials in children. The efficacy of orally administered
58
antihistamines in paediatric patients is generally extrapolated
from adults or older paediatric patients,6 33 which does not
match with the current ‘Better Medicines for Children’ policy.34
As stated before, this is clinically relevant because ‘off knowl-
edge’ use of drugs in children might result in underdosing, over-
dosing and ADRs.
The European Union (EU) Paediatric Regulation, implemented
in 2007, created a new type of marketing authorisation to give
an incentive for medicinal products that have been on the market
in the EU states for some time and therefore are no longer
covered by a patent. A successful application results in 10 years
of data and market protection.34 This Paediatric Use Marketing
Authorisation (PUMA) could be a solution for the lack of
De Bruyne P, et al. Arch Dis Child 2017;102:56–60. doi:10.1136/archdischild-2015-310416
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Table 4 Summarising the available studies with oral dimethindene maleate in children
Investigational
Citation Study group Study type product
31
Englisch and Bauer 128 patients Double-blind, Oral dimethindene
(age 1–6 years) with randomised maleate
chickenpox controlled trial
knowledge on efficacy and safety of off-patent drugs in children.
However, until now, only two drugs received a PUMA.35
Although some first-generation antihistamines may be associated
with less sedation than others, sedation associated with this group
of antihistamines is so common that these antihistamines have
been termed by the US Food and Drug Administration (FDA) as
‘sedating antihistamines’. First-generation antihistamine-induced
sedation has been described to occur in more than 50% of
patients receiving therapeutic doses, which may adversely affect a
child’s learning abilities.36–39 Yet, many of the first-generation anti-
histamines are available to the consumer OTC as sleeping aids
underscoring their soporific effects. Moreover, the high accessibil-
ity on the market and thus the widespread use of first-generation
antihistamines in paediatrics have been accompanied by frequent
intoxication. Typically, children ingesting large quantities of first-
generation antihistamines experience marked sedation, lethargy
and anticholinergic-like symptoms, including dry mouth, tachycar-
dia and hyperactivity, with potential progression to acute psych-
osis.37 There is probably an under-reporting of these side effects
to the pharmacovigilance systems, as most clinicians see these side
effects as an already known problem. Paediatric pharmacovigilance
will be essential to reduce ADRs with these antihistamines through
better detection and prevention of the ADRs.40 41 Education of
health professionals about the importance of pharmacovigilance
has been shown to be effective in increasing reporting of
ADRs.41 42 Unfortunately, we did not obtain information on the
actual use of these antihistamines in the evaluated countries, which
would help to assess the possible impact of these ADRs.
Before the treatment with any antihistamine is started, the
child and family should be counselled on the appropriate use.
That is, age of licensed use, frequency and dosing, clinical
effects and possible side effects.43 Moreover, based on the lack
of evidence of efficacy and the safety problem of the first-
generation H1-antihistamines, Schad and Skoner44 stated that
the paediatric use of first-generation antihistamines should even
be restricted to two uncommon situations. First, in children
with urticaria or dermatitis whose pruritus is so severe that sed-
ation is a benefit rather than a risk and second, if there is ana-
phylaxis requiring intravenous antihistamine as adjunctive
therapy to epinephrine.
In conclusion, this case of first-generation H1-antihistamines
demonstrates that on-label prescriptions in children are not free
from risks. A broad range of vague indications, as a result of
lack of evidence brings a lack of clarity for clinicians, pharma-
cists and patients. Obviously, this problem is not restricted to
the first-generation antihistamines. This article argues for a
wider discussion on evaluation of labelled indications for chil-
dren in general.
Contributors PDB, TC, KB, EM and MVW have expertise in clinical pharmacology
and/or pharmaceutical care, including drug evaluation. MVW conceived the idea for
this paper. PDB analysed the SPCs and the literature and wrote the first draft of the
manuscript. All authors contributed substantially to the interpretation of the data,
revised the manuscript, approved the final version and are accountable for it. PDB is
the guarantor of the article.
De Bruyne P, et al. Arch Dis Child 2017;102:56–60. doi:10.1136/archdischild-2015-310416
Original article
Primary
Comparator outcome Key result
Placebo Itching severity Dimethindene maleate group showed
score significant reduction of itching severity score
compared with placebo
Funding This work was supported by an IWT (Innovation by Science and
Technology in Flanders) grant number SB-111279 (recipient: PDB).
Competing interests PDB is the recipient of a doctoral grant for Strategic Basic
Research of the Agency for Innovation by Science and Technology (IWT) in Flanders.
Provenance and peer review Not commissioned; externally peer reviewed.
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Are antihistamines effective in children? A

review of the evidence
Pauline De Bruyne, Thierry Christiaens, Koen Boussery, Els Mehuys and
Myriam Van Winckel

Arch Dis Child 2017 102: 56-60 originally published online June 22, 2016
doi: 10.1136/archdischild-2015-310416

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Topic Articles on similar topics can be found in the following collections

Collections Unwanted effects / adverse reactions (120)
Drugs: CNS (not psychiatric) (497)

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