Pregnancy Category C: There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine. Desloratadine was not teratogenic in rats or rabbits but affected implantation in rats. Because animal reproduction studies are not always predictive of human response, CLARINEX-D 12 HOUR Extended Release Tablets should be used during pregnancy only if clearly needed.

Desloratadine was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the AUC in humans at the recommended daily oral dose). An increase in pre-implantation loss and a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose). Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Desloratadine had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose). The AUCs in comparison referred to the desloratadine exposure in rabbits and the sum of desloratadine and its metabolites exposures in rats, respectively [see Nonclinical Toxicology (13.2)].

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 5mg group over the 28 day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc: In clinical trials for CLARINEX-D 12 HOUR Extended Release Tablets, ECGs were recorded at baseline and endpoint within 1 to 3 hours after the last dose. The majority of ECGs were normal at both baseline and endpoint. No clinically meaningful changes were observed following treatment with CLARINEX-D 12 HOUR Extended Release Tablets for any ECG parameter, including the QTc interval. An increase in the ventricular rate of 7.1 and 6.4 bpm was observed in the CLARINEX-D 12 HOUR Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in subjects receiving desloratadine alone. Single daily doses of CLARINEX 45 mg were given to normal male and female volunteers for 10 days.

All ECGs obtained in this study were manually read in a blinded fashion by a cardiologist. In the CLARINEX-treated subjects, there was a mean increase in the maximum heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both Bazett's and Fridericia methods. Using the QTc (Bazett) there was a mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

Absorption:

In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately 4 to 5 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6 ng∙hr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (Cmax and AUC) of desloratadine.

For pseudoephedrine, the mean Tmax occurred at 6 to 7 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 ng∙hr/mL, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of pseudoephedrine.

Following oral administration of CLARINEX-D 12 HOUR Extended Release Tablets twice daily for 14 days in healthy volunteers, steady-state conditions were reached on Day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean steady-state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC 0–12 h) of approximately 1.7 ng/mL and 16 ng∙hr/mL were observed, respectively. For pseudoephedrine, mean steady state peak plasma concentrations (Cmax) and AUC (0–12 h) of 459 ng/mL and 4658 ng∙hr/mL were observed.

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 with desloratadine 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 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 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 prospectively identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with CLARINEX Syrup for 15 to 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.

Pseudoephedrine alone is incompletely metabolized (less than 1%) in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in the urine. About 55% to 96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.

Elimination:

Following single dose administration of CLARINEX-D 12 HOUR Extended Release Tablets, the mean plasma elimination half-life of desloratadine was approximately 27 hours. In another study, following administration of single oral doses of desloratadine 5 mg, 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.

The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately 3 to 6 or 9 to 16 hours when the urinary pH is 5 or 8, respectively.

Geriatric Subjects: 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 2 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 vs. younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly patients.

Pediatric Subjects: CLARINEX-D 12 HOUR Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age.

Renally Impaired: Following a single dose of desloratadine 7.5 mg pharmacokinetics were characterized in subjects with mild (n=7; creatinine clearance 51–69 mL/min/1.73m2), moderate (n=6; creatinine clearance 34–43 mL/min/1.73m2) and severe (n=6; creatinine clearance 5–29 mL/min/1.73m2) renal impairment or hemodialysis dependent (n=6) subjects. In subjects 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 subjects 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.

Pseudoephedrine is primarily excreted unchanged in the urine as unchanged drug with the remainder apparently being metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal impairment.

Hepatically Impaired: Following a single oral dose of desloratadine, pharmacokinetics were characterized in subjects with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic impairment and 8 subjects with normal hepatic function. Subjects 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 subjects 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 subjects with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for subjects with hepatic impairment combined were not statistically significantly different from subjects with normal hepatic function.

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 considered to be clinically relevant.

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 considered to be clinically relevant.

Drug interaction: In 2 controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) subjects, desloratadine 7.5 mg (1.5 times the daily dose) once daily was co-administered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In 3 separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of 5 mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady state conditions to healthy male and female subjects. Although increased plasma concentrations (Cmax and AUC 0–24 hrs) of desloratadine and 3-hydroxydesloratadine were observed (see Table 2), there were no clinically relevant changes in the safety profile of desloratadine, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs and adverse events.

Carcinogenicity Studies:

The carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated desloratadine and desloratadine metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. The clinical significance of these findings during long-term use of desloratadine is not known.

In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day desloratadine, respectively, did not show significant increases in the incidence of any tumors. The estimated desloratadine and desloratadine metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.

Genotoxicity Studies:

In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

Impairment of Fertility:

There was no effect on female fertility in rats at desloratadine doses up to 24 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). A male-specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral desloratadine dose of 12 mg/kg (estimated desloratadine and desloratadine metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).

Reproductive Toxicology Studies:

Desloratadine was not teratogenic in rats at doses up to 48 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 210 times the AUC in humans at the recommended daily oral dose) or in rabbits at doses up to 60 mg/kg/day (estimated desloratadine exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). In a separate study, an increase in pre-implantation loss and a decreased number of implantations and fetuses were noted in female rats at 24 mg/kg (estimated desloratadine and desloratadine metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). Reduced body weight and slow righting reflex were reported in pups at doses of 9 mg/kg/day or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on pup development at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 7 times the AUC in humans at the recommended daily oral dose).