You are on page 1of 10

Dermatologic Therapy, Vol.

13, 2000, 374–383 Copyright © Blackwell Science 2000


Printed in the United States · All rights reserved
DERMATOLOGIC THERAPY
ISSN 1396-0296

Use and safety of antihistamines


in children
K. Mireille Chae & Michael D. Tharp
Department of Dermatology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois

ABSTRACT: Although first-generation antihistamines remain popular for the treatment of seasonal
allergic rhinitis, atopic dermatitis, and urticaria in children, second- and third-generation antihista-
mines hold clear advantages over the first-generation agents, especially for the pediatric patient. The
less frequent dosing schedule of the second- and third-generation agents makes administration easier
for the parent. With less sedation and lower risk of adverse effects, the safety profile of second- and
third-generation agents appears superior to that of first-generation agents. After briefly discussing the
use of first-generation antihistamines, the pharmacokinetics, safety, and use of the newer antihista-
mines loratadine, cetirizine, and fexofenadine in the pediatric patient are reviewed.

KEYWORDS: allergic rhinitis, antihistamine/antihistamines, atopic dermatitis, cetirizine, child/chil-


dren, fexofenadine, loratadine, pediatric/pediatrics, urticaria.

Dermatologists and pediatricians use H1 receptor First-generation H1 receptor


antagonists in children for the treatment of a antagonists
number of conditions including urticaria, allergic
rhinitis, and atopic dermatitis. In the last several First-generation antihistamines are still widely
years it has become apparent, however, that used in children despite the fact that they have
the newer antihistamines or second- and third- relatively shorter serum half-lives and a higher
generation antihistamines offer advantages over incidence of sedation than the newer H1 receptor
first-generation agents. These newer antihista- antagonists (H1Ras). In addition to urticaria and
mines require less frequent dosing, are less sedat- allergic rhinitis, first-generation H1RAs continue
ing, and appear to be safer than first-generation to be used in patients with atopic dermatitis, al-
agents. While a great deal of information has been though their efficacy is debatable (1,2). One con-
gathered on the safety and efficacy of second- and dition in which first-generation antihistamines
third-generation antihistamines in adults, there are superior to the newer agents is in the treat-
are far less data about the effects and side effects of ment of patients with anaphylaxis, where formula-
these agents in children. The purpose of this arti- tions of chlorpheniramine and diphenhydramine
cle is to briefly review the benefits and problems are available for parenteral use (3,4).
that are incumbent with the use of first-generation First-generation antihistamines are generally
antihistamines in children and compare those well-absorbed after oral administration, and peak
with the use of second- and third-generation serum concentrations are reached within 1–3
agents in this patient population. hours (5). The first-generation H1RAs chlorphen-
iramine, hydroxyzine, and diphenhydramine are
eliminated more rapidly and have a shorter dura-
Address correspondence to Michael D. Tharp, MD, Department tion of action in children than in adults (5–8). Of in-
of Dermatology, RPSLMC, 630 S. Hermitage St., Kidston House, terest, while the half-life values for the antihista-
Rm. 507, Chicago, IL 60612. mines are shorter in children than in adults, the

374
Use and safety of antihistamines in children

recommended dosing schedule is the same (Ta- Hypotension secondary to ␣-adrenergic blockade
ble 1). also has been reported, and cardiorespiratory ar-
rest and death are possible.
Treatment of first-generation H1RA overdose
Safety in children includes supportive measures such as
anticonvulsants and cardiorespiratory support
Health care professionals and parents often as-
when indicated. Activated charcoal cannot pre-
sume that the first-generation H1RAs are safe to
vent H1RA absorption unless administered near
use in infants and children. However, adverse ef-
the time of ingestion. When possible, multiple,
fects may follow recommended doses as well as
maximal doses of activated charcoal are recom-
overdoses. First-generation H1RAs are lipophilic
mended (14). Antiemetics are not recommended
and thus are able to cross the blood–brain bar-
as they are likely to be ineffective if the H1RA is re-
rier. As a result, there are significant central ner-
lated structurally to phenothiazines, which have
vous system (CNS) effects such as fatigue, som-
antiemetic properties. The slow intravenous ad-
nolence, lethargy, and impairment of cognitive
ministration of physostigmine 0.5–2 mg can re-
function and school performance (9,10). In addi-
verse the central and peripheral anticholinergic
tion, first-generation H1RAs have been reported
effects caused by excess first-generation antihis-
to induce respiratory depression and sleep apnea
tamines, but currently this approach is recom-
in healthy children (11). Furthermore, in some
mended only for diagnostic use. Exchange trans-
infants and children, a paradoxical stimulatory
fusion is a consideration in severe intoxications
effect on the CNS may occur with the use of first-
since most H1RAs are highly protein bound and
generation antihistamines, leading to irritability,
concentrated in the serum (15).
nervousness, hyperactivity, and convulsions (12).
First-generation H1RAs also have activity on cho-
linergic receptors, resulting in blurred vision and Pregnancy and lactation
dry mouth. It has been noted that anticholinergic
Although some first-generation H1RAs are terato-
effects and drug-seeking behavior occur in chil-
genic in animals, teratogenicity has never been
dren with chronic diseases who have received
proven in humans. In the Collaborative Perinatal
diphenhydramine (13). Thus the possibility of
Project in which 56,990 pregnancies occurring in
CNS dysfunction and anticholinergic side effects
the United States from 1959 to 1966 were re-
should be considered when choosing a first-gen-
viewed, there was no evidence that H1 antago-
eration antihistamine for an infant or child.
nists were teratogenic (16). In another report of
6509 infants born to mothers who used a variety
of drugs, including diphenhydramine and chlor-
Overdose
pheniramine, during the first trimester of preg-
Intoxication with first-generation H1RAs is poten- nancy, there were no significant associations
tially lethal. A full-blown anticholinergic syn- between antihistamine use and congenital disor-
drome can occur, with agitation, hallucinations, ders (17). However, withdrawal symptoms have
seizures, hot, dry, flushed skin, fever, dilated pu- been reported in infants whose mothers received
pils, tachycardia, hypertension, and arrhythmias. large doses of a first-generation H1RA immedi-

Table 1. Comparison of half-lives of antihistamines


Children Adults
Half-life (hours) Dose Age range Reference Half-life (hours) Reference
Chlorpheniramine 13.1 ⫾ 6.3 0.12 mg/kg 6–16 years 6 24.6 ⫹ 6 78
Diphenhydramine 5.4 ⫾ 1.8 1.25 mg/kg 8.9 ⫾ 1.7 years 8 13.5 ⫾ 4.2 8
Hydroxyzine 7.1 ⫾ 2.3 0.7 mg/kg 6.1 ⫾ 4.6 years 7 20–25 7
Loratadine Not reported 7.8–11 23
Decarboethoxyloratadine Not reported 17–24 23
Cetirizine 4.9 ⫾ 0.6 5 mg 2–4 years 31 8.6 ⫾ 2.1 31
Fexofenadine 18.3 ⫾ 2 30 mg 9.8 ⫾ 1.8 years 43 14 43
17.6 ⫾ 1 60 mg

375
Chae & Tharp

ately before delivery (18,19). Symptoms such as tively binds to H1 peripheral receptors and pene-
infant tremulousness and irritability can occur trates poorly into the CNS. It has a lower affinity
within several days after birth. Because H1 antag- for CNS H1 receptors, as well as for serotonin, cho-
onists are excreted in breast milk, drowsiness and linergic, and ␣-adrenergic receptors (22). There is
irritability may occur in nursing babies whose little published information on the pharmacoki-
mothers are taking a first-generation H1RA (20). netics of loratadine in children. In adults, lorata-
Withdrawal symptoms have not been described dine is rapidly absorbed from the gastrointestinal
in neonates born to women who received ther- (GI) tract, with a mean half-life of approximately
apeutic doses of second-generation antihista- 7.8–11 hours (23). It undergoes extensive first-
mines (21). pass metabolism through the liver, being princi-
pally metabolized by the cytochrome P-450 mi-
crosomal enzyme system, and is rapidly trans-
Second- and third-generation formed into various metabolites including the
H1RAs active metabolite decarboethoxy-loratadine (also
known as descarboethoxyloratadine) (23,24). Us-
While a number of second- and third-generation ing suppression of the histamine-induced wheal
antihistamines are available in Canada, Europe, and flare reaction as the primary outcome in 15
and Asia, only loratadine, cetirizine, and fex- allergic children (mean age 9 years), Simons et al.
ofenadine are currently available in the United (25) showed that loratadine significantly sup-
States. Thus this discussion will focus on the use presses this reaction beginning within 45 minutes
of these agents in children (Table 2). and lasts up to 24 hours.
Loratadine appears to be effective and safe in
the treatment of childhood seasonal allergic rhin-
Use in children
itis. At a dose of either 2.5 or 5 mg/day of lorata-
Loratadine. This is the ethoxycarbonyl derivative dine (0.11–0.24 mg/kg/day ideal body weight), 21
of azatadine, a piperidine class H1RA. It selec- children with allergic rhinitis experienced signifi-

Table 2. Recommended pediatric dosages for second- and third-generation antihistamines


Drug and dosage forms 2–5 years ⱖ6 years ⱖ12 years
Loratadine
Claritin® Syrup 5 mg/5 mL Under physician 10 mg once 10 mg once a Safety and efficacy in children
solution care, 5 mg once a day day less than 6 years of age not
Claritin® 10 mg tablet a day established. Has been used in
Claritin® Reditabs 10 mg children 3–6 years without
rapidly dissolving unusual toxicity.
Claritin-D® 12 Hour 5 mg/ One tablet
120 mg pseudoephedrine twice a day
Claritin-D® 24 Hour 10 mg/ One tablet
240 mg pseudoephedrine once a day
Cetirizine
Zyrtec® Syrup 5 mg/ml Initial 2.5 mg/day, 5–10 mg/ 10 mg/day Doses 5–20 mg/day have been
solution up to 5 mg/day day used in patients more than 12
Zyrtec® 5 mg tablet or 2.5 mg twice years old. Safety and efficacy
Zyrtec® 10 mg tablet a day in children less than 2 years
of age not established.
Fexofenadine
Allegra® 180 mg tablet 30 mg twice 180 mg once Safety and efficacy in children
Allegra® 60 mg capsule or a day a day or 60 less than 6 years of age not
tablets mg twice a established.
day
Allegra® 30 mg tablet
Allegra-D® 60 mg/120 mg One tablet
pseudoephedrine twice a day

376
Use and safety of antihistamines in children

cant improvement of nasal and ocular symptoms of 15 children ranging in age from 6 to 23.5
without associated drowsiness (26). In clinical tri- months, the recovery of unchanged cetirizine in
als in adults with urticaria, loratadine has shown the urine also was lower than in adults, but the
efficacy in helping to control urticarial wheals drug was cleared three times faster in children
(27,28), but it appears to be less effective than than in adults (33). Moreover, the duration of the
oral corticosteroids (29). Studies also have shown inhibition of histamine-induced wheal and flare
efficacy of loratadine for the treatment of pruritus reactions was prolonged in these infants and
in atopic dermatitis (2,30). In a double-blind mul- children when compared to older patients, thus
ticrossover study, 16 patients (19.5–37.3 years, confirming earlier observations that cetirizine
mean age 24.8 years) with moderate or severe appears to accumulate in the skin.
atopic dermatitis received 10 mg loratadine or Several large placebo-controlled trials have
placebo every day, alternating between lorata- shown cetirizine to be efficacious in the treat-
dine and placebo every 2 weeks (30). Nine of the ment of seasonal allergic rhinitis (34–40). In a
16 loratadine-treated patients showed significant study of 124 children ranging in age from 6 to 12
improvement of their pruritus and atopic derma- years, those treated with cetirizine (5 mg twice a
titis. In another study of 41 patients with atopic day) had fewer symptoms than children receiving
dermatitis, the daily symptom scores decreased placebo (39). The effects of cetirizine adminis-
by 57% in the loratadine-treated group, which tered either as 2.5 mg or 5 mg twice a day over 2
was significantly greater than the hydroxyzine- weeks were evaluated in 138 children with peren-
treated group (38%) or placebo-treated patients nial allergic rhinitis. Children receiving cetirizine
(33%) (28). Somnolence was no greater in the lor- 10 mg/day had significantly greater improvement
atadine-treated group than those given placebo. in their allergic symptoms than placebo-treated
There are no published controlled studies of the patients and greater improvement in nasal ob-
use of loratadine in the treatment of children struction and rhinorrhea than patients receiving
with urticaria or with atopic dermatitis. cetirizine 5 mg/day (36). In another study of 84
children with allergic rhinitis who received one of
Cetirizine. This agent is the active carboxylic acid three doses of cetirizine (2.5, 5, and 10 mg/day)
metabolite of hydroxyzine. Unlike loratadine, it is for 14 days, those treated with 10 mg once a day
not metabolized by the cytochrome P-450 system showed the greatest reduction in symptoms (38).
and is excreted in the urine mostly unchanged Other studies also have confirmed that 10 mg/day
(70% in urine, 10% in feces). Although hepatic of cetirizine is superior to 5 mg/day for the treat-
metabolism of cetirizine is considered negligible, ment of allergic rhinitis in children and that ad-
patients with chronic liver disease have shown a verse events are infrequent and generally mild (40).
50% increase in its half-life and a 40% decrease in The safety of cetirizine in children has been
its clearance. The metabolism of cetirizine ap- confirmed in the largest and longest prospective
pears to be faster in children than in adults. In a study of an H1 antagonist ever conducted. The
study of eight children less than 4 years of age, ce- 18-month long Early Treatment of the Atopic
tirizine was absorbed more slowly when com- Child (ETAC) study included 817 children ranging
pared to adults, but the plasma half-life of this in age from 12 to 24 months with an atopic di-
antihistamine was significantly shorter than in athesis (41,42). Children received either cetirizine
adult patients (4.9 ⫾ 0.6 hours versus 8.6 ⫾ 2.1 0.25 mg/kg (n ⫽ 399) or placebo (n ⫽ 396) twice a
hours; see Table 1). Since urinary recovery of un- day. Few adverse events occurred in these chil-
changed cetirizine also was lower in children dren and most were attributed to intercurrent
than in adults, it has been postulated that this respiratory or GI infections, exacerbations of al-
antihistamine may accumulate in tissues to a lergic disorders, or age-related rather than medi-
greater degree in children than in adults (31). In cation-related effects. There were no significant
keeping with this idea, cetirizine’s duration of H1 differences in adverse events between treatment
inhibition in the skin appears to be longer than and placebo groups, except for urticaria, which
its pharmacokinetic profile would suggest. Si- was less frequent in the cetirizine group (16.2%
mons et al. (32) showed through repeated biop- for placebo versus 5.8% for cetirizine, P ⬍ 0.001)
sies that cetirizine slowly accumulates in the skin, (Table 3). Agitation, appetite increase, and elec-
with a maximum concentration at 3 hours and an trocardiogram abnormalities occurred at a fre-
estimated half-life of 18 hours. In another study quency of less than 1% in both groups. The only

377
Chae & Tharp

serious adverse event considered by the Scientific inhibitory effect from 2 to 24 hours (43). In adults,
Advisory Board to be related to cetirizine in- fexofenadine has been shown to be safe and ef-
volved a child who entered the study with ele- fective in the treatment of seasonal allergic rhini-
vated transaminases (AST 48 IU/L, ALT 54 IU/L) tis (44–49) and urticaria (50,51). There are no
that peaked after 5 weeks of cetirizine (AST 1100 published controlled studies on the use of fex-
IU/L, ALT 1300 IU/L). The values returned to 61 ofenadine in the treatment of children with aller-
and 67 IU/L, respectively, after 1 month of with- gic rhinitis, atopic dermatitis, or urticaria.
drawal from the study. All other laboratory values
were within normal ranges, including C-reactive Safety of second- and
protein and viral cultures. The child remained
asymptomatic throughout observation and after
third-generation antihistamines
the study.
CNS effects
Fexofenadine. This antihistamine is the active car-
The second-generation H1RAs are relatively free
boxylic metabolite of terfenadine, and thus rep-
from adverse CNS effects in children. Because
resents a third-generation agent. As with lo-
they are hydrophilic compounds, they have lim-
ratadine, there are little published data on the
ited access to central H1 receptors. Unfortunately
pharmacokinetics of fexofenadine in children.
many studies assessing the sedative effects of
Fexofenadine is rapidly absorbed from the GI
H1RAs have used only single doses of the agents
tract and is only minimally metabolized in the
(52). Nevertheless, the use of these antihista-
liver. Eighty percent of this antihistamine is elim-
mines in children with allergic rhinitis and the
inated unchanged in the feces and 10% is elimi-
ETAC study have demonstrated that significant
nated unchanged in the urine (43). The pharma-
CNS events are rare with second- and third-gen-
cokinetics of fexofenadine in children appear to
eration agents.
be similar to those reported in adults. The mean
Loratadine is considered to be nonsedating,
elimination half-life is approximately 18 hours in
and at the recommended dose (10 mg/day), no
children versus 14 hours in adults. Children,
significant differences in mood, sedation, or cog-
however, attain higher plasma levels of the drug
nitive or psychomotor performance have been
when compared to adults. In a study of 14 chil-
observed between loratadine and placebo-treated
dren, the plasma levels achieved after a single
patients (53). At two to four times the recom-
dose of 60 mg was 56% greater than in adult sub-
mended dose, however, loratadine causes signifi-
jects receiving the same dose (43). The effects of
cant sedation and impairment of performance
fexofenadine also have been investigated in the
(53). Data suggest that cetirizine is less sedating
skin. At 30 or 60 mg, fexofenadine suppressed
than older antihistamines, but may be more se-
histamine-induced wheal and flare reactions
dating than either loratadine or fexofenadine (54).
within 1–2 hours of ingestion and maintained this
Sedation can occur at recommended doses of ce-
tirizine. Mild sedation, impairment of driving per-
formance, and dose-related sedation have been
Table 3. ETAC study adverse events
reported in adults using cetirizine (54). In con-
Adverse events Cetirizine Placebo trast, fexofenadine is nonsedating even at doses
Allergic reaction 9.1 13.4 of 690 mg twice a day in adults (55). It has been
Insomnia 8.8 5.3 well-tolerated at single daily doses ranging from
Laryngitis 7.3 9.3 10 to 800 mg and after multiple-dose administra-
Urticaria 5.8 16.1
tion of 20–690 mg every 12 hours for 28.5 days.
Abdominal pain 4.3 4.3
Anorexia 3.3 4.0
The most common reported adverse events (re-
Fatigue 3.3 1.3 ported by three or more subjects) with the use of
Vaccination complication 3.3 5.5 fexofenadine have been headache, tiredness, and
Somnolence 2.3 2.0 dizziness. However, no dose-related trends in ad-
Hepatic enzymes increased 1.3 1.8 verse events or obvious differences between fex-
Hyperkinesia 1.3 2.5 ofenadine and placebo treatment groups have
Appetite increased 0.5 0.3 been found.
Agitation 0.3 0.5 Second-generation H1RAs may prove to be
ECG abnormalities 0.0 0.3
beneficial not only in the relief of allergic rhinitis

378
Use and safety of antihistamines in children

symptoms but also in impaired learning associ- Loratadine had been thought to be nonar-
ated with the disease. Nasal symptoms such as rhythmogenic because it does not appear to in-
itching, sneezing, rhinorrhea, and congestion are crease the QT interval. More recently it has been
felt to contribute to learning problems in children shown that loratadine is capable of blocking po-
during school hours. Poorly controlled symptoms tassium channels in human atrial myocytes (64,65).
at night lead to sleep loss and daytime fatigue, This blocking effect, however, was seen at concen-
further contributing to learning impairment. Fur- trations between 1000 and 5000 times higher than
thermore, the use of a sedating antihistamine in the recommended dose of 10 mg/day. Loratadine
the treatment of patients with allergic symptoms also has been administered in combination with
can add to this learning impairment (56). In a the cytochrome P-450 inhibitor erythromycin
study of 52 children with allergic rhinitis during without any adverse cardiac effects being ob-
pollen season, learning impairment was aggra- served (66). Potential drug-drug interactions also
vated by the use of sedating diphenhydramine have been evaluated in patients taking lorata-
and partially improved by the administration of dine and ketoconazole, erythromycin, and cime-
nonsedating loratadine (10). tidine. While plasma loratadine concentrations
First-generation antihistamines such as pro- increased with the coadministration of erythro-
methazine have been associated with apnea and mycin (40% increase), cimetidine (103%), and ke-
sudden death in infants. However, it is unclear toconazole (307%), no cardiac arrhythmias were
whether there is a direct cause-and-effect rela- seen (54).
tionship between antihistamines and apnea. Gros- Cetirizine also is free of cardiac side effects. In
wasser et al. (57) studied the potential influence a randomized, controlled clinical trial, Winder et
of a single administration of cetirizine versus pla- al. (68) showed that cetirizine, in doses up to 10
cebo on the development of sleep apnea in a dou- mg/day, did not prolong the QTc interval in pedi-
ble-blind crossover study. Cetirizine was not as- atric patients. When cetirizine was given with
sociated with significant cardiorespiratory changes erythromycin and azithromycin, no electrocar-
during sleep, and in 5 of 10 infants with previous diographic changes could be detected (66,68,69).
obstructive events, cetirizine significantly reduced In the ETAC study in which 399 children received
their frequency. cetirizine, no electrocardiogram abnormalities
were noted (Table 3).
Unlike its parent compound terfenadine, fex-
Cardiovascular effects
ofenadine has not been reported to cause prolon-
Adverse cardiac effects, such as torsade de gation of the QTc interval in human beings (44).
pointes, have been reported with the use of ter- The effects of fexofenadine on potassium chan-
fenadine and astemizole after overdose or with nels also have been investigated in vitro. The
concomitant use of macrolide antibiotics and ke- blocking effect of fexofenadine on cloned K⫹
toconazole (58–62). Concerns over the safety of channels from human heart was 583-fold less po-
terfenadine and astemizole have led to discontin- tent than that of terfenadine (70). Fexofenadine
uation of their use in the United States. In a com- given as 800 mg once a day or 690 mg twice a day
parison study examining the incidence of ventric- for 28 days in adults caused no increase in QTc
ular arrhythmias associated with the use of five intervals (55,71).
nonsedating antihistamines (acrivastine, astemi-
zole, cetirizine, loratadine, and terfenadine), it
Overdose
has been suggested that collectively these agents
may increase the risk of ventricular arrhythmias Little published data exist for overdoses with sec-
by a factor of 4 in the general population. How- ond-generation H1 antagonists. In the ETAC
ever, the incidence of such an adverse reaction study, two children receiving cetirizine experi-
appears to be extremely low since it has also been enced accidental overdoses. Only one of these
calculated that 57,000 prescriptions or 5300 per- children, an 18-month-old boy who ingested 180
son-years of use would be needed for one event mg of cetirizine, required monitoring in the hos-
to occur (63). The exception to this projection pital. Other than a brief period of agitation ini-
may be in infants and children with the long-QT tially, the child displayed no other symptoms and
syndrome who are theoretically at greater risk for his electrocardiogram remained normal (41,72).
ventricular arrhythmias. A 4-year-old boy who accidentally ingested 60 mg

379
Chae & Tharp

of cetirizine in a single dose also has been re- nursing infant could potentially receive a dose
ported. Vomiting was induced 1.5 hours after in- equivalent to nearly 50% of the loratadine dose
gestion because of severe drowsiness that lasted ingested by the mother (75). Cetirizine also has
for 5–6 hours. The patient experienced no other been reported to be excreted in human breast
side effects (73). milk, and thus it is not recommended in nursing
mothers. Fexofenadine also should be used with
caution in the nursing mothers because it is not
Pregnancy and lactation known if this agent is excreted into breast milk.
Although there is no evidence for teratogenicity
with second- and third-generation H1 antago-
nists, these agents are classified as pregnancy Conclusion
category B or C (74), and are recommended for
For the pediatric patient, second- and third-gen-
use during pregnancy only when the benefits to
eration antihistamines clearly hold advantages
the mother exceed the unknown risks to the fe-
over the first-generation agents and should be
tus. [The US Food and Drug Administration uses
used when the need arises. While the once-a-day
5 categories for drugs in pregnancy (A, B, C, D, X).
recommended dosage of these newer antihista-
Category B is defined drugs for which animal
mines may promote compliance, twice-a-day in-
studies show no risk, but human studies are inad-
tervals may prove to be more efficacious. The
equate, or animal studies show some risk that is
safety profiles of the newer antihistamines, spe-
not supported by human studies. With category
cifically loratadine, cetirizine, and fexofenadine,
C, animal studies show risk, but human studies
are superior to those of the first-generation anti-
are inadequate or lacking, or there are no studies
histamines. There is less toxicity associated with
in animals or humans.] Loratadine is classified as
the newer agents because they have more specific
pregnancy category B. There is no evidence of
activity at H1 receptors and thus are less likely to
teratogenicity in animal studies, however, there
cause anticholinergic side effects. The newer anti-
are no adequate and well-controlled studies in
histamines also are less likely to cross the blood–
pregnant women. Since animal reproduction
brain barrier, thus greatly reducing their potential
studies are not always predictive of human re-
for sedation. Adverse cardiac effects which were
sponse, loratadine should be used only if neces-
problematic with astemizole and terfenadine are
sary. There is a recent prospective, controlled
lacking in loratadine, cetirizine, and fexofenadine.
study that followed 53 women exposed to hy-
Many studies, and in particular the ETAC study,
droxyzine and 39 women exposed to cetirizine
have corroborated the safety of second- and third-
during pregnancy. No significant differences
generation antihistamines in children.
were found between the hydroxyzine- or cetiri-
The issue of safety with the use of first-, second-,
zine-treated groups versus age-matched controls
and third-generation antihistamines in pregnant
in rate of live births and spontaneous or thera-
and nursing patients is less well defined. Large,
peutic abortions. In addition, no differences were
placebo-controlled trials have not been performed
found in the mean birth weight, mode of delivery,
in these patient groups due to ethical and moral
gestational age, and rates of neonatal distress and
concerns. Unfortunately animal studies are im-
fetal anomalies (74). Currently cetirizine is classi-
perfect in their ability to predict outcomes in hu-
fied as pregnancy category B. Fexofenadine is
mans. Thus it is prudent to abstain from the use of
classified as pregnancy category C. While there is
antihistamines in pregnant and nursing patients
no evidence of teratogenicity in animal studies,
whenever possible. In those pregnant patients
there is a report of decreases in pup weight and
who require antihistamine therapy, the risks ap-
survival in rats exposed to doses equivalent to
pear to be relatively low to the mother and fetus.
three times the human therapeutic dose (60 mg
twice a day).
Loratadine and its metabolite descarboethoxy-
loratadine readily pass into breast milk (75,76).
References
The concentrations of loratadine and descarboet-
hoxyloratadine in breast milk increase in parallel 1. Wahlgren CF. Itch and atopic dermatitis: clinical and
to the plasma concentrations of loratadine and experimental studies. Acta Derm Venereol 1991:
descarboethoxyloratadine in the mother. A 4 kg 165(suppl): 1–53.

380
Use and safety of antihistamines in children

2. Behrendt H, Ring J. Histamine, antihistamines and 20. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren
atopic eczema. Clin Exp Allergy 1990: 20(suppl 4): 25–30. G. Prospective follow-up of adverse reactions in breast-
3. Stewart AG, Ewan PW. The incidence, aetiology and fed infants exposed to maternal medication. Am J Ob-
management of anaphylaxis presenting to an accident stet Gynecol 1993: 168: 1393–1399.
and emergency department. Q J Med 1996: 89: 859–864. 21. Neonatal drug withdrawal. American Academy of Pedi-
4. Anaphylaxis: statement on initial management in non- atrics Committee on Drugs. Pediatrics 1998: 101: 1079–
hospital settings. Laboratory Centre for Disease Con- 1088 [published erratum appears in Pediatrics 1998:
trol. Can Med Assoc J 1996: 154: 1519–1522. 102(3 pt 1): 660].
5. Simons FE, Simons KJ, Chung M, Yeh J. The compara- 22. Simons FE, Lukowski JL, Becker AB, Simons KJ. Com-
tive pharmacokinetics of H1-receptor antagonists. Ann parison of the effects of single doses of the new H 1-
Allergy 1987: 59(6 pt 2): 20–24. receptor antagonists loratadine and terfenadine versus
6. Simons FE, Luciuk GH, Simons KJ. Pharmacokinetics placebo in children. J Pediatr 1991: 118: 298–300.
and efficacy of chlorpheniramine in children. J Allergy 23. Estelle F, Simons R, Simons KJ. Pharmacokinetic opti-
Clin Immunol 1982: 69: 376–381. mization of histamine H1-receptor antagonist therapy.
7. Simons FE, Simons KJ, Becker AB, Hayday RP. Pharma- Clin Pharmacokinet 1991: 21: 372–393.
cokinetics and antipruritic effects of hydroxyzine in 24. Johnson R, Christensen J, Lin CC. Sensitive gas-liquid
children with atopic dermatitis. J Pediatr 1984: 104: chromatographic method for the determination of lora-
123–127. tadine and its major active metabolite, descarboethoxy-
8. Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE. loratadine, in human plasma using a nitrogen-phos-
Diphenhydramine: pharmacokinetics and pharmaco- phorus detector. J Chromatogr B Biomed Appl 1994:
dynamics in elderly adults, young adults and children. 657: 125–131.
J Clin Pharmacol 1990: 30: 665–671. 25. Simons FE, Johnston L, Simons KJ. Clinical pharmacol-
9. Simons FE, Fraser TG, Reggin JD, Roberts JR, Simons KJ. ogy of the H1-receptor antagonists cetirizine and lora-
Adverse central nervous system effects of older antihis- tadine in children. Pediatr Allergy Immunol 2000: 11:
tamines in children. Pediatr Allergy Immunol 1996: 7: 116–119.
22–27. 26. Boner AL, Miglioranzi P, Richelli C, Marchesi E, Andre-
10. Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, oli A. Efficacy and safety of loratadine suspension in the
O’Hanlon JF. Seasonal allergic rhinitis and antihista- treatment of children with allergic rhinitis. Allergy 1989:
mine effects on children’s learning. Ann Allergy 1993: 44: 437–441.
71: 121–126. 27. Belaich S, Bruttmann G, DeGreef H, et al. Comparative
11. Kahn A, Hasaerts D, Blum D. Phenothiazine-induced effects of loratadine and terfenadine in the treatment of
sleep-apneas in normal infants. Pediatrics 1985: 75: chronic idiopathic urticaria. Ann Allergy 1990: 64(2 pt 2):
844–847. 191–194.
12. Yokoyama H, Iinuma K, Yanai K, Watanabe T, Sakurai E, 28. Monroe EW. Relative efficacy and safety of loratadine,
Onodera K. Proconvulsant effect of ketotifen, a hista- hydroxyzine, and placebo in chronic idiopathic urti-
mine H1-antagonist, confirmed by the use of d-chlor- caria and atopic dermatitis. Clin Ther 1992: 14: 17–21.
pheniramine with monitoring electroencephalography. 29. Zuberbier T, Ifflander J, Semmler C, Henz BM. Acute ur-
Methods Find Exp Clin Pharmacol 1993: 15: 183–188. ticaria: clinical aspects and therapeutic responsiveness.
13. Dinndorf PA, McCabe MA, Frierdich S. Risk of abuse of Acta Derm Venereol 1996: 76: 295–297.
diphenhydramine in children and adolescents with 30. Langeland T, Fagertun HE, Larsen S. Therapeutic effect
chronic illnesses. J Pediatrics 1998: 133: 293–295. of loratadine on pruritus in patients with atopic derma-
14. Guay DR, Meatherall RC, Macaulay PA, Yeung C. Acti- titis. A multi-crossover-designed study. Allergy 1994: 49:
vated charcoal adsorption of diphenhydramine. Int J 22–26.
Clin Pharmacol Ther Toxicol 1984: 22: 395–400. 31. Desager JP, Dab I, Horsmans Y, Harvengt C. A phar-
15. Battan FK, Dart RC, Rumack BH. Emergencies, injuries macokinetic evaluation of the second-generation H 1-
and poisonings. In: Hay WW, Groothuis JR, Hayward receptor antagonist cetirizine in very young children.
AR, Levin MJ, eds. Current pediatric diagnosis and Clin Exp Allergy 1990: 20(suppl 4): 25–30.
treatment, 13th ed. Stamford, CT: Appleton & Lange, 32. Simons FE, Murray HE, Simons KJ. Quantitation of H 1-
1997: 311. receptor antagonists in skin and serum. J Allergy Clin
16. The Collaborative Perinatal Study of the National Insti- Immunol 1995: 95: 759–764.
tute of Neurological Diseases and Stroke: the women 33. Špicák V, Dab I, Hulhoven R, et al. Pharmacokinetics
and their pregnancies. U.S Department of Health Edu- and pharmodynamics of cetirizine in infants and tod-
cation and Welfare, Public Health Service, National In- dlers. Clin Pharmacol Ther 1997: 61: 325–330.
stitutes of Health, 1972. 34. De Benedictis FM, Forenza N, Armenia L, et al. Efficacy
17. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. and safety of cetirizine and oxatomide in young chil-
First-trimester drug use and congenital disorders. Ob- dren with perennial allergic rhinitis: a 10-day, multicenter,
stet Gynecol 1985: 65: 451–455. double-blinded, randomized, parallel-group study. Pe-
18. Parkin DE. Probable benadryl withdrawal manifesta- diatr Asthma Allergy Immunol 1997: 11: 119–128.
tions in a newborn infant. J Pediatr 1974: 85: 580. 35. Allegra L, Paupe AL, Weiseman HG, Baelde Y. Cetirizine
19. Prenner BM. Neonatal withdrawal syndrome associated for seasonal allergic rhinitis in children aged 2–6 years.
with hydroxyzine hydrochloride. Am J Dis Child 1977: Pediatr Allergy Immunol 1993: 40: 157–161.
131: 529–530. 36. Baelde Y, Dupont P. Cetirizine in children with chronic

381
Chae & Tharp

allergic rhinitis: a multicentre double-blind study of two safe and effective for treatment of chronic idiopathic ur-
doses of cetirizine and placebo. Drug Invest 1992: 4: ticaria. Ann Allergy Asthma Immunol 2000: 84: 517–522.
466–472. 52. Spencer CM, Faulds D, Peters DH. Cetirizine: a re-
37. Berkowitz RB, Dockhorn R, Lockey R, et al. Comparison appraisal of its pharmacological properties and thera-
of efficacy, safety, and skin test inhibition of cetirizine peutic use in selected allergic disorders. Drugs 1993: 46:
and astemizole. Ann Allergy Asthma Immunol 1996: 76: 1055–1080.
363–368. 53. Philpot EE. Safety of second generation antihistamines.
38. Jobst S, van den Wijngaart W, Schubert A, van de Venne Allergy Asthma Proc 2000: 21: 15–20.
H. Assessment of the efficacy and safety of three dose 54. Horak F, Stübner UP. Comparative tolerability of second
levels of cetirizine given once daily in children with pe- generation antihistamines. Drug Saf 1999: 20: 385–401.
rennial allergic rhinitis. Allergy 1995: 49: 598–604. 55. Russell T, Stoltz M, Weir S. Pharmacokinetics, pharma-
39. Masi M, Candiani R, van de Venne H. A placebo-con- codynamics, and tolerance of single- and multiple-dose
trolled trial of cetirizine in seasonal allergic rhino-con- fexofenadine hydrochloride in healthy male volunteers.
junctivitis in children aged 6–12 years. Pediatr Allergy Clin Pharmacol Ther 1998: 64: 612–621.
Immunol 1993: 4(suppl 4): 47–52. 56. Simons FE. Learning impairment and allergic rhinitis.
40. Pearlman DS, Lumry WR, Winder JA, Noonan MJ. Once- Allergy Asthma Proc 1996: 17: 185–189.
daily cetirizine effective in the treatment of seasonal al- 57. Groswasser J, Brusquet Y, Cornus A, de Sake JK,
lergic rhinitis in children aged 6–11 years: a randomized Longueville M, Kahn A. Effects of cetirizine in night
double-blind, placebo-controlled study. Clin Pediatr polygraphic recording in infants. Pediatr Allergy Immu-
1997: 4: 209–215. nol 1995: 8 (6 suppl): 96.
41. ETAC® Study Group. Allergic factors associated with 58. Hoppu K, Tikanoja T, Tapanainen P, Remes M, Saaren-
the development of asthma and the influence of asthma paa-Heikkila O, Kouvalainen K. Accidental astemizole
and the influence of cetirizine in a double-blind, ran- overdose in young children. Lancet 1991: 338: 538–540.
domised, placebo-controlled trial: first results of ETAC®. 59. MacConell TJ, Stanners AJ. Torsades de pointes compli-
Pediatr Allergy Immunol 1998: 9: 116–124. cating treatment with terfenadine. Br Med J 1991: 302:
42. Simons FER, ETAC® Study Group. Prospective, long- 1049.
term safety evaluation of the H1-receptor antagonist ce- 60. Simon FE, Kesselman MS, Giddins NG, et al. Astemizole
tirizine in very young children with atopic dermatitis. induced torsades de pointes. Lancet 1988: 2: 624.
J Allergy Clin Immunol 1999: 104: 433–440. 61. Davies AJ, Harindra V, McEwan A, Ghose RR. Car-
43. Simons FE, Bergman JN, Watson WT, Simons KJ. The diotoxic effect with convulsions in terfenadine over-
clinical pharmacology of fexofenadine in children. J Al- dose. Br Med J 1989: 298: 325–326.
lergy Clin Immunol 1996: 98(6 pt 1):1062–1064. 62. Monahan BP, Gerguson CL, Kelleavy ES, et al. Torsades
44. Mason J, Reynolds R, Rao N. The systemic safety of fexo- de pointes occurring in association with terfenadine
fenadine HCl. Clin Exp Allergy 1999: 29(suppl 3): 163–170. use. JAMA 1990: 264: 2788–2790.
45. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, 63. De Abajo FJ, Rodriguez LAG. Risk of ventricular arrhyth-
Ahlbrandt R, Mason J. Efficacy and safety of fexofena- mias associated with nonsedating antihistamine drugs.
dine hydrochloride for treatment of seasonal allergic Br J Clin Pharmacol 1999: 47: 307–313.
rhinitis. Ann Allergy Asthma Immunol 1997: 79: 443–448. 64. Delpon E, Valenzuela C, Gay P, Franqueza L, Snyders
46. Casale TB, Andrade C, Qu R. Safety and efficacy of once- DJ, Tamargo J. Block of human cardiac Kv1.5 channels
daily fexofenadine HCl in the treatment of autumn sea- by loratadine: voltage-, time-, and use-dependent block
sonal allergic rhinitis. Allergy Asthma Proc 1999: 20: at concentrations above therapeutic levels. Cardiovasc
193–198. Res 1997: 35: 341–350.
47. Howarth PH, Stern MA, Roi L, Reynolds R, Bousquet J. 65. Lacerda AE, Roy ML, Lewis EW, Rampe D. Interactions
Double-blind, placebo-controlled study comparing the of the non-sedating antihistamine loratadine with a
efficacy and safety of fexofenadine hydrochloride (120 Kv1.5 type potassium channel cloned from human
and 180 mg once daily) and cetirizine in seasonal aller- heart. Mol Pharmacol 1997: 52: 314–322.
gic rhinitis. J Allergy Clin Immunol 1999: 104: 927–933. 66. Delgado LF, Pferferman A, Solé D, Naspitz CK. Evaluation
48. Meltzer EO, Casale TB, Nathan RA, Thompson AK. of the potential cardiotoxicity of the antihistamines ter-
Once-daily fexofenadine HCl improves quality of life fenadine, astemizole, loratadine, and cetirizine in atopic
and reduces work and activity impairment in patients children. Ann Allergy Asthma Immunol 1998: 80: 333–337.
with seasonal allergic rhinitis. Ann Allergy Asthma Im- 67. Winder JA, Noonan MJ, Lumry WR, Pearlman DS. Ab-
munol 1999: 83: 311–317. sence of QTc prolongation with cetirizine in children
49. Sussman GL, Mason J, Compton D, Stewart J, Ricard N. aged 6–11 years. Pediatr Asthma Allergy Immunol 1996:
The efficacy and safety of fexofenadine HCl and pseu- 10: 181–190.
doephedrine, alone and in combination, in seasonal al- 68. Sale ME, Woosley RL, Thakker K, Phillips K, Caridi F,
lergic rhinitis. J Allergy Clin Immunol 1999: 104: 100–106. Chung M. Effects of cetirizine and erythromycin, alone
50. Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A dou- and in combination, on QT interval and pharmacoki-
ble-blind, placebo-controlled trial of fexofenadine HCl netics in healthy subjects. Ann Allergy Asthma Immunol
in the treatment of chronic idiopathic urticaria. J Allergy 1996: 76: 93.
Clin Immunol 1999: 104: 1071–1078. 69. Sale M, Woosley R, Thakker K, Phillips K, Caridi F,
51. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is Chung M. A randomized, placebo-controlled, multiple-

382
Use and safety of antihistamines in children

dose study to evaluate the electrocardiographic and 74. Einarson A, Bailey B, Jung G, Spizzirri D, Baillie M, Ko-
pharmacokinetic interactions of azithromycin and ceti- ren G. Prospective controlled study of hydroxyzine and
rizine. Ann Allergy Asthma Immunol 1996: 76: 93. cetirizine in pregnancy. Ann Allergy Asthma Immunol
70. Woosley RL. Cardiac actions of antihistamines. Ann Rev 1997: 78: 183–186.
Pharmacol Toxicol 1996: 36: 233–252. 75. Hilbert J, Radwanski E, Affrime MB, Perentesis G, Sym-
71. Pratt CM, Mason J, Russell T, et al. Cardiovascular safety chowicz S, Zampaglione N. Excretion of loratadine in
of fexofenadine HCl. Am J Cardiol 1999: 83: 1451–1454. human breast mild. J Clin Pharmacol 1988: 28: 234–239.
72. Ridout SM, Tariq SM. Cetirizine overdose in a young child 76. Mitchell JL. Use of cough and cold preparations during
[letter]. J Allergy Clin Immunol 1997: 99(6 pt 1): 860–861. breastfeeding. J Hum Lactat 1999: 15: 347–349.
73. Hansen JJ, Feilberg Jorgensen NH. Accidental cetirizine 77. Vallner JJ, Needham TE, Chan W, Viswanathan CT. In-
poisoning in a four-year-old boy [in Danish]. Ugeskrift travenous administration of chlorpheniramine in seven
Laeger 1998: 160: 5946–5947. subjects. Curr Ther Res 1979: 26: 449.

383