cetirizine hydrochloride
DESCRIPTION:
Cetirizine hydrochloride, the active component of ZYRTEC(R) 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:
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.
ACTIONS/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.
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.
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 to 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. 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 250mg once daily). There was no significant increase in OTc 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 significantly increase QTc
versus placebo. The effects of ZYRTEC on the QTc interval at doses higher than
the 10 mg dose have not been studied in children less than 12 years of age. The
effect of ZYRTEC on the QTc interval in children less than 6 years of age has
not been studied.
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 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 2 years 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 2
years 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.
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/m(squared) basis, or approximately 10 times the maximum
recommended daily oral dose in children on a mg/m(squared) 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/m(squared)
basis, or approximately 4 times the maximum recommended daily oral dose in
children on a mg/m(squared) 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/m(squared) basis, or
approximately equal to the maximum recommended daily oral dose in children on a
mg/m(squared) 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/m(squared) 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/m(squared) 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/m(squared) 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.
GERIATRIC USE: In placebo-controlled trials, 186 patients aged 65 to 94 years
received doses of 5 to 20 mg of ZYRTEC per day. Adverse events were similar in
this group to patients under age 65. Subset analysis of efficacy in this group
was not done.
PEDIATRIC USE: 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 effectiveness of ZYRTEC for the treatment of seasonal and perennial allergic
rhinitis and chronic idiopathic urticaria in pediatric patients aged 2 to 11
years is based on an extrapolation of the demonstrated efficacy of ZYRTEC in
adults in these conditions and the likelihood that the disease course,
pathophysiology and the drug's effect are substantially similar between these
two populations. The recommended doses for the pediatric population are based on
cross-study comparisons of the pharmacokinetics and pharmacodynamics of
cetirizine in adult and pediatric subjects and on the safety profile of
cetirizine in both adult and pediatric patients at doses equal to or higher than
the recommended doses. The cetirizine AUC and Cmax in pediatric subjects aged 2
to 5 years who received a single dose of 5 mg of cetirizine syrup and in
pediatric subjects aged 6 to 11 years who received a single dose of 10 mg of
cetirizine syrup were estimated to be intermediate between that observed in
adults who received a single dose of 10 mg of cetirizine tablets and those who
received a single dose of 20 mg of cetirizine tablets.
The safety and effectiveness of cetirizine in pediatric patients under the age
of 2 years have not yet been established.
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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Controlled and uncontrolled clinical trials conducted in the United States and
Canada included more than 6000 patients aged 12 years and older, with more than
3900 receiving ZYRTEC at doses of 5 to 20 mg per day. The duration of treatment
ranged from 1 week to 6 months, with a mean exposure of 30 days.
Most adverse reactions reported during therapy with ZYRTEC were mild or
moderate. In placebo- controlled trials, the incidence of discontinuations due
to adverse reactions in patients receiving ZYRTEC 5 or 10 mg was not
significantly different from placebo (2.9% vs. 2.4%, respectively).
The most common adverse reaction in patients aged 12 years and older that
occurred more frequently on ZYRTEC than placebo was somnolence. The incidence of
somnolence associated with ZYRTEC was dose related, 6% in placebo, 11% at 5 mg
and 14% at 10 mg. Discontinuations due to somnolence for ZYRTEC were uncommon
(1.0% on ZYRTEC vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be
treatment-related adverse reactions. There were no differences by age, race,
gender or by body weight with regard to the incidence of adverse reactions.
Table 1 lists adverse experiences in patients aged 12 years and older which were
reported for ZYRTEC 5 and 10 mg in controlled clinical trials in the United
States and that were more common with ZYRTEC than placebo.
TABLE 1.
ADVERSE EXPERIENCES REPORTED IN PATIENTS AGED 12 YEARS
AND OLDER IN PLACEBO-CONTROLLED UNITED STATES ZYRTEC
TRIALS (MAXIMUM DOSE OF 10 MG) AT RATES OF 2% OR
GREATER (PERCENT INCIDENCE)
ADVERSE ZYRTEC PLACEBO
EXPERIENCE (N=2034) (N=1612)
Somnolence 13.7 6.3
Fatigue 5.9 2.6
Dry Mouth 5.0 2.3
Pharyngitis 2.0 1.9
Dizziness 2.0 1.2
In addition, headache and nausea occurred in more than 2% of the patients, but
were more common in placebo patients.
Pediatric studies were also conducted with ZYRTEC. More than 1300 pediatric
patients aged 6 to 11 years with more than 900 treated with ZYRTEC at doses of
1.25 to 10 mg per day were included in controlled and uncontrolled clinical
trials conducted in the United States. The duration of treatment ranged from 2
to 12 weeks. Placebo-controlled trials up to 4 weeks duration included 168
pediatric patients aged 2 to 5 years who received cetirizine, the majority of
whom received single daily doses of 5 mg.
The majority of adverse reactions reported in pediatric patients aged 2 to 11
years with ZYRTEC were mild or moderate. In placebo-controlled trials, the
incidence of discontinuations due to adverse reactions in pediatric patients
receiving up to 10 mg of ZYRTEC was uncommon (0.4% on ZYRTEC vs. 1.0% on
placebo).
Table 2 lists adverse experiences which were reported for ZYRTEC 5 and 10 mg in
pediatric patients aged 6 to 11 years in placebo-controlled clinical trials in
the United States and were more common with ZYRTEC than placebo. Of these,
abdominal pain was considered treatment-related and somnolence appeared to be
dose-related, 1.3% in placebo, 1.9% at 5 mg and 4.2% at 10 mg. The adverse
experiences reported in pediatric patients aged 2 to 5 years in placebo-
controlled trials were qualitatively similar in nature and generally similar in
frequency to those reported in trials with children aged 6 to 11 years.
TABLE 2.
ADVERSE EXPERIENCES REPORTED IN PEDIATRIC PATIENTS AGED
6 TO 11 YEARS IN PLACEBO-CONTROLLED UNITED STATES ZYRTEC
TRIALS (5 OR 10 MG DOSE) WHICH OCCURRED AT A FREQUENCY
OF (>/=)2% IN EITHER THE 5-MG OR THE 10-MG ZYRTEC GROUP,
AND MORE FREQUENTLY THAN IN THE PLACEBO GROUP
ZYRTEC
ADVERSE EXPERIENCES PLACEBO 5 MG 10 MG
(N=309) (N=161) (N=215)
Headache 12.3% 11.0% 14.0%
Pharyngitis 2.9% 6.2% 2.8%
Abdominal pain 1.9% 4.4% 5.6%
Coughing 3.9% 4.4% 2.8%
Somnolence 1.3% 1.9% 4.2%
Diarrhea 1.3% 3.1% 1.9%
Epistaxis 2.9% 3.7% 1.9%
Bronchospasm 1.9% 3.1% 1.9%
Nausea 1.9% 1.9% 2.8%
Vomiting 1.0% 2.5% 2.3%
The following events were observed infrequently (less than 2%), in either 3982
adults and children 12 years and older or in 659 pediatric patients aged 6 to 11
years who received ZYRTEC in U.S. trials, including an open adult study of six
months duration. A causal relationship of these infrequent events with ZYRTEC
administration has not been established.
AUTONOMIC NERVOUS SYSTEM: anorexia, flushing, increased salivation, urinary
retention.
CARDIOVASCULAR: cardiac failure, hypertension, palpitation, tachycardia.
CENTRAL AND PERIPHERAL NERVOUS SYSTEMS: abnormal coordination, ataxia,
confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg
cramps, migraine, myelitis, paralysis, paresthesia, ptosis, syncope, tremor,
twitching, vertigo, visual field defect.
GASTROINTESTINAL: abnormal hepatic function, aggravated tooth caries,
constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids,
increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative
stomatitis, tongue discoloration, tongue edema.
GENITOURINARY: cystitis, dysuria, hematuria, micturition frequency, polyuria,
urinary incontinence, urinary tract infection.
HEARING AND VESTIBULAR: deafness, earache, ototoxicity, tinnitus.
METABOLIC/NUTRITIONAL: dehydration, diabetes mellitus, thirst.
MUSCULOSKELETAL: arthralgia, arthritis, arthrosis, muscle weakness, myalgia.
PSYCHIATRIC: abnormal thinking, agitation, amnesia, anxiety, decreased libido,
depersonalization, depression, emotional lability, euphoria, impaired
concentration, insomnia, nervousness, paroniria, sleep disorder.
RESPIRATORY SYSTEM: bronchitis, dyspnea, hyperventilation, increased sputum,
pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract
infection.
REPRODUCTIVE: dysmenorrhea, female breast pain, intermenstrual bleeding,
leukorrhea, menorrhagia, vaginitis.
RETICULOENDOTHELIAL: lymphadenopathy.
SKIN: acne, alopecia, angioedema, bullous eruption, dermatitis, dry skin,
eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis,
increased sweating, maculopapular rash, photosensitivity reaction,
photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin
disorder, skin nodule, urticaria.
SPECIAL SENSES: parosmia, taste loss, taste perversion.
VISION: blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation,
ocular hemorrhage, xerophthalmia.
BODY AS A WHOLE: accidental injury, asthenia, back pain, chest pain, enlarged
abdomen, face edema, fever, generalized edema, hot flashes, increased weight,
leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral
edema, rigors.
Occasional instances of transient, reversible hepatic transaminase elevations
have occurred during cetirizine therapy. Hepatitis with significant transaminase
elevation and elevated bilirubin in association with the use of ZYRTEC has been
reported.
In foreign marketing experience the following additional rare, but potentially
severe adverse events have been reported: anaphylaxis, cholestasis,
glomerulonephritis, hemolytic anemia, hepatitis, orofacial dyskinesia, severe
hypotension, stillbirth, and thrombocytopenia.
DRUG ABUSE AND DEPENDENCE:
There is no information to indicate that abuse or dependency occurs with ZYRTEC.
OVERDOSAGE:
Overdosage has been reported with ZYRTEC. In one adult patient who took 150 mg
of ZYRTEC, the patient was somnolent but did not display any other clinical
signs or abnormal blood chemistry or hematology results. In an 18 month old
pediatric patient who took an overdose of ZYRTEC (approximately 180 mg),
restlessness and irritability were observed initially; this was followed by
drowsiness. Should overdose occur, treatment should be symptomatic or
supportive, taking into account any concomitantly ingested medications. There is
no known specific antidote to ZYRTEC. ZYRTEC is not effectively removed by
dialysis, and dialysis will be ineffective unless a dialyzable agent has been
concomitantly ingested. The acute minimal lethal oral doses were 237 mg/kg in
mice (approximately 95 times the maximum recommended daily oral dose in adults
on a mg/m(squared) basis, or approximately 55 times the maximum recommended
daily oral dose in children on a mg/m(squared) basis) and 562 mg/kg in rats
(approximately 460 times the maximum recommended daily oral dose in adults on a
mg/m(squared) basis, or approximately 270 times the maximum recommended daily
oral dose in children on a mg/m(squared) basis). In rodents, the target of acute
toxicity was the central nervous system, and the target of multiple-dose
toxicity was the liver.
DOSAGE AND ADMINISTRATION:
ADULTS AND CHILDREN 12 YEARS AND OLDER: The recommended initial dose of ZYRTEC
is 5 or 10 mg per day in adults and children 12 years and older, depending on
symptom severity. Most patients in clinical trials started at 10 mg. ZYRTEC is
given as a single daily dose, with or without food. The time of administration
may be varied to suit individual patient needs.
CHILDREN 6 TO 11 YEARS: The recommended initial dose of ZYRTEC in children aged
6 to 11 years is 5 or 10 mg (1 or 2 teaspoons) once daily depending on symptom
severity. The time of administration may be varied to suit individual patient
needs.
CHILDREN 2 TO 5 YEARS: The recommended initial dose of ZYRTEC syrup in children
aged 2 to 5 years is 2.5 mg ( 1/2 teaspoon) once daily. The dosage in this age
group can be increased to a maximum dose of 5 mg per day given as 1 teaspoon (5
mg) once daily, or as 1/2 teaspoon (2.5 mg) given every 12 hours, depending on
symptom severity and patient response.
DOSE ADJUSTMENT FOR RENAL AND HEPATIC IMPAIRMENT: In patients 12 years of age
and older with decreased renal function (creatinine clearance 11-31 mL/min),
patients on hemodialysis (creatinine clearance less than 7 mL/min), and in
hepatically impaired patients, a dose of 5 mg once daily is recommended.
Similarly, pediatric patients aged 6 to 11 years with impaired renal or hepatic
function should use the lower recommended dose. Because of the difficulty in
reliably administering doses of less than 2.5 mg ( 1/2 teaspoon) of ZYRTEC syrup
and in the absence of pharmacokinetic and safety information for cetirizine in
children below the age of 6 years with impaired renal or hepatic function, its
use in this impaired patient population is not recommended.
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