Mechanism Of Action
Cetirizine hydrochloride, 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 hydrochloride 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 hydrochloride than with placebo. In vitro receptor binding studies have shown no measurable affinity for receptors other than H1 receptors.
Studies in 69 adult normal volunteers (aged 20 to 61 years) showed that cetirizine hydrochloride oral tablets 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 oral 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. Cetirizine hydrochloride tablets 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 cetirizine hydrochloride oral tablets was found. In 10 infants 7 to 25 months of age who received 4 to 9 days of cetirizine hydrochloride 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 oral cetirizine hydrochloride, as was response to a cold challenge in patients with cold-induced urticaria. In mildly asthmatic subjects, cetirizine hydrochloride oral tablets 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 oral tablets at a dose of 20 mg.
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.
In a single dose crossover study in healthy volunteers under fasting conditions, cetirizine reached a mean Cmax of 495 ng/mL and 1344 ng/mL following single dose intravenous (IV) administration of 5 mg and 10 mg, respectively, injected over a period of 1 to 1.5 minutes. Peak concentrations were reached at 0.06 hour (range 0.03 to 0.07 hour) and 0.03 hour (range 0.03 to 2.00 hour) for cetirizine hydrochloride 5 mg and 10 mg IV injection, respectively. The mean systemic exposure (AUC0-inf ) for cetirizine hydrochloride 5 mg and 10 mg IV injection was 1318 ng·hr/mL and 2746 ng·hr/mL, respectively. The AUC0-inf for cetirizine hydrochloride 10 mg oral tablet in the study was 2651 ng·hr/mL.
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.
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 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.
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.
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.
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.
When pediatric patients aged 7 to 12 years received a single, 5-mg oral cetirizine hydrochloride 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 oral tablets of cetirizine hydrochloride, 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. In pediatric patients aged 6 to 23 months who received a single dose of 0.25 mg/kg cetirizine hydrochloride oral solution (mean dose 2.3 mg), the mean Cmax 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 <less than 2 years of age receiving the maximum dose of cetirizine hydrochloride 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 hydrochloride oral tablets once a day.
Male And Female Patients
The effect of gender of cetirizine pharmacokinetics has not been adequately studied.
Racial Or Ethnic Groups
No race-related difference in the kinetics of cetirizine has been observed.
Patients With Renal Impairment
The kinetics of cetirizine were studied following multiple, oral, 10-mg daily doses of cetirizine hydrochloride for 7 days in 7 normal volunteers (creatine 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 (creatine clearance 11-31 mL/min). The pharmacokinetics of oral 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 oral dose of cetirizine hydrochloride 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.
The pharmacokinetics of IV cetirizine has not been evaluated in patients with renal impairment.
Patients With Hepatic Impairment
Sixteen patients with chronic liver diseases (hepatocellular, cholestatics, and biliary cirrhosis), given 10 or 20 mg of cetirizine hydrochloride 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 pharmacokinetics of IV cetirizine has not been evaluated in patients with hepatic impairment.
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.
The safety and efficacy of QUZYTTIR for the treatment of acute urticaria was demonstrated in a randomized, active-controlled, double-blind, single dose, multicenter (US and Canada), parallel group trial in 262 patients 18 years of age and older presenting to Emergency Departments or Urgent care Centers (NCT02935699). Subjects were treated with 10 mg of
QUZYTTIR or 50 mg diphenhydramine injection. Patients with acute urticaria with or without other diseases were enrolled, including patients with concomitant angioedema. The majority of the patients were Caucasian (48%) and female (63%) with a mean age of 39 years.
The primary efficacy endpoint was the change from baseline in patient-rated pruritus score assessed 2 hrs post treatment for the intent-to-treat (ITT) population. Pruritus was graded on a severity score of 0 to 3 with 0 = no pruritus, 1 = mild, 2 =moderate, and 3 = severe. The trial was non-inferiority design with the pre-specified non-inferiority margin of 0.50 for the difference between treatment groups. Two key secondary efficacy outcome measures: (i) the need to return to any ED or clinic after patient discharge, and (ii) time spent at the treatment center (time from treatment administration to readiness for discharge) were adjusted for multiplicity.
Result for the change from baseline in the pruritus scores are shown in Table 1. The difference between treatment groups excluded the pre-specified non-inferiority margin, i.e. the lower bound of the 95% confidence interval for the difference of diphenhydramine minus
QUZYTTIR did not include – 0.50. The primary efficacy data are presented in Table 1.
Table 1. Primary Efficacy Endpoint: Patient-rated Pruritus Score Change from Baseline at 2 hrs (using LOCF); ITT population
||Diphenhydramine injection 50 mg
(N = 135)
|QUZYTTIR injection 10 mg
(N = 127)
|Adjusted Difference between treatment
|Baseline: mean (SD)
|Change from Baseline: mean (SD)
||0.06 (-0.28, 0.40)*
|LOCF: last observation carried forward; ITT: intent-to-treat
*Since the lower bound of the 95% CI for the treatment difference was > -0.50, effectiveness of
QUZYTTIR injection was demonstrated to be non-inferior to the effectiveness of diphenhydramine injection. The treatment difference and 95% CI were obtained from a generalized linear mixed-effects model. The model consisted of the change from baseline at 2 hours as the dependent variable and site, treatment and site-by-treatment interaction as the fixed effect.
Additionally, in this trial the proportion of patients returning to any emergency department or clinic was lower in the
QUZYTTIR treatment group (6%) compared to the diphenhydramine treatment group (14%), and the time spent in the treatment center (hours spent reported as mean (SD): ) was shorter in the
QUZYTTIR treatment group (1.7 (0.9)) compared to the diphenhydramine treatment group (2.1 (1.1)).