Mechanisms of Action
Cetirizine, a metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of 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 trials, 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.
Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.
The bioavailability of cetirizine hydrochloride and pseudoephedrine hydrochloride from ZYRTEC-D 12 HOUR Extended Release Tablets is not significantly different from that achieved with separate administration of a cetirizine 5 mg tablet and a pseudoephedrine 120 mg extended release caplet. Co-administration of cetirizine and pseudoephedrine does not significantly affect the bioavailability of either component.
Following a single dose of the ZYRTEC-D 12 HOUR Extended Release Tablet, a mean peak plasma concentration (Cmax) of 114 ng/mL at a time (Tmax) of 2.2 hours postdose was observed for cetirizine and a mean Cmax of 309 ng/mL at a Tmax of 4.4 hours postdose was observed for pseudoephedrine.
When healthy volunteers were administered multiple doses of the ZYRTEC-D 12 HOUR Extended Release Tablet to reach steady-state concentrations (cetirizine hydrochloride 5 mg and pseudoephedrine hydrochloride 120 mg twice daily for seven days), a mean Cmax of 178 ng/mL was observed for cetirizine and 526 ng/mL for pseudoephedrine.
Food had no significant effect on the extent of cetirizine absorption (AUC), but Tmax was delayed by 1.8 hours and Cmax was decreased by 30%. Food had no significant effect on the pharmacokinetics of pseudoephedrine. ZYRTEC-D 12 HOUR Extended Release Tablets may be given with or without food (see DOSAGE AND ADMINISTRATION).
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. The apparent volume of distribution (V/F) of pseudoephedrine has been reported to be 2.6–3.3 L/kg. No plasma protein binding data in humans are available.
A human mass balance study of cetirizine 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 low 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.
One to seven percent of the pseudoephedrine dose appeared to be metabolized to norpseudoephedrine by N-demethylation after a single dose.
After administration of the ZYRTEC-D 12 HOUR Extended Release Tablet, the mean elimination half-life of cetirizine was 7.9 hours and the mean elimination half-life of pseudoephedrine was 6.0 hours.
It was reported that 0.4–0.7% of the pseudoephedrine dose was estimated to be excreted in the breast milk over 24 hours after a single dose. The pattern of the relative milk/plasma drug concentration profile showed that pseudoephedrine concentrations in milk were 2- to 3-fold higher than those in plasma.
Pharmacokinetic interaction trials 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.
Although cetirizine pharmacokinetics have been studied in children, ZYRTEC-D 12 HOUR Extended Release Tablets contain 120 mg of pseudoephedrine hydrochloride, which exceeds the recommended dose for patients less than 12 years of age. Therefore, ZYRTEC-D 12 HOUR Extended Release Tablets are not recommended for patients under 12 years of age.
Following a single, 10-mg oral dose of cetirizine, 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.
The pharmacokinetics of pseudoephedrine has not been adequately studied in geriatric subjects.
The effect of gender on cetirizine or pseudoephedrine pharmacokinetics has not been adequately studied.
The effect of race on cetirizine or pseudoephedrine pharmacokinetics has not been adequately studied.
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.
About 55–75% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine; the remainder is apparently metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal insufficiency.
Dosing adjustment is necessary in patients with moderate or severe renal impairment and in patients on dialysis (see DOSAGE AND ADMINISTRATION).
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.
The effect of hepatic impairment on pseudoephedrine pharmacokinetics is unknown.
Dosing adjustment may be necessary in patients with hepatic impairment (see DOSAGE AND ADMINISTRATION).
Trials in 69 adult normal volunteers (aged 20–61 years) showed that cetirizine at doses of 5 and 10 mg 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. The effects of intradermal injection of various other mediators or histamine releasers were also inhibited by cetirizine. In mildly asthmatic subjects, cetirizine at 5 to 20 mg blocked bronchoconstriction due to nebulized histamine, with virtually total blockade after a 20 mg dose. In trials 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 at a dose of 20 mg. The clinical significance of these findings is not known.
In four clinical trials in healthy adult males, no clinically significant mean increases in QTc were observed in cetirizine treated subjects. In the first study, a placebo-controlled crossover trial, cetirizine 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 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 alone. In the third trial, also a crossover study, cetirizine 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 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 20 mg alone or in combination with azithromycin.
In a six-week, placebo-controlled study of 186 patients (aged 12–64 years) with allergic rhinitis and mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic rhinitis patients with mild to moderate asthma.
ZYRTEC-D 12 HOUR Extended Release Tablets
Two multicenter, randomized, double-blind, placebo-controlled clinical trials (n=1094 and n=1000) comparing ZYRTEC -D 12 HOUR Extended Release Tablets (cetirizine hydrochloride 5 mg and pseudoephedrine hydrochloride 120 mg) to active control and placebo for two weeks in patients 12 years and older with seasonal allergic rhinitis were conducted in the United States. In the two trials, 390 patients were aged 12 to 17 years. The primary efficacy measure in both trials was the mean change from baseline in the subject-rated Total Symptom Severity Complex (TSSC) score, which included the following symptoms: sneezing, runny nose, itchy nose, itchy eyes, watery eyes, postnasal drip, and nasal congestion. In both trials patients who received ZYRTEC -D showed a significant reduction in the TSSC score compared to those who received placebo.
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. 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.