Oral cetirizine hydrochloride

The following adverse reactions associated with the use of oral cetirizine hydrochloride were identified in clinical trials.

In clinical trials in patients 12 years and older the most common adverse reactions to oral cetirizine hydrochloride occurring with a 2% or greater incidence and greater than placebo were somnolence (14%), fatigue (6%), dry mouth (5%), pharyngitis (2%), and dizziness (2%). In clinical trials in children 6 to 11 years of age with oral cetirizine hydrochloride the most common adverse reactions occurring with a 2% or greater incidence and greater than placebo were headache, pharyngitis, abdominal pain, coughing, somnolence, diarrhea, epistaxis, bronchospasm, nausea, and vomiting. Somnolence appeared to be dose related. Adverse reactions reported in placebo-controlled trials with oral cetirizine hydrochloride in pediatric patients 2 to 5 years were qualitatively similar in nature and generally similar in frequency to those reported in trials with children 6 to 11 years of age. In placebo-controlled trials of pediatric patients 6 to 24 months of age, the incidences of adverse experiences were similar in the oral cetirizine hydrochloride and placebo treatment groups in each trial. In a trial of 1 week duration in children 6 to 11 months of age patients who received oral cetirizine hydrochloride exhibited greater irritability/fussiness than patients on placebo. In a trial of 18 months duration in patients 12 months and older, insomnia occurred more frequently in patients who received oral cetirizine hydrochloride compared to patients who received placebo.

QUZYTTIR

The safety data of QUZYTTIR was evaluated in a randomized, double-blind, single-dose, non-inferiority study comparing QUZYTTIR to intravenous diphenhydramine in 262 adults with acute urticaria.

The adverse reactions with QUZYTTIR occurred at an incidence of less than 1% and include: dyspepsia, feeling hot, dysgeusia, headache, paresthesia, presyncope, and hyperhidrosis.

An additional randomized, double-blind, single dose study was conducted in 33 adults which showed similar safety results.

Sedation

Subject-rated sedation scores were assessed at baseline, 1 hr, and/or 2 hrs, and/or "Readiness for Discharge”. Sedation was rated on a 0 to 3 scale (0 = none, to 3 = severe) with lower sedation scores indicating less sedation. Subjects in the QUZYTTIR treatment group reported less sedation at all time points compared to subjects treated with diphenhydramine.

Risk Summary

There are no adequate and well-controlled studies in pregnant women with cetirizine hydrochloride the active ingredient in QUZYTTIR. In animal reproduction studies, there was no evidence of fetal harm with administration of cetirizine hydrochloride by the oral route to pregnant mice, rats, and rabbits, during the period of organogenesis, at doses that were 45 times and higher than the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine hydrochloride had no effects on pup development at oral doses up to approximately 30 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine hydrochloride administered by the oral route to the dams had no effects on pup development at a dose that was approximately 10 times the MRHD in adults; however, lower pup weight gain during lactation was observed at a dose that was 45 times the MRHD in adults (See Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively.

Data

Risk Summary

Cetirizine hydrochloride has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine hydrochloride was excreted in milk (See Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QUZYTTIR and any potential adverse effects on the breastfed child from QUZYTTIR or from the underlying maternal condition.

Data

Cardiac Electrophysiology

In four clinical studies in healthy adult males, no clinically significant mean increases in QTc were observed in subjects treated with cetirizine hydrochloride oral tablets. In the first study, a placebo-controlled crossover trial, cetirizine hydrochloride oral tablets were 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 oral tablets 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 oral tablet 20 mg and ketoconazole (400 mg per day) were given alone and in combination. Cetirizine 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 and ketoconazole. In the fourth study, a placebo-controlled parallel trial, cetirizine hydrochloride oral tablet 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 oral tablet 5 or 10 mg did not increase QTc versus placebo. In a one week clinical trial (N=86) of cetirizine hydrochloride oral 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 cetirizine hydrochloride oral 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.

Absorption

Following oral administration of tablets or syrup in adults, cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of approximately 1 hour. When healthy volunteers were administered multiple doses of cetirizine hydrochloride (10 mg oral tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/mL was observed and there was no accumulation. 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 when cetirizine hydrochloride was administered orally.

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.

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.

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.

Excretion

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.

Specific Populations

Drug Interaction Studies

No interactions were observed in pharmacokinetic interaction studies conducted with oral cetirizine hydrochloride and pseudoephedrine, antipyrine, ketoconazole, erythromycin and azithromycin. In a multiple dose study of theophylline (400 mg once daily for 3 days) and cetirizine hydrochloride (20 mg oral tablets 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 hydrochloride administration.

Carcinogenesis

In a 2-year carcinogenicity study in rats, cetirizine hydrochloride was not carcinogenic at dietary doses up to 20 mg/kg (approximately 20, 10, 25, and 6 times the MRHDs in adults, children 6 to 11 years of age, children 2 to 5 years of age, and children 6 months to less than 2 years of age, respectively, on a mg/m2 basis). In a 2-year carcinogenicity study in mice, cetirizine hydrochloride caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 8, 4, 9, and 2 times the MRHDs in adults, children 6 to 11 years of age, children 2 to 5 years of age, and children 6 months to less than 2 years of age, respectively, on a mg/m2 basis). No increased incidence of benign hepatic tumors was observed in mice at a dietary dose of 4 mg/kg (approximately 2, 1, 2, and 0.5 times the MRHDs in adults, children 6 to 11 years of age, children 2 to 5 years of age, and children 6 months to less than 2 years of age, respectively, on a mg/m 2 basis). The clinical significance of these findings during long-term use of QUZYTTIR is not known.

Mutagenesis

Cetirizine hydrochloride 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.

Impairment of Fertility

Fertility and reproductive performance were unaffected in male and female mice and rats that received cetirizine hydrochloride at oral doses up to 64 and 200 mg/kg/day, respectively (approximately 30 and 190 times the MRHD in adults on a mg/m2 basis).