CETIRIZINE HYDROCHLORIDE 1 mg/mL Solution, 120 mL — NDC 16571-134-12 (Billing 16571-0134-12)

CLINICAL PHARMACOLOGY Mechanism of Actions Cetirizine, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H 1 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 H 1 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 H 1 receptors. Pharmacokinetics Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (T max ) of approximately 1 hour following oral administration of tablets or oral solution in adults. Comparable bioavailability was found between the tablet and oral solution 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 to 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 cetirizine the mean C max 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 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 oral 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 tabl… [Excerpted — this section continues on DailyMed.]

Pharmacokinetics Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (T max ) of approximately 1 hour following oral administration of tablets or oral solution in adults. Comparable bioavailability was found between the tablet and oral solution 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 to 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.

Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (T max ) of approximately 1 hour following oral administration of tablets or oral solution in adults. Comparable bioavailability was found between the tablet and oral solution 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 to 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 cond… [Excerpted — this section continues on DailyMed.]

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, USP (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 to 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… [Excerpted — this section continues on DailyMed.]

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 to 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.