Label: CLARINEX- desloratadine tablet, film coated

Absorption

Following oral administration of desloratadine 5 mg once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (Tmax) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of 4 ng/mL and 56.9 ng∙hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (Cmax and AUC) of desloratadine.

The pharmacokinetic profile of CLARINEX Syrup was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of CLARINEX Syrup containing 5 mg of desloratadine was bioequivalent to a single dose of 5 mg CLARINEX Tablet. Food had no effect on the bioavailability (AUC and Cmax) of CLARINEX Syrup.

The pharmacokinetic profile of CLARINEX RediTabs Tablets was evaluated in a three-way crossover study in 24 adult volunteers. A single CLARINEX RediTabs Tablet containing 5 mg of desloratadine was bioequivalent to a single 5 mg CLARINEX RediTabs Tablet (original formulation) for both desloratadine and 3-hydroxydesloratadine. Water had no effect on the bioavailability (AUC and Cmax) of CLARINEX RediTabs Tablets.

Distribution

Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound to plasma proteins, respectively. Protein binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism

Desloratadine (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2–5 years, 1575 subjects aged 6–11 years, and 1196 subjects aged 12–70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with CLARINEX Syrup for 15–35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.

Elimination

The mean elimination half-life of desloratadine was 27 hours. Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to desloratadine.

Geriatric

In older subjects (≥ 65 years old; n=17) following multiple-dose administration of CLARINEX Tablets, the mean Cmax and AUC values for desloratadine were 20% greater than in younger subjects (< 65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the two age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects ≥ 65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects

In subjects 6 to 11 years old, a single dose of 5 mL of CLARINEX Syrup containing 2.5 mg of desloratadine resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg CLARINEX Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of CLARINEX Syrup containing 1.25 mg of desloratadine resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg CLARINEX Tablet. However, the Cmax and AUCt of the metabolite (3-OH desloratadine) were 1.27 and 1.61 times higher for the 5 mg dose of syrup administered in adults compared to the Cmax and AUCt obtained in children 2–11 years of age receiving 1.25–2.5 mg of CLARINEX Syrup.

A single dose of either 2.5 mL or 1.25 mL of CLARINEX Syrup containing 1.25 mg or 0.625 mg, respectively, of desloratadine was administered to subjects 6 to 11 months of age and 12 to 23 months of age. The results of a population pharmacokinetic analysis indicated that a dose of 1 mg for subjects aged 6 to 11 months and 1.25 mg for subjects 12 to 23 months of age is required to obtain desloratadine plasma concentrations similar to those achieved in adults administered a single 5 mg dose of CLARINEX Syrup.

The CLARINEX RediTabs Tablet 2.5 mg tablet has not been evaluated in pediatric patients. Bioequivalence of the CLARINEX RediTabs Tablet and the original CLARINEX RediTabs Tablets was established in adults. In conjunction with the dose finding studies in pediatrics described, the pharmacokinetic data for CLARINEX RediTabs Tablet supports the use of the 2.5 mg dose strength in pediatric patients 6–11 years of age.

Renally Impaired

Desloratadine pharmacokinetics following a single dose of 7.5 mg were characterized in patients with mild (n=7; creatinine clearance 51–69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34–43 mL/min/1.73 m2), and severe (n=6; creatinine clearance 5–29 mL/min/1.73 m2) renal impairment or hemodialysis-dependent (n=6) patients. In patients with mild and moderate renal impairment, median Cmax and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who were hemodialysis dependent, Cmax and AUC values increased by approximately 1.7- and 2.5-fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended (see DOSAGE AND ADMINISTRATION section).

Hepatically Impaired

Desloratadine pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in patients with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of desloratadine in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Dosage adjustment for patients with hepatic impairment is recommended (see DOSAGE AND ADMINISTRATION section).

Gender

Female subjects treated for 14 days with CLARINEX Tablets had 10% and 3% higher desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine Cmax and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race

Following 14 days of treatment with CLARINEX Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

Wheal and Flare

Human histamine skin wheal studies following single and repeated 5 mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5 mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc

Single dose administration of desloratadine did not alter the corrected QT interval (QTc) in rats (up to 12 mg/kg, oral), or guinea pigs (25 mg/kg, intravenous). Repeated oral administration at doses up to 24 mg/kg for durations up to 3 months in monkeys did not alter the QTc at an estimated desloratadine exposure (AUC) that was approximately 955 times the mean AUC in humans at the recommended daily oral dose. See OVERDOSAGE section for information on human QTc experience.

Seasonal Allergic Rhinitis

The clinical efficacy and safety of CLARINEX Tablets were evaluated in over 2,300 patients 12 to 75 years of age with seasonal allergic rhinitis. A total of 1,838 patients received 2.5–20 mg/day of CLARINEX in four double-blind, randomized, placebo-controlled clinical trials of 2 to 4 weeks' duration conducted in the United States. The results of these studies demonstrated the efficacy and safety of CLARINEX 5 mg in the treatment of adult and adolescent patients with seasonal allergic rhinitis. In a dose ranging trial, CLARINEX 2.5–20 mg/day was studied. Doses of 5, 7.5, 10, and 20 mg/day were superior to placebo; and no additional benefit was seen at doses above 5.0 mg. In the same study, an increase in the incidence of somnolence was observed at doses of 10 mg/day and 20 mg/day (5.2% and 7.6%, respectively), compared to placebo (2.3%).

In two 4-week studies of 924 patients (aged 15 to 75 years) with seasonal allergic rhinitis and concomitant asthma, CLARINEX Tablets 5 mg once daily improved rhinitis symptoms, with no decrease in pulmonary function. This supports the safety of administering CLARINEX Tablets to adult patients with seasonal allergic rhinitis with mild to moderate asthma.

CLARINEX Tablets 5 mg once daily significantly reduced the Total Symptom Scores (the sum of individual scores of nasal and non-nasal symptoms) in patients with seasonal allergic rhinitis. See Table 2.

There were no significant differences in the effectiveness of CLARINEX Tablets 5 mg across subgroups of patients defined by gender, age, or race.

Perennial Allergic Rhinitis

The clinical efficacy and safety of CLARINEX Tablets 5 mg were evaluated in over 1,300 patients 12 to 80 years of age with perennial allergic rhinitis. A total of 685 patients received 5 mg/day of CLARINEX in two double-blind, randomized, placebo-controlled clinical trials of 4 weeks' duration conducted in the United States and internationally. In one of these studies CLARINEX Tablets 5 mg once daily was shown to significantly reduce symptoms of perennial allergic rhinitis (Table 3).

Chronic Idiopathic Urticaria

The efficacy and safety of CLARINEX Tablets 5 mg once daily was studied in 416 chronic idiopathic urticaria patients 12 to 84 years of age, of whom 211 received CLARINEX. In two double-blind, placebo-controlled, randomized clinical trials of six weeks' duration, at the pre-specified one-week primary time point evaluation, CLARINEX Tablets significantly reduced the severity of pruritus when compared to placebo (Table 4). Secondary endpoints were also evaluated and during the first week of therapy CLARINEX Tablets 5 mg reduced the secondary endpoints, "Number of Hives" and the "Size of the Largest Hive," when compared to placebo.

The clinical safety of CLARINEX Syrup was documented in three, 15-day, double-blind, placebo-controlled safety studies in pediatric subjects with a documented history of allergic rhinitis, chronic idiopathic urticaria, or subjects who were candidates for antihistamine therapy. In the first study, 2.5 mg of CLARINEX Syrup was administered to 60 pediatric subjects 6 to 11 years of age. The second study evaluated 1.25 mg of CLARINEX Syrup administered to 55 pediatric subjects 2 to 5 years of age. In the third study, 1.25 mg of CLARINEX Syrup was administered to 65 pediatric subjects 12 to 23 months of age and 1.0 mg of CLARINEX Syrup was administered to 66 pediatric subjects 6 to 11 months of age. The results of these studies demonstrated the safety of CLARINEX Syrup in pediatric subjects 6 months to 11 years of age.

Allergic Rhinitis

In multiple-dose placebo-controlled trials, 2,834 patients ages 12 years or older received CLARINEX Tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between CLARINEX and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the CLARINEX group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving desloratadine. All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of CLARINEX Tablets (5.0 mg once-daily), and that were more common with CLARINEX Tablets than placebo, are listed in Table 5.

The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in CLARINEX and placebo-treated patients.

There were no differences in adverse events for subgroups of patients as defined by gender, age, or race.

Chronic Idiopathic Urticaria

In multiple-dose, placebo-controlled trials of chronic idiopathic urticaria, 211 patients ages 12 years or older received CLARINEX Tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received CLARINEX Tablets and that were more common with CLARINEX than placebo were (rates for CLARINEX and placebo, respectively): headache (14%, 13%), nausea (5%, 2%), fatigue (5%, 1%), dizziness (4%, 3%), pharyngitis (3%, 2%), dyspepsia (3%, 1%), and myalgia (3%, 1%).