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Allergologia et
immunopathologia
Sociedad Española de Inmunologı́a Clı́nica,
Alergologı́a y Asma Pediátrica
www.elsevier.es/ai

REVIEW

Antihistamines in children and adolescents: A practical

update
G.F. Parisi a,∗ , S. Leonardi a , G. Ciprandi b , A. Corsico c , A. Licari d ,
M. Miraglia del Giudice e , D. Peroni f , C. Salpietro g , G.L. Marseglia d

a
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
b
Allergy Clinic, Casa di Cura Villa Montallegro, Genoa, Italy
c
Pulmonology Clinic, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
d
Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
e
Department of Woman, Child and of General and Specialized Surgery, University of Campania ‘‘Luigi Vanvitelli’’, Naples, Italy
f
U.O. Pediatria, Azienda Ospedaliero-Universitaria Pisana, Scuola di Specializzazione in Pediatria, University of Pisa, Pisa, Italy
g
Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Messina, Italy

Received 11 December 2019; accepted 24 February 2020

KEYWORDS Abstract Histamine is a chemical mediator, released predominantly by tissue mast cells, cir-
Histamine; culating basophils, and neurons, which are activated in response to various immunological and
H1 receptor; non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological
Antihistamines; and pathophysiological functions. Endogenous histamine is the main mediator of the immedi-
Allergic disorders; ate allergic response, which moreover, performs other multiple functions, including regulation
Children; of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory
Adolescents activity. The involvement of histamine in various disorders and the importance of receptors
in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines
contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous
itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This
review updates the practical use of antihistamines in children and adolescents.
© 2020 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Abbreviations: AD, atopic dermatitis; ARIA, allergic rhinitis and its impact on asthma; BBB, blood---brain barrier; EMA, European Medicines
Agency; GPCR, G protein-coupled receptor; NARES, non-allergic rhinitis with eosinophils; NICE, National Institute for Health and Care
Excellence.
∗ Corresponding author.

E-mail address: [email protected] (G.F. Parisi).

https://doi.org/10.1016/j.aller.2020.02.005
0301-0546/© 2020 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Please cite this article in press as: Parisi GF, et al. Antihistamines in children and adolescents: A practical update. Allergol
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Introduction Table 1 Most common first- and second-generation oral

antihistamines in alphabetic order.
Histamine is an important mediator of inflammation and is
largely released by tissue mast cells, circulating basophils, First-generation Second-generation
and neurons as a result of both immunological and non- antihistamines antihistamines
immunological stimuli, such as allergenic, inflammatory, Alimemazine, Bilastine, Cetirizine,
toxic, chemical, and iatrogenic agents. Chlorphenamine, Desloratadine, Ebastine,
Discovered in the early 1900s by Sir Henry Dale, histamine Clemastine, Fexofenadine, Ketotifen,
is produced in the cytoplasm from the decarboxylation of Cyproheptadine, Levocetirizine, Loratadine,
histidine via the enzyme histidine decarboxylase; it has a Dimetindene, Oxatomide, Rupatadine
short-term action (1---10 min) and is rapidly degraded to Diphenhydramine,
imidazole acetic acid. Endogenous histamine is the main Hydroxyzine,
mediator of the immediate allergic response, participates in Promethazine
the regulation of gastric secretion (through the action of H2
receptors), and has immunomodulating activity.1 Moreover,
histamine plays an important role as a neurotransmitter
in the central nervous system (CNS), where it is catab- (Table 1). First-generation anti-H1 antihistamines (e.g.,
olized by the enzyme histamine N-methyltransferase to clemastine, diphenhydramine, promethazine) can be admin-
tele-methylhistamine.2 istered by injection, orally, or topically, including dermato-
Histamine performs its actions by binding to specific logical, intranasal, and ocular formulation.7
receptors on the membrane of various cells, such as mast After oral administration, most of them are well absorbed
cells, endothelial cells of the vessels, cells of sensitive nerve from the gastrointestinal tract; they bind to plasma proteins
fibers, and bronchial smooth muscles, resulting in differ- (70---97%) and are then metabolized by the liver and mostly
ent effects depending on the site and type of receptor excreted in the urine within 24 h of intake. The therapeu-
with which it interacts. To date, four types of histamine tic effect begins to appear within 30---60 min, peaks within
receptors have been discovered: H1, H2, H3, and H4, 1---3 h, and usually persists for 4---6 h. Some preparations,
which belong to the superfamily of G protein-coupled however, have a more prolonged effect (e.g., chlorpheni-
receptors (GPCRs).3 The receptor activation causes various ramine, hydroxyzine), with a half-life of over 20 h in the
biological effects, including vasodilation, increased vascular adult, less time in the child, which metabolizes these drugs
permeability, itchiness, smooth muscle contraction, spasm more quickly.1 The action mechanism is to bind to the
of coronary arteries, and regulation of the sleep---wake H1 receptor, which in the first-generation molecules rep-
rhythm.4 The current review will focus exclusively on H1 resents the prevalent or perhaps the only activity of the
receptor and anti-H1 antihistamines. drug; it is perfected and expanded in the second-generation
The H1 receptor for histamine is in a dynamic equilibrium molecules.
between two isoforms: active and passive. However, this In addition, for the second-generation molecules, there
receptor shows spontaneous basal activity via the nuclear are different formulations, such as for oral use (e.g., drops,
factor ␬B (NF-␬B). syrup, tablets) and for topical nasal, ocular, and cuta-
NF-␬B is a transcription factor involved in inflammation neous use. After oral administration, the plasma peak is
that has obtained a great interest as a drug target for earlier with cetirizine (30---60 min) and later with lorata-
the treatment of various allergic conditions. Histamine H1 dine (45---60 min), terfenadine (1---2 h), fexofenadine (1---3 h),
receptor activates NF-␬B in both a constitutive and agonist- astemizole (1---3 h), and bilastine (1---4 h). The elimination
dependent manner.5 half-life is extremely variable, from 24 h for loratadine,
Anti-H1 antihistamines cause an imbalance in favor of the desloratadine, cetirizine, and levocetirizine, up to 18 days
isoform characterized by inactivity; they behave, in prac- for astemizole.1,3,4 In children, the cetirizine half-life is
tice, as inverse agonists. An inverse agonist is a ligand that reduced due to increased hepatic metabolism; this practice
binds to the same receptor-binding site as an agonist and entails the need for a twice-daily administration.8 The dura-
not only antagonizes the effects of an agonist but, more- tion of the pharmacological effect of all these drugs presents
over, exerts the opposite effect by suppressing spontaneous a marked variability, and is much longer than the plasma
receptor signaling.6 As a result, they are capable of shifting half-life, being linked to the volume of distribution of the
the receptor balance from the biochemically active form drug as well as to the action of the metabolites that also
to an inactive form. In this way, they also reduce the acti- remain in active form for long periods. The binding of these
vation of NF-␬B and thereby may reduce the synthesis of drugs to plasma proteins is generally high (88---98%). From a
pro-inflammatory cytokines, cell adhesion molecules, and clinical point of view, the therapeutic effect is, therefore,
chemotactic factors.1 Antihistamines are, therefore, a cor- prolonged. The inhibition of the cutaneous response to his-
nerstone in the treatment of histamine-mediated diseases.7 tamine (histamine hives) persists for 12---24 h after a single
dose of loratadine and cetirizine9 ; the inhibitory effect on
the skin response can endure for 7---10 days depending on
Classification and pharmacological properties the type of molecule taken. For this reason, antihistaminic
of anti-H1 antihistamines therapy should be suspended before the skin prick test. Most
second-generation antihistamines are metabolized in the
Anti-H1 antihistamines are functionally classified into two liver by the cytochrome P450 system. The intake of some
groups, namely first- and second-generation molecules antihistamines, such as terfenadine or astemizole, together

Please cite this article in press as: Parisi GF, et al. Antihistamines in children and adolescents: A practical update. Allergol
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Histamine H1 Antagonists in childhood 3

with drugs capable of inhibiting this system (e.g., anti-fungal Side-effects

agents such as ketoconazole or macrolide antibiotics) or
some foods (e.g., grapefruit, pomelo, raspberry) can cause Currently, the clinical use of first-generation molecules is
an abnormal accumulation of these agents and their metabo- markedly limited by some of their pharmacological charac-
lites in the body, with consequent risk of adverse reaction, teristics. Due to their high lipo-solubility, first-generation
even serious, especially at the cardiac level (e.g., tach- anti-H1 antihistamines can easily cross the blood---brain
yarrhythmias, torsade de pointes, or prolongation of the QT barrier (BBB) and induce sedation, drowsiness, decreased
interval until ventricular fibrillation). These effects are not attention and reaction times, which comprise their most
the result of the action on the H1 receptor but arise from the common side-effects.14 In this regard, a study about cere-
direct blockage of the potassium channels that control the bral histamine H1 receptor occupancy (H1RO) using positron
cardiac repolarization phase. For this reason, terfenadine emission tomography (PET) has shown that the most pen-
and astemizole were withdrawn from clinical use in many etrating antihistamines in the brain are chlorphenamine,
countries. ketotifen and hydroxyzine.15
Other molecules, such as loratadine and desloratadine, First-generation anti-H1 antihistamines also exert a
are instead metabolized by more enzyme systems over poorly selective action on H1 receptors because they
the hepatic cytochrome P450 system, thus limiting the can also interact with non-histamine receptors (especially
potential resultant clinical interactions. It is unlikely that serotonergic, cholinergic, and ␣-adrenergic receptors). As
multiple systems will be simultaneously inhibited with a consequence, the other main side-effects include dry
consequent accumulation of the molecule.10 Fexofenadine mouth, nausea, vomiting, diarrhea, constipation, pollaki-
is minimally metabolized by the organism; its main route uria, dysuria, urinary retention, increased appetite, and
of elimination is by biliary excretion (approximately 80%), tachycardia.14 Cyproheptadine and ketotifen can increase
while −10% of the ingested dose is eliminated unchanged in appetite and cause weight gain, which does not occur
the urine.1 About 60---70% of cetirizine and levocetirizine are with other antihistamines (except sporadically by astemi-
eliminated via the urinary tract, with only 10% eliminated zole), mainly acting on serotoninergic pathways.16 Because
hepatically.11 Elimination is mainly fecal for astemizole, of the unfavorable risk/benefit ratio due to relevant side-
and fecal and urinary for loratadine.12 Furthermore, the effects, first-generation antihistamines, if possible, should
binding of the new antihistamines with the H1 receptor is no longer be used in the treatment of rhinitis and urticaria.14
more stable and persistent; thus, the administrations can As regards the safety of these drugs, warnings have been
be more delayed over time and, for some molecules such issued, more recently in 2015, by the European Medicines
as loratadine, desloratadine, cetirizine, levocetirizine, Agency (EMA) on the use of first-generation anti-H1 for chil-
bilastine, fexofenadine and rupatadine, it is possible to use dren under two years of age, especially for hydroxyzine.
once-daily administration.3 These characteristics are par- That drug is associated with a low but definite risk of QT
ticularly advantageous in clinical practice, as the reduced tract prolongation and torsade de pointes, conditions that
frequency of daily drug administrations consequently entails can lead to an abnormal rhythm until cardiac arrest.
improvement of tolerability and compliance by patients and For this reason, its use must be limited to the mini-
prolonged activity.11 It should also be noted that new anti- mum effective dose for the shortest possible duration; it
histamines hold little or no risk of ‘‘pharmacological is also imperative to avoid its use in patients who present
addiction’’ (tachyphylaxis) following long-lasting risk factors for heart rhythm disorders. Regarding the pedi-
administration.3 atric age, the maximum daily dose of hydroxyzine should not
Along with the antihistaminic effects, some second- exceed 2 mg/kg (maximum 50 mg/day) in children weigh-
generation drugs (e.g., loratadine, desloratadine, ing less than 40 kg.17 Given their low lipo-solubility, the
cetirizine, levocetirizine, ebastine, fexofenadine) were second-generation molecules have a reduced capacity to
believed to have potential anti-inflammatory properties cross the BBB. These molecules are also able to bind to P-
in the following manners: (1) reduction of the produc- glycoprotein, which acts as a transporter at the BBB and can
tion of pro-inflammatory cytokines (e.g., IL-4 and IL-13, actively ‘‘expel’’ these molecules from the BBB.
chemokines) and the release of both histamine and other Among the second-generation antihistamines, cetirizine
pre-formed or neo-formed mediators by activated mas- appears to be most frequently associated with a greater inci-
tocytes and basophils; (2) reduction of the recruitment dence of drowsiness in comparison to placebo, although to
of eosinophils in the late phase of allergic reaction or a lesser extent than that observed with the use of first-
the phase of tissue damage and chronicization of the generation antihistamines.18 However, this effect is less
allergic inflammation; and (3) reduced expression of relevant in comparison with adult patients.
adhesion molecules on epithelial cells and/or endothe- Antihistamine overdose remains a risk, especially in chil-
lium, thus inhibiting cellular trafficking.12,13 However, the dren. Historically, diphenhydramine has been involved in
anti-inflammatory activity of antihistamines has probably episodes of overdose poisoning (some fatal), especially in
to be reduced because these effects would seem evident children, partly because many preparations are sold with-
only in vitro at very high concentrations. Therefore, the out a prescription (over-the-counter products).19 The most
anti-inflammatory activity of antihistamines administered serious effects of overdose are attributable to neurologi-
at therapeutic doses seems to be scarcely relevant in cal or cardiac alterations; for example, convulsions that
clinical practice. are followed (at high dosages) by states of coma, which

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are sometimes irreversible.14 Some second-generation anti- fexofenadine exert a relevant antiallergic activity able
histamines, such as ebastine, or mizolastine can cause a to reduce nasal inflammation and consequently nasal
prolongation of the QT tract. Considering this potential obstruction.24---28 Such drugs can be used as needed if symp-
risk, particular attention should be paid to the simultane- toms are occasional. In rhinitis from seasonal allergens,
ous administration of other drugs that can also prolong the treatment with anti-H1 antihistamines could be initiated
QT tract, such as macrolides, which are among the classes of before allergen exposure and must then be continued for
drugs most frequently prescribed in pediatric populations.10 the entire duration of the pollination.29 A close link has
been reported between allergic inflammation and nasal
Therapeutic indications of anti-H1 airflow in patients with pollen allergy.30 In perennial allergic
rhinitis, the treatment should instead be based on clinical
antihistamines symptoms and has the dual purpose of controlling the per-
sistent inflammation by reducing the inflammatory mucosal
The main indications of anti-H1 antihistamines are aller- infiltrate and the expression of adhesion molecules.31
gic manifestations with prevalent exudative and irritative Among antihistamines, bilastine was recently approved
neurogenic features; however, the efficacy of antihis- for children aged 6---11 years. This license is the consequence
tamines varies in different pathologies depending on of the results of studies included in the bilastine Pediatric
the prominence of histamine’s contribution to the clin- Investigation Plan, approved by the EMA Pediatric Commit-
ical symptomatology and local health agency rules.11,18 tee, for children aged 2---12 years.32
Second-generation antihistamines should be preferred since In even younger children, among the newest antihis-
they are endowed with few sedative properties. Treat- tamines, rupatadine 1 mg/mL oral solution has been shown
ment with a second-generation anti-H1 antihistamine (e.g., to be safe and effective in a cohort of 44 children with
loratadine) in children suffering from allergic rhinitis allergic rhinitis.33
did not impair scholar performance, unlike treatment Topical preparations (nasal and ocular) have good clin-
with a first-generation molecule (e.g., diphenhydramine).14 ical efficacy and high tolerability, even if they act only at
Second-generation anti-H1 antihistamines also have the the site of administration.34 The rapid and prolonged action
advantage, due to their pharmacological characteristics, of permits only two daily administrations, with the advan-
being used not only in the treatment of an acute episode tage of obtaining high concentrations of the drug at the
but also in the long-term treatment of allergic diseases.20 target organ, diminishing the risk of systemic side-effects.
The oral route is the main way of administration, while The most common topical antihistamines are astemizole,
the parenteral route, which is only possible with some first- olopatadine, emedastine, and levocabastine.35
generation molecules, is reserved for the prevention or The effect of antihistamines in vasomotor rhinitis and
treatment of serious and rare eventualities (e.g., episodes non-allergic rhinitis with eosinophils (NARES) is modest.36,37
of anaphylaxis, blood transfusions, adverse drug reactions). In adolescents, the use of topical nasal azelastine is con-
The topical route is reserved for eyes, nose, or cutaneous sidered the first-line treatment. Moreover, a combination
disease (eye drops, spray, cream, gel). The topical dermal of an intranasal corticosteroid (fluticasone) and azelas-
route, despite having indications of insect bites and pruritic tine demonstrated good efficacy, there was evidence that
dermatitis, should be used with great caution as it commonly this combination was superior to either intranasal corticos-
induces photosensitivity.21 A summary of the most common teroids or topical intranasal antihistamines alone.38
antihistamines is available in Table 2.

Allergic rhinitis and conjunctivitis Urticaria

Allergic rhinitis with or without concomitant ocular involve- Urticaria is another important indication for the use of
ment is a clinical indication for the use of such drugs and antihistamines, which have been proven to have unques-
for impairment of scholar learning that occurs in affected tionable efficacy.39 Anti-H1 antihistamines are effective
and untreated children and adolescents.22 Histamine is the in reducing itching and the number, size, and duration
mediator released during the early phase of the allergic of cutaneous manifestations (e.g., wheals, erythema) in
reaction and causes itching, sneezing, and watery rhinor- patients with both acute and chronic urticaria. In both
rhea; the late phase is clinically dominated by the presence cases, the current European guidelines recommend the use
of nasal obstruction, which is linked more to inflammatory of second-generation molecules for their tolerability and
cell infiltration and the action of other mediators (e.g., safety profile, which allows easy modification of their use
prostaglandins, leukotrienes) than to a purely vasodilatory and dose over time. Among these, the most tested drugs
action from histamine. For this reason, allergic inflammation were: loratadine, desloratadine, fexofenadine, cetirizine,
is less favorably affected by the action of antihistamines but levocetirizine, rupatadine, and bilastine.40 Bilastine was
more sensitive to corticosteroids.23 recently tested for safety and tolerability in 6---11-year-
As regards antihistaminic therapy, allergic rhinitis and children with chronic urticarial showing with great outcomes
its impact on asthma (ARIA) guidelines recommend using also in terms of efficacy.41
second-generation oral molecules for both intermittent A double-blind, randomized, parallel-group, multicen-
and persistent allergic rhinitis; these molecules represent ter, placebo-controlled study involving 257 children aged
the most suitable preparations in the treatment of allergic 2---11 years with chronic spontaneous urticaria showed that
rhinitis. In this regard, it has been reported that some anti- rupatadine is well tolerated and improves quality of life over
histamines, including azelastine, cetirizine, desloratadine, six weeks.42

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Table 2 Summary of the most common antihistamines in alphabetic order.

Antihistamine Properties Indications Pharmaceutical Licensing age Children’s dose
formulation
Bilastine Highly selective second-generation • Allergic • 2.5 mg/mL oral >6 years • 6---11 years (20 kg
H1 receptor antagonist with rapid rhino-conjunctivitis, solution minimum): 10 mg (=4 mL)
onset and prolonged duration of chronic idiopathic • 10 mg tablets once daily
action. urticaria • 20 mg tablets • >12 years: 10---20 mg

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once daily
Cetirizine Second generation antihistamine that • Hay-fever, atopic • 10 mg/mL drops >2 years • 2---6 years: 2.5 mg (=5
blocks histamine H1 receptors, eczema, chronic • 10 mg tablets drops) twice daily
mostly outside the brain and does not idiopathic urticaria, • 6---12 years: 5 mg (=10
exhibit anticholinergic effects. allergic conjunctivitis drops, ½ tablet) twice
daily
• >12 years: 10 mg (=20
drops, 1 tablet) once
daily
Chlorphenamine First-generation antihistamine and • Symptomatic relief of • 10 mg/mL vials >12 years • 0.2 mg/kg (off-label
serotonin reuptake inhibitor with allergy, anaphylaxis, <12 years) up to three
weak anticholinergic activity. urticaria, hay-fever, times a day
allergic conjunctivitis • 10---20 mg im, sc, iv
(max 40 mg/day)
Cyproheptadine First-generation antihistamine with • Hay-fever, urticaria, • 0.4 mg/mL syrup >2 years • 2---6 years: 2 mg
additional anticholinergic, allergic conjunctivitis, • 4 mg tablets twice/three times daily
anti-serotonergic, and local pruritus • 7---14 years: 4 mg three
anesthetic properties. times daily
Desloratadine Second generation tricyclic • Allergic rhinitis, • 0.5 mg/mL oral >1 year • 1---5 years: 1.25 mg
antihistamine with a selective and chronic idiopathic solution (=2.5 mL) once daily
peripheral H1-antagonist action. It is urticaria • 2.5 mg tablets • 6---11 years: 2.5 mg
the active descarboethoxy • 5 mg tablets (=5 mL) once daily
metabolite of loratadine. • >12 years: 5 mg once
daily

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Table 2 (Continued)

Antihistamine Properties Indications Pharmaceutical Licensing age Children’s dose

formulation
Dimetindene First-generation H1 antagonist with • Symptomatic • 1 mg/mL drops >1 month • 0.1 mg/kg/day (=2
anticholinergic activity which treatment of allergic • 1 mg tablets drops/kg) in three
minimally crosses the BBB. reactions: urticaria, divided doses
hay-fever, food and drug • >12 years: 20---40 drops
allergies three times a day; 1---2
• Pruritus in eruptive tablets three times a day
skin diseases such as
chickenpox and as an

ARTICLE IN PRESS
adjuvant in eczema and
other pruriginous
dermatoses of allergic
origin
Ebastine Second-generation H1 receptor • Allergic rhinitis, • 1 mg/mL oral >6 years • 6---11 years: 5 mg once
antagonist with rapid and long-lasting chronic idiopathic solution daily
inhibition of histamine-induced urticaria • 10 mg tablets • >12 years: 10---20 mg
effect. • 20 mg tablets once daily
• 10 mg oral
lyophilizate tablet
• 20 mg oral
lyophilizate tablet
Fexofenadine Selective second-generation • Hay-fever, chronic • 120 mg tablets >12 years • Hay-fever: 120 mg once
peripheral H1-blocker. No idiopathic urticaria • 180 mg tablets daily
anticholinergic, antidopaminergic, • Urticaria: 180 mg once
␣1 -adrenergic, or daily
␤-adrenergic-receptor-blocking
effects.
Hydroxyzine First-generation H1 receptor inverse • Pruriginous dermatoses • 20 mg/10 mL >1 year • <40 kg: 2 mg/kg/day
agonist. Very low affinity for the of allergic origin syrup (=1 mL/kg) in 1---4
muscarinic acetylcholine receptors. • Anxiety and nausea • 25 mg tablets divided doses
Weak antagonist of the serotonin due to motion sickness • >40 kg: max
5-HT2A receptor, the dopamine D2 100 mg/day
receptor, and the ␣1-adrenergic
receptor. Hydroxyzine crosses the

G.F. Parisi et al.

BBB easily and exerts effects in the
CNS.
 Histamine H1 Antagonists in childhood

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Table 2 (Continued)

Antihistamine Properties Indications Pharmaceutical Licensing age Children’s dose

formulation
Ketotifen Second-generation non-competitive • Allergic rhinitis, • 0.2 mg/mL syrup >6 months • 6 months to 3 years:
H1-antihistamine and mast cell allergic conjunctivitis • 2 mg/mL drops 0.05 mg/kg twice daily
• 1 mg tablets • >3 years: 2 mg once

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stabilizer.
• 2 mg sustained daily
release tablets • Eye drops/eye gel: 1
• 0.5 mg/mL eye drop twice daily
drops
• 0.5 mg/g eye gel
Levocetirizine Active levorotary enantiomer of • Hay-fever, atopic • 5 mg/mL drops >2 years • 2---6 years: 1.25 mg (=5
cetirizine. eczema, chronic • 5 mg tablets drops) twice daily
idiopathic urticaria, • >6 years: 5 mg (=20
allergic conjunctivitis drops, 1 tablet) once
daily
Loratadine Second generation tricyclic • Allergic rhinitis, • 1 mg/mL syrup >2 years • <30 kg: 5 mg once daily
antihistamine, which acts as a chronic idiopathic • 10 mg tablets • >30 kg: 10 mg once
selective inverse agonist of urticaria daily
peripheral histamine H1 receptors.
Rupatadine Second generation antihistamine and • Allergic rhinitis, • 1 mg/mL oral >2 years • 10---25 kg: 2.5 mg once
platelet-activating factor (PAF) chronic idiopathic solution daily
antagonist. It inhibits the release of urticaria • 10 mg tablets • >25 kg: 5 mg once daily
cytokines, particularly tumor necrosis • >12 years: 10 mg once
factors (TNFs) in human mast cells daily
and monocytes with
anti-inflammatory activity.

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In chronic spontaneous urticaria, complex pathogenesis is regard, it has been reported that early impairment of
generally more difficult to treat; in the absence of response lung function may predict the asthma development in AR
at standard doses, it is recommended to gradually increase patients.54 Combined treatment with nasal steroids and
the dose of second-generation anti-H1 antihistamines (up to antihistamines in children with allergic rhinitis has been
four times the standard dose) and to eventually introduce shown to significantly improve asthma symptoms. In this
another drug (e.g., omalizumab, ciclosporin).40,43 context, therapy with anti-H1 antihistamines confers an
additional benefit in controlling asthma symptoms in individ-
uals affected by concomitant allergic rhinitis and bronchial
Atopic dermatitis
asthma.55 However, it has to be outlined that antihistamines
have no indication for asthma, but they can be used in AR
The use of anti-H1 antihistamines in the management of
patients with comorbid asthma.56
atopic dermatitis (AD) remains a controversial topic. The
presence of histamine in AD skin lesions has been, in
the past, the main rationale for their use. These com- Anaphylaxis
pounds, however, only partially control skin itching, whose
intensity mainly depends on the severity of dermatitis.44
Adrenaline given by injection is the first-line and life-saving
The itching characteristic of dermatitis has a rather com-
treatment in case of an anaphylactic reaction. As part of
plex pathogenesis, which is not only attributable to the
the international guidelines for the management of ana-
release of histamine, but also to the involvement of several
phylaxis, the administration of systemic antihistamines by
other mediators able to evoke pruritus, such as proteases,
injection is part of emergency interventions in addition
gastrin-releasing peptide, substance P, and IL-31. It has
to adrenaline and steroids, although some guidelines dis-
also been recently shown that the predominant compo-
courage their use as they reduce vigilance and may have
nent of pruritus is mediated by PAR-2 receptors present
vasodilatory effects (from first-generation antihistamines)
on keratinocytes and other skin cells, and is activated
when administered in an intravenous bolus. Instead, there
by protease.33 Moreover, complex neural pathways are
is an advantage for antagonists of H2-receptor as they con-
involved with the profound relationship between neural and
trast histamine-dependent vasodilation, but they should be
mental mechanisms, mainly concerning the cognitive and
administered per parenteral route.57
behavioral aspects of itching.45 As a result, anxiety and
Oral antihistamines, on the other hand, can control cer-
sleeplessness are frequently associated with AD.46 As first-
tain symptoms (e.g., rhinitis, urticaria) once the acute phase
generation antihistamines frequently induce sedation, this
of anaphylaxis has passed. In this context, a greater role can
is the main reason for their popular use in AD management
have molecules endowed with the ability to antagonize the
in clinical practice.47 In this regard, minimizing itchiness is
PAF (e.g., rupatadine), in consideration of the role played
an important element in the management of AD to reduce
by this molecule in anaphylaxis.58
discomfort, improve quality of life, and prevent scratch-
ing injuries that may result in impetigo. The release of
auto-allergens by keratinocytes following scratching is also Other diseases
believed to contribute to a vicious circle in patients with
eczema. Pruritus is substantially controlled with careful skin
Some clinical trials support the use of anti-H1 antihis-
care and the use of creams with anti-inflammatory activity
tamines for the control of pruritus and skin lesions in
(e.g., steroids, topical calcineurin inhibitors). The use of
mastocytosis,59 in contact dermatitis, in case of allergic
anti-H1 antihistamines has, therefore, an adjunctive role in
reactions to insect bites, and an allergy to the venom of
controlling itching.48 The National Institute for Health and
Hymenoptera.60 These drugs are also used for the control of
Care Excellence (NICE) guidelines for treating atopic eczema
pruritus during varicella.61 No efficacy is demonstrated by
suggest a one-month trial of a non-sedating antihistamine
the preventive use of antihistamines in recurrent respiratory
in children with severe itching; if successful, this treatment
infections and the therapeutic management of the common
may be continued while symptoms persist, but this regimen
cold in non-atopic subjects.62 Finally, some first-generation
should be reviewed every three months.49 Finally, the top-
anti-H1 antihistamines (diphenhydramine, doxepin, doxy-
ical use of antihistamines is not recommended in patients
lamine, pyrilamine) are used at low doses for the prophylaxis
with AD due to the risk of absorption and contact allergy.50
and treatment of insomnia, while others (diphenhydramine,
hydroxyzine, promethazine) can be administered, in combi-
Asthma nation with other drugs, for sedation and analgesia and the
prophylaxis of motion sickness.11
Epidemiological, pathophysiological, and clinical evidence
demonstrates the existence of a tightly linked relationship
between the upper and lower airways, which are often Conclusions
considered a single entity (united airways).51,52 During aller-
gic rhinitis and asthma, the upper and lower airways are Anti-H1 antihistamines are frequently used in children and
affected by a common inflammatory process that can be adolescents to treat allergic diseases. The effectiveness
sustained and amplified by interconnected mechanisms.53 of second-generation antihistamines has been well stud-
Allergic rhinitis and non-specific vasomotor rhinitis are some ied, and they should be preferred to minimize adverse
of the most important risk factors for the onset of asthma effects and to take advantage of their antiallergic activity.
and, subsequently, an important aggravating factor. In this The choice of the preferred molecule should be based and

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Immunopathol (Madr). 2020. https://doi.org/10.1016/j.aller.2020.02.005
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Histamine H1 Antagonists in childhood 9

individualized on the clinical and pharmacological charac- 17. De Bryne P, Christiaens T, Boussery k, Mehuys E, Van Winckel
teristics of each subject. M. Are antihistamines effective in children? A review of the
evidence. Arch Dis Child. 2017;102:56---60.
18. Hu Y, Sieck DE, Hsu WH. Why are second-generation
Conflicts of interest H1-antihistamines minimally sedating? Eur J Pharmacol.
2015;765:100---6.
The authors declare no conflicts of interest. 19. Nine JS, Rund CR. Fatality from diphenhydramine monointoxi-
cation: a case report and review of the infant, pediatric, and
adult literature. Am J Forensic Med Pathol. 2006;27:36---41.
Funding
20. Giallongo A, Parisi GF, Licari A, Pulvirenti G, Cuppari C, Salpietro
C, et al. Novel therapeutic targets for allergic airway disease in
The authors did not receive any funding for the research. children. Drugs Context. 2019;8:212590.
21. Goindi S, Dhatt B, Kaur A. Ethosomes-based topical delivery
References system of antihistaminic drug for the treatment of skin allergies.
J Microencapsul. 2014;31:716---24.
22. Simons FE. Learning impairment and allergic rhinitis. Allergy
1. Tiligada E, Ennis M. Histamine pharmacology: from Sir
Asthma Proc. 1996;17:185---9.
Henry Dale to the 21st century. Br J Pharmacol. 2018,
23. Licari A, Ciprandi G, Marseglia A, Castagnoli R, Barberi S,
http://dx.doi.org/10.1111/bph.14524.
et al. Current recommendations and emerging options for
2. Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M. His-
the treatment of allergic rhinitis. Expert Rev Clin Immunol.
taminergic transmission in the mammalian brain. Physiol Rev.
2014;10:1337---47.
1991;71:1---5.
24. Ciprandi G, Buscaglia S, Catrullo A, Pesce G, Fiorino N, Montagna
3. Tatarkiewicz J, Rzodkiewicz P, Żochowska M, Staniszewska
P. Azelastine eye drops reduce and prevent allergic conjuncti-
A, Bujalska-Zadrożny M. New antihistamines --- per-
val reaction and exert anti-allergic activity. Clin Exp Allergy.
spectives in the treatment of some allergic and
1997;27:182---91.
inflammatory disorders. Arch Med Sci. 2019;15:537---53,
25. Ciprandi G, Tosca M, Passalaqua G, Canonica G. Long-term
http://dx.doi.org/10.5114/aoms.2017.68534.
cetirizine treatment reduces allergic symptoms and drug pre-
4. Church MK. Allergy, histamine and antihistamines. Handb Exp
scriptions in children with mite allergy. Ann Allergy Asthma
Pharmacol. 2017;241:321---31.
Immunol. 2001;87:222---6.
5. Bakker RA, Schoonus S, Smit MJ, Timmerman H, Leurs R. His-
26. Ciprandi G, Cosentino C, Milanese M, Mondino C. Fexofenadine
tamine H1-receptor activation of NF-␬B: roles for G␤␥ and
reduces nasal congestion in perennial allergic rhinitis. Allergy.
G␣q/11-subunits in constituitive and agonist-mediated signal-
2001;56:1068---70.
ing. Mol Pharm. 2001;60:1133---42.
27. Ciprandi G, Tosca MA, Cosentino C, Riccio AM. Effects of fex-
6. Berg KA, Clarke WP. Making sense of pharmacology: inverse ago-
ofenadine and other antihistamines on components of the
nism and functional selectivity. Int J Neuropsychopharmacol.
allergic response: adhesion molecules. J Allergy Clin Immunol.
2018;21:962---77.
2003;112:S78---82.
7. Parisi GF, Licari A, Papale M, Manti S, Salpietro C, Marseglia GL,
28. Ciprandi G, Pronzato C, Ricca V, Varese P, Giacco GSD. Terfe-
Leonardi S. Antihistamines: ABC for the pediatricians. Pediatr
nadine exerts antiallergic activity reducing ICAM-1 expression
Allergy Immunol. 2020;31 Suppl. 24:34---6.
on nasal epithelial cells in patients with pollen allergy. Clin Exp
8. Curran MP, Scott LJ, Perry CM. Cetirizine: a review of its use in
Allergy. 1995;25:871---8.
allergic disorders. Drugs. 2004;64:523---61.
29. Brożek JL, Bousquet J, Agache I, Agarwal A, Bachert C, Bosnic-
9. Haria M, Fitton A, Peters DH. Loratadine. A reappraisal of its
Anticevich S, et al. Allergic rhinitis and its impact on asthma
pharmacological properties and therapeutic use in allergic dis-
(ARIA) guidelines --- 2016 revision. J Allergy Clin Immunol.
orders. Drugs. 1994;48:617---37.
2017;140:950---8.
10. Motola D, Donati M, Biagi C, Calamelli E, Cipriani F, Melis M,
30. Ciprandi G, Cirillo I, Vizzaccaro A, Milanese M, Tosca MA. Nasal
et al. Safety profile of H1-antihistamines in paediatrics: an anal-
obstruction in patients with seasonal allergic rhinitis: relation-
ysis based on data from VigiBase. Pharmacoepidemiol Drug Saf.
ships between allergic inflammation and nasal airflow. Intern
2017;26:1164---71.
Arch Allergy Immunol. 2004;134:34---40.
11. Simons FE, Simons KJ. Histamine and H1-antihistamines: cele-
31. Licari A, Castagnoli R, Bottino C, Marseglia A, Marseglia G,
brating a century of progress. J Allergy Clin Immunol. 2011;128,
Ciprandi G. Emerging drugs for the treatment of perennial aller-
1139---50.e4.
gic rhinitis. Expert Opin Emerg Drugs. 2016;21:57---67.
12. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Antihistamines as
32. Church MK, Tiongco-Recto M, Ridolo E, Novák Z. Bilastine: a
important tools for regulating inflammation. Curr Med Chem ---
lifetime companion for the treatment of allergies. Curr Med
Anti-Inflamm Anti-Allergy Agents. 2005;4:81---9.
Res Opin. 2019;13:1---10.
13. Ritchie AI, Farne HA, Singanayagam A, Jackson DJ, Mallia P,
33. Santamaría E, Izquierdo I, Valle M, Vermeulen J, Potter P.
Johnston SL. Pathogenesis of viral infection in exacerbations of
Rupatadine oral solution for 2---5-year-old children with aller-
airway disease. Ann Am Thorac Soc. 2015;12 Suppl. 2:S115---23.
gic rhinitis: a safety, open-label, prospective study. J Asthma
14. Church MK, Maurer M, Simons FE, Bindslev-Jensen C, van
Allergy. 2018;4:225---31.
Cauwenberge P, Bousquet J, et al. Risk of first-generation
34. Castillo M, Scott NW, Mustafa MZ, Mustafa MS, Azuara-Blanco A,
H(1)-antihistamines: a GA(2)LEN position paper. Allergy.
et al. Topical antihistamines and mast cell stabilisers for treat-
2010;65:459---66.
ing seasonal and perennial allergic conjunctivitis. Cochrane
15. Yanai K, Yoshikawa T, Yanai A, Nakamura T, Iida T, Leurs R,
Database Syst Rev. 2015;6:CD009566.
et al. The clinical pharmacology of non-sedating antihistamines.
35. Ciprandi G, Buscaglia S, Pesce G, Bagnasco M. Ocular challenge
Pharmacol Ther. 2017;178:148---56.
and hyperresponsiveness to histamine in patients with allergic
16. Bousquet J, Van Cauwenberge P, Khaltaev N, Aria Work-
conjunctivitis. J Allergy Clin Immunol. 1993;91:1227---30.
shop Group, World Health Organization. Allergic rhinitis and
36. Roberts G, Xatzipsalti M, Borrego LM, Custovic A, Halken S,
its impact on asthma. J Allergy Clin Immunol. 2001;108
Hellings PW, et al. Paediatric rhinitis: position paper of the
Suppl.:S147---334.

Please cite this article in press as: Parisi GF, et al. Antihistamines in children and adolescents: A practical update. Allergol
Immunopathol (Madr). 2020. https://doi.org/10.1016/j.aller.2020.02.005
+Model
ALLER-1144; No. of Pages 10 ARTICLE IN PRESS
10 G.F. Parisi et al.

European Academy of Allergy and Clinical Immunology. Allergy. 49. National Institute for Health and Clinical Excellence. Atopic
2013;68:1102---16. eczema in children: management of atopic eczema in
37. Ciprandi G. Treatment of nonallergic perennial rhinitis. Allergy. children from birth up to the age of 12 years; 2007.
2004;59:16---23. http://www.nice.org.uk/guidance/CG57
38. Berger W, Sher E, Gawchik S, Fineman S. Safety of 50. Church MK, Maurer M. H1-Antihistamines and itch in atopic der-
a novel intranasal formulation of azelastine hydrochlo- matitis. Exp Dermatol. 2015;24:332---3.
ride and fluticasone propionate in children: a random- 51. Ciprandi G, Cirillo I. The lower airway pathology of rhinitis.
ized clinical trial. Allergy Asthma Proc. 2018;39:110---6, Update review. J Allergy Clin Immunol. 2006;118:1105---9.
http://dx.doi.org/10.2500/aap.2018.39.4116. 52. Ciprandi G, Caimmi D, Miraglia del Giudice M, La Rosa M, Salpi-
39. Sharma M, Bennett C, Carter B, Cohen SN. H1-antihistamines etro C, Marseglia GL. Recent developments in united airways
for chronic spontaneous urticaria: an abridged Cochrane Sys- disease. Allergy Asthma Immunol Res. 2012;4:171---7.
tematic Review. J Am Acad Dermatol. 2015;73, 710---6.e4. 53. Ciprandi G, Marseglia GL, Klersy C, Tosca MA. Relationships
40. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker between allergic inflammation and nasal airflow in children with
D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO persistent allergic rhinitis due to mite sensitization. Allergy.
Guideline for the Definition, Classification, Diagnosis and Mana- 2005;60:957---60.
gement of Urticaria. The 2017 Revision and Update. Allergy. 54. Ciprandi G, Cirillo I, Klersy C, Marseglia GL, Vizzaccaro A,
2018;73:1393---414. Pallestrini E, et al. Role of FEF25---75 as an early marker of
41. Papadopoulos NG, Zuberbier T. The safety and tolerability pro- bronchial impairment in patients with seasonal allergic rhinitis.
file of bilastine for chronic urticaria in children. Clin Transl Am J Rhinol. 2006;20:641---7.
Allergy. 2019;9:55. 55. Bachert C, Maspero J. Efficacy of second-generation antihis-
42. Potter P, Mitha E, Barkai L. Rupatadine is effective in the treat- tamines in patients with allergic rhinitis and comorbid asthma.
ment of chronic spontaneous urticaria in children aged 2---11 J Asthma. 2011;48:965---73.
years. Pediatr Allergy Immunol. 2016;27:55---61. 56. Licari A, Manti S, Castagnoli R, Parisi GF, Salpietro C, Leonardi
43. Parisi GF, Papale M, Tardino LG, Manti S, Cuppari C, Salpietro S, Marseglia GL. Targeted therapy for severe asthma in chil-
C, Leonardi S. Omalizumab treatment in a 12 year-old girl with dren and adolescents: current and future perspectives. Paediatr
chronic spontaneous urticaria. J Dermatol Treat. 2018;29 Suppl. Drugs. 2019;21:215---37.
4:10---1. 57. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fer-
44. Metz M, Wahn U, Gieler U, Stock P, Schmitt J, Blume-Peytavi nández Rivas M, et al. Anaphylaxis: guidelines from the
U. Chronic pruritus associated with dermatologic disease in European Academy of Allergy and Clinical Immunology. Allergy.
infancy and childhood: update from an interdisciplinary group 2014;69:1026---45.
of dermatologists and pediatricians. Pediatr Allergy Immunol. 58. Muraro A, Mendoza Hernandez DA. Managing food allergy and
2013;24:527---39. anaphylaxis: a new model for an integrated approach. Aller-
45. Klinnert MD, Booster G, Copeland M, Darr JM, Meltzer LJ, Miller gol Int. 2019, http://dx.doi.org/10.1016/j.alit.2019.10.004.
M, et al. Role of behavioral health in management of pediatric S1323-8930(19)30168-6.
atopic dermatitis. Ann Allergy Asthma Immunol. 2018;120:42---8. 59. Nurmatov UB, Rhatigan E, Simons FE, Sheikh A. H1-
46. Yeom M, Ahn S, Oh JY, Kim SY, Lee H, Hahm DH, et al. Atopic antihistamines for primary mast cell activation syndromes:
dermatitis induces anxiety- and depressive-like behaviors with a systematic review. Allergy. 2015;70(9):1052---61,
concomitant neuronal adaptations in brain reward circuits in http://dx.doi.org/10.1111/all.12672, sep; Epub 2015 Jul
mice. Neuropsychopharmacol Biol Psychiatry. 2019;98:109818. 6.
47. Hong CH, Joseph M, Kim VH, Lansang P, Lara-Corrales I. 60. Juckett G. Arthropod bites. Am Fam Physician. 2013;88:841---7.
Approach to the assessment and management of pediatric 61. Tebruegge M, Kuruvilla M, Margarson I. Does the use of calamine
patients with atopic dermatitis: a consensus document. Sec- or antihistamine provide symptomatic relief from pruritus
tion II: Comorbid disease in pediatric atopic dermatitis. J Cutan in children with varicella-zoster infection? Arch Dis Child.
Med Surg. 2019;23 Suppl.:12S---8S. 2006;91:1035---6.
48. Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzen- 62. De Sutter AI, Saraswat A, van Driel ML. Antihistamines for the
berger K, et al. Guidelines of care for the management of common cold. Cochrane Database Syst Rev. 2015;11:CD009345.
atopic dermatitis: section 2. Management and treatment of
atopic dermatitis with topical therapies. J Am Acad Dermatol.
2014;71:116---32.

Please cite this article in press as: Parisi GF, et al. Antihistamines in children and adolescents: A practical update. Allergol
Immunopathol (Madr). 2020. https://doi.org/10.1016/j.aller.2020.02.005