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70-4573-00-5
ZYRTEC®
(cetirizine hydrochloride)
Tablets and Syrup
For Oral Use
DESCRIPTION
Cetirizine hydrochloride, the active component of ZYRTEC® tablets and syrup, is an orally
active and selective H1-receptor antagonist. The chemical name is (±) - [2- [4- [ (4-
chlorophenyl)phenylmethyl] -1- piperazinyl] ethoxy]acetic acid, dihydrochloride. Cetirizine
hydrochloride is a racemic compound with an empirical formula of C21H25ClN2O3•2HCl. The
molecular weight is 461.82 and the chemical structure is shown below:
Cl
CH - N N - CH2 - CH2 - O - CH2 - COOH • 2HCl
Cetirizine hydrochloride is a white, crystalline powder and is water soluble. ZYRTEC tablets are
formulated as white, film-coated, rounded-off rectangular shaped tablets for oral administration
and are available in 5 and 10 mg strengths. Inactive ingredients are: lactose; magnesium stearate;
povidone; titanium dioxide; hydroxypropyl methylcellulose; polyethylene glycol; and corn starch.
ZYRTEC syrup is a colorless to slightly yellow syrup containing cetirizine hydrochloride at a
concentration of 1 mg/mL (5 mg/5 mL) for oral administration. The pH is between 4 and 5. The
inactive ingredients of the syrup are: banana flavor; glacial acetic acid; glycerin; grape flavor;
methylparaben; propylene glycol; propylparaben; sodium acetate; sugar syrup; and water.
CLINICAL PHARMACOLOGY
Mechanism of Actions: Cetirizine, a human metabolite of hydroxyzine, is an antihistamine; its
principal effects are mediated via selective inhibition of peripheral H1 receptors. The
antihistaminic activity of cetirizine has been clearly documented in a variety of animal and
human models. In vivo and ex vivo animal models have shown negligible anticholinergic and
antiserotonergic activity. In clinical studies, however, dry mouth was more common with
cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity
for other than H1 receptors. Autoradiographic studies with radiolabeled cetirizine in the rat have
shown negligible penetration into the brain. Ex vivo experiments in the mouse have shown that
systemically administered cetirizine does not significantly occupy cerebral H1 receptors.
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Pharmacokinetics:
Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of
approximately 1 hour following oral administration of tablets or syrup in adults. Comparable
bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers
were administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean
peak plasma concentration (Cmax) of 311 ng/mL was observed. No accumulation was observed.
Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no
effect on the extent of cetirizine exposure (AUC) but Tmax was delayed by 1.7 hours and Cmax
was decreased by 23% in the presence of food.
Distribution: The mean plasma protein binding of cetirizine is 93%, independent of
concentration in the range of 25-1000 ng/mL, which includes the therapeutic plasma levels
observed.
Metabolism: A mass balance study in 6 healthy male volunteers indicated that 70% of the
administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50%
of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in
peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass
metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a
metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this
metabolism have not been identified.
Elimination: The mean elimination half-life in 146 healthy volunteers across multiple
pharmacokinetic studies was 8.3 hours and the apparent total body clearance for cetirizine was
approximately 53 mL/min.
Interaction Studies
Pharmacokinetic interaction studies with cetirizine in adults were conducted with
pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. No interactions were
observed. In a multiple dose study of theophylline (400 mg once daily for 3 days) and cetirizine
(20 mg once daily for 3 days), a 16% decrease in the clearance of cetirizine was observed. The
disposition of theophylline was not altered by concomitant cetirizine administration.
Special Populations
Pediatric Patients: When pediatric patients aged 7 to 12 years received a single, 5-mg oral
cetirizine capsule, the mean Cmax was 275 ng/mL. Based on cross-study comparisons, the
weight-normalized, apparent total body clearance was 33% greater and the elimination half-life
was 33% shorter in this pediatric population than in adults. In pediatric patients aged 2 to 5 years
who received 5 mg of cetirizine, the mean Cmax was 660 ng/mL. Based on cross-study
comparisons, the weight-normalized apparent total body clearance was 81 to 111% greater and
the elimination half-life was 33 to 41% shorter in this pediatric population than in adults. In
pediatric patients aged 6 to 23 months who received a single dose of 0.25 mg/kg cetirizine oral
solution (mean dose 2.3 mg), the mean Cmax was 390 ng/mL. Based on cross-study
comparisons, the weight-normalized, apparent total body clearance was 304% greater and the
elimination half-life was 63% shorter in this pediatric population compared to adults. The
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average AUC(0-t) in children 6 months to < 2 years of age receiving the maximum dose of
cetirizine solution (2.5mg twice a day) is expected to be two-fold higher than that observed in
adults receiving a dose of 10 mg cetirizine tablets once a day.
Geriatric Patients: Following a single, 10-mg oral dose, the elimination half-life was prolonged
by 50% and the apparent total body clearance was 40% lower in 16 geriatric subjects with a mean
age of 77 years compared to 14 adult subjects with a mean age of 53 years. The decrease in
cetirizine clearance in these elderly volunteers may be related to decreased renal function.
Effect of Gender: The effect of gender on cetirizine pharmacokinetics has not been adequately
studied.
Effect of Race: No race-related differences in the kinetics of cetirizine have been observed.
Renal Impairment: The kinetics of cetirizine were studied following multiple, oral, 10-mg daily
doses of cetirizine for 7 days in 7 normal volunteers (creatinine clearance 89-128 mL/min),
8 patients with mild renal function impairment (creatinine clearance 42-77 mL/min) and
7 patients with moderate renal function impairment (creatinine clearance 11-31 mL/min). The
pharmacokinetics of cetirizine were similar in patients with mild impairment and normal
volunteers. Moderately impaired patients had a 3-fold increase in half-life and a 70% decrease in
clearance compared to normal volunteers.
Patients on hemodialysis (n=5) given a single, 10-mg dose of cetirizine had a 3-fold increase in
half-life and a 70% decrease in clearance compared to normal volunteers. Less than 10% of the
administered dose was removed during the single dialysis session.
Dosing adjustment is necessary in patients with moderate or severe renal impairment and in
patients on dialysis (see DOSAGE AND ADMINISTRATION).
Hepatic Impairment: Sixteen patients with chronic liver diseases (hepatocellular, cholestatic,
and biliary cirrhosis), given 10 or 20 mg of cetirizine as a single, oral dose had a 50% increase in
half-life along with a corresponding 40% decrease in clearance compared to 16 healthy subjects.
Dosing adjustment may be necessary in patients with hepatic impairment (see DOSAGE AND
ADMINISTRATION).
Pharmacodynamics: Studies in 69 adult normal volunteers (aged 20 to 61 years) showed that
ZYRTEC at doses of 5 and 10 mg strongly inhibited the skin wheal and flare caused by the
intradermal injection of histamine. The onset of this activity after a single 10-mg dose occurred
within 20 minutes in 50% of subjects and within one hour in 95% of subjects; this activity
persisted for at least 24 hours. ZYRTEC at doses of 5 and 10 mg also strongly inhibited the
wheal and flare caused by intradermal injection of histamine in 19 pediatric volunteers (aged 5 to
12 years) and the activity persisted for at least 24 hours. In a 35-day study in children aged 5 to
12, no tolerance to the antihistaminic (suppression of wheal and flare response) effects of
ZYRTEC was found. In 10 infants 7 to 25 months of age who received 4 to 9 days of cetirizine in
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an oral solution (0.25 mg/kg bid), there was a 90% inhibition of histamine-induced (10 mg/mL)
cutaneous wheal and 87% inhibition of the flare 12 hours after administration of the last dose.
The clinical relevance of this suppression of histamine-induced wheal and flare response on skin
testing is unknown.
The effects of intradermal injection of various other mediators or histamine releasers were also
inhibited by cetirizine, as was response to a cold challenge in patients with cold-induced
urticaria. In mildly asthmatic subjects, ZYRTEC at 5 to 20 mg blocked bronchoconstriction due
to nebulized histamine, with virtually total blockade after a 20-mg dose. In studies conducted for
up to 12 hours following cutaneous antigen challenge, the late phase recruitment of eosinophils,
neutrophils and basophils, components of the allergic inflammatory response, was inhibited by
ZYRTEC at a dose of 20 mg.
In four clinical studies in healthy adult males, no clinically significant mean increases in QTc
were observed in ZYRTEC treated subjects. In the first study, a placebo-controlled crossover
trial, ZYRTEC was given at doses up to 60 mg per day, 6 times the maximum clinical dose, for
1 week, and no significant mean QTc prolongation occurred. In the second study, a crossover
trial, ZYRTEC 20 mg and erythromycin (500 mg every 8 hours) were given alone and in
combination. There was no significant effect on QTc with the combination or with ZYRTEC
alone. In the third trial, also a crossover study, ZYRTEC 20 mg and ketoconazole (400 mg per
day) were given alone and in combination. ZYRTEC caused a mean increase in QTc of 9.1 msec
from baseline after 10 days of therapy. Ketoconazole also increased QTc by 8.3 msec. The
combination caused an increase of 17.4 msec, equal to the sum of the individual effects. Thus,
there was no significant drug interaction on QTc with the combination of ZYRTEC and
ketoconazole. In the fourth study, a placebo-controlled parallel trial, ZYRTEC 20 mg was given
alone or in combination with azithromycin (500 mg as a single dose on the first day followed by
250 mg once daily). There was no significant increase in QTc with ZYRTEC 20 mg alone or in
combination with azithromycin.
In a four-week clinical trial in pediatric patients aged 6 to 11 years, results of randomly obtained
ECG measurements before treatment and after 2 weeks of treatment showed that ZYRTEC 5 or
10 mg did not increase QTc versus placebo. In a one week clinical trial (N=86) of ZYRTEC
syrup (0.25 mg/kg bid) compared with placebo in pediatric patients 6 to 11 months of age, ECG
measurements taken within 3 hours of the last dose did not show any ECG abnormalities or
increases in QTc interval in either group compared to baseline assessments. Data from other
studies where ZYRTEC was administered to patients 6-23 months of age were consistent with
the findings in this study.
The effects of ZYRTEC on the QTc interval at doses higher than 10 mg have not been studied in
children less than 12 years of age.
In a six-week, placebo-controlled study of 186 patients (aged 12 to 64 years) with allergic rhinitis
and mild to moderate asthma, ZYRTEC 10 mg once daily improved rhinitis symptoms and did
not alter pulmonary function. In a two-week, placebo-controlled clinical trial, a subset analysis of
65 pediatric (aged 6 to 11 years) allergic rhinitis patients with asthma showed ZYRTEC did not
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alter pulmonary function. These studies support the safety of administering ZYRTEC to pediatric
and adult allergic rhinitis patients with mild to moderate asthma.
Clinical Studies: Nine multicenter, randomized, double-blind, clinical trials comparing
cetirizine 5 to 20 mg to placebo in patients 12 years and older with seasonal or perennial allergic
rhinitis were conducted in the United States. Five of these showed significant reductions in
symptoms of allergic rhinitis, 3 in seasonal allergic rhinitis (1 to 4 weeks in duration) and 2 in
perennial allergic rhinitis for up to 8 weeks in duration. Two 4-week multicenter, randomized,
double-blind, clinical trials comparing cetirizine 5 to 20 mg to placebo in patients with chronic
idiopathic urticaria were also conducted and showed significant improvement in symptoms of
chronic idiopathic urticaria. In general, the 10-mg dose was more effective than the 5-mg dose
and the 20-mg dose gave no added effect. Some of these trials included pediatric patients aged 12
to 16 years. In addition, four multicenter, randomized, placebo-controlled, double-blind 2-4 week
trials in 534 pediatric patients aged 6 to 11 years with seasonal allergic rhinitis were conducted in
the United States at doses up to 10 mg.
INDICATIONS AND USAGE
Seasonal Allergic Rhinitis: ZYRTEC is indicated for the relief of symptoms associated with
seasonal allergic rhinitis due to allergens such as ragweed, grass and tree pollens in adults and
children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea,
nasal pruritus, ocular pruritus, tearing, and redness of the eyes.
Perennial Allergic Rhinitis: ZYRTEC is indicated for the relief of symptoms associated with
perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in adults
and children 6 months of age and older. Symptoms treated effectively include sneezing,
rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.
Chronic Urticaria: ZYRTEC is indicated for the treatment of the uncomplicated skin
manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older. It
significantly reduces the occurrence, severity, and duration of hives and significantly reduces
pruritus.
CONTRAINDICATIONS
ZYRTEC is contraindicated in those patients with a known hypersensitivity to it or any of its
ingredients or hydroxyzine.
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PRECAUTIONS
Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has
been reported in some patients taking ZYRTEC; due caution should therefore be exercised when
driving a car or operating potentially dangerous machinery. Concurrent use of ZYRTEC with
alcohol or other CNS depressants should be avoided because additional reductions in alertness
and additional impairment of CNS performance may occur.
Drug-Drug Interactions: No clinically significant drug interactions have been found with
theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There
was a small decrease in the clearance of cetirizine caused by a 400-mg dose of theophylline; it is
possible that larger theophylline doses could have a greater effect.
Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year carcinogenicity study in
rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the
maximum recommended daily oral dose in adults on a mg/m2 basis, or approximately 7 times the
maximum recommended daily oral dose in infants on a mg/m2 basis). In a 2-year carcinogenicity
study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a
dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in
adults on a mg/m2 basis, or approximately 3 times the maximum recommended daily oral dose in
infants on a mg/m2 basis). No increase in the incidence of liver tumors was observed in mice at a
dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in
adults on a mg/m2 basis, or approximately equivalent to the maximum recommended daily oral
dose in infants on a mg/m2 basis). The clinical significance of these findings during long-term
use of ZYRTEC is not known.
Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte
assay, the mouse lymphoma assay, and in vivo micronucleus test in rats.
In a fertility and general reproductive performance study in mice, cetirizine did not impair
fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum recommended daily
oral dose in adults on a mg/m2 basis).
Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up
to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum
recommended daily oral dose in adults on a mg/m2 basis). There are no adequate and
well-controlled studies in pregnant women. Because animal studies are not always predictive of
human response, ZYRTEC should be used in pregnancy only if clearly needed.
Nursing Mothers: In mice, cetirizine caused retarded pup weight gain during lactation at an oral
dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose
in adults on a mg/m2 basis). Studies in beagle dogs indicated that approximately 3% of the dose
was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because
many drugs are excreted in human milk, use of ZYRTEC in nursing mothers is not
recommended.
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Geriatric Use: Of the total number of patients in clinical studies of ZYRTEC, 186 patients were
65 years and older, and 39 patients were 75 years and older. No overall differences in safety
were observed between these patients and younger patients, but greater sensitivity of some older
individuals cannot be ruled out. With regard to efficacy, clinical studies of ZYRTEC for each
approved indication did not include sufficient numbers of patients aged 65 years and older to
determine whether they respond differently than younger patients.
ZYRTEC is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function. (See Geriatric Patients and Renal Impairment subsections in
CLINICAL PHARMACOLOGY).
Pediatric Use: The safety of ZYRTEC has been demonstrated in pediatric patients aged 6
months to 11 years. The safety of ZYRTEC, at daily doses of 5 or 10 mg, has been demonstrated
in 376 pediatric patients aged 6 to 11 years in placebo-controlled trials lasting up to four weeks
and in 254 patients in a non-placebo-controlled 12-week trial. The safety of cetirizine has been
demonstrated in 168 patients aged 2 to 5 years in placebo-controlled trials of up to 4 weeks
duration. On a mg/kg basis, most of the 168 patients received between 0.2 and 0.4 mg/kg of
cetirizine HCl. The safety of cetirizine in 399 patients aged 12 to 24 months has been
demonstrated in a placebo-controlled 18-month trial, in which the average dose was 0.25 mg/kg
bid, corresponding to a range of 4 to 11 mg/day. The safety of ZYRTEC syrup has been
demonstrated in 42 patients aged 6 to 11 months in a placebo-controlled 7-day trial. The
prescribed dose was 0.25 mg/kg bid, which corresponded to a mean of 4.5 mg/day, with a range
of 3.4 to 6.2 mg/day.
The effectiveness of ZYRTEC for the treatment of allergic rhinitis and chronic idiopathic
urticaria in pediatric patients aged 6 months to 11 years is based on an extrapolation of the
demonstrated efficacy of ZYRTEC in adults inwith these conditions and the likelihood that the
disease course, pathophysiology and the drug’s effect are substantially similar between these two
populations. Efficacy is extrapolated down to 6 months of age for perennial allergic rhinitis and
down to 2 years of age for seasonal allergic
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