s, the incidence of discontinuations due to adverse reactions in pediatric patients receiving up to 10 mg of cetirizine hydrochloride was uncommon (0.4% on cetirizine hydrochloride vs. 1.0% on placebo). table 1 lists adverse experiences which were reported for cetirizine hydrochloride 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 cetirizine hydrochloride 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. in the placebo-controlled trials of pediatric patients 6 to 24 months of age, the incidences of adverse experiences, were similar in the cetirizine and placebo treatment groups in each study. somnolence occurred with essentially the same frequency in patients who received cetirizine and patients who received placebo. in a study of 1 week duration in children 6-11 months of age, patients who received cetirizine exhibited greater irritability/fussiness than patients on placebo. in a study of 18 months duration in patients 12 months and older, insomnia occurred more frequently in patients who received cetirizine compared to patients who received placebo (9.0% v. 5.3%). in those patients who received 5 mg or more per day of cetirizine as compared to patients who received placebo, fatigue (3.6% v. 1.3%) and malaise (3.6% v. 1.8%) occurred more frequently. table 1 adverse experiences reported in pediatric patients aged 6 to 11 years in placebo-controlled united states cetirizine hydrochloride trials (5 or 10 mg dose) which occurred at a frequency of ≥ 2% in either the 5-mg or the 10-mg cetirizine hydrochloride group, and more frequently than in the placebo group adverse experiences placebo (n=309) cetirizine hydrochloride 5 mg (n=161) 10 mg (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 cetirizine hydrochloride in u.s. trials, including an open adult study of six months duration. a causal relationship of these infrequent events with cetirizine hydrochloride 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 cetirizine hydrochloride has been reported. post-marketing experience in the post-marketing period, the following additional rare, but potentially severe adverse events have been reported: aggressive reaction, anaphylaxis, cholestasis, convulsions, glomerulonephritis, hallucinations, hemolytic anemia, hepatitis, orofacial dyskinesia, severe hypotension, stillbirth, suicidal ideation, suicide, thrombocytopenia, acute generalized exanthematous postulosis (agep) and rebound pruritus-pruritus within a few days after discontinuation of cetirizine, usually after long-term use (e.g., months to years) of cetirizine.

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 (c max ) 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 t max was delayed by 1.7 hours and c max 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: in pediatric patients aged 2 to 5 years who received 5 mg of cetirizine, the mean c max was 660 ng/ml. based on cross study comparisons, the weight normalized, apparent total body clearance was 81-111% greater and the elimination half life was 33 to 41% shorter in the 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 c max 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 average auc(0-t) in children 6 months to <2 years of age receiving the maximum dose of cetirizine solution (2.5 mg 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. 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. pharmacodynamics: cetirizine hydrochloride at doses of 5 and 10 mg 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 cetirizine hydrochloride was found. in 10 infants 7 to 25 months of age who received 4 to 9 days of cetirizine in 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, cetirizine hydrochloride 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 cetirizine hydrochloride at a dose of 20 mg. in four clinical studies in healthy adult males, no clinically significant mean increases in qtc were observed in cetirizine hydrochloride treated subjects. in the first study, a placebo-controlled crossover trial, cetirizine hydrochloride 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, cetirizine hydrochloride 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 cetirizine hydrochloride alone. in the third trial, also a crossover study, cetirizine hydrochloride 20 mg and ketoconazole (400 mg per day) were given alone and in combination. cetirizine hydrochloride 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 cetirizine hydrochloride and ketoconazole. in the fourth study, a placebo-controlled parallel trial, cetirizine hydrochloride 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 cetirizine hydrochloride 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 cetirizine hydrochloride 5 or 10 mg did not increase qtc versus placebo. in a one week clinical trial (n=86) of cetirizine hydrochloride oral solution (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 cetirizine hydrochloride was administered to patients 6-23 months of age were consistent with the findings in this study. the effects of cetirizine hydrochloride 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, cetirizine hydrochloride 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 cetirizine hydrochloride did not alter pulmonary function. these studies support the safety of administering cetirizine hydrochloride to pediatric and adult allergic rhinitis patients with mild to moderate asthma. clinical studies: multicenter, randomized, double-blind, clinical trials comparing cetirizine 5 to 20 mg to placebo in patients 12 years and older with perennial allergic rhinitis were conducted in the united states. two of these showed significant reductions in symptoms of 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.