CLARINEX-D 12 HOUR (Page 5 of 7)

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 co-administered 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.

Table 2: Changes in Desloratadine and 3-hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Subjects
Desloratadine 3-hydroxydesloratadine
Cmax AUC 0-24hrs Cmax AUC 0-24hrs
Erythromycin(500 mg Q8h) +24% +14% +43% +40%
Ketoconazole(200 mg Q12h) +45% +39% +43% +72%
Azithromycin(500 mg Day 1,250 mg QD × 4 days) +15% +5% +15% +4%
Fluoxetine(20 mg QD) +15% +0% +17% +13%
Cimetidine(600 mg Q12h) +12% +19% -11% -3%

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or laboratory studies on the combination product of desloratadine and pseudoephedrine sulfate or pseudoephedrine alone to evaluate carcinogenesis, mutagenesis, or impairment of fertility.

Carcinogenicity Studies:

Desloratadine

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 (approximately 45 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD) and in males and females given 25 mg/kg/day of loratadine. 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 (approximately 30 and 70 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD, respectively), did not show significant increases in the incidence of any tumors.

Pseudoephedrine

The carcinogenic potential of pseudoephedrine was assessed using ephedrine sulfate studies in F344/N rats and B6C3F1 mice conducted under the National Toxicology Program (NTP). In a 2-year dietary study in rats, male and female rats given up to 9 and 11 mg/kg/day ephedrine sulfate (approximately 0.4 and 0.5 times the RHD of 240 mg/day on a mg/m2 basis, respectively) did not show any evidence of tumorigenicity. In a 2-year dietary study in mice, male and female mice given up to 29 and 25 mg/kg/day ephedrine sulfate (approximately 0.7 and 0.6 times the RHD of pseudoephedrine on a mg/m2 basis, respectively) did not show any evidence of tumorigenicity.

Genotoxicity Studies:

Desloratadine

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).

Pseudoephedrine

Mutagenicity studies with pseudoephedrine have not been conducted.

Impairment of Fertility:

Desloratadine

In a female fertility study, desloratadine was given to female rats orally 14 days prior to and throughout mating until Gestation Day 7 at doses of 6, 12 and 24 mg/kg/day. An increase in preimplantation loss and a decrease in number of implantations and fetuses noted at 24 mg/kg (approximately 200 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD) was likely due to maternal toxicities including reduced body weight gain and food consumption. In a male fertility study in rats, desloratadine was given orally to male rats for 70 days prior to mating and throughout the mating period (total dosing period 106-108 days) at doses of 3, 12 and 40 mg/kg/day. Reduced body weight gain, food consumption, and absolute organ weights of testes, epididymis, and cauda epididymis were noted at 40 mg/kg/day. A male-specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic changes in testes and epididymis, occurred at a dose of 12 mg/kg or greater (approximately 65 times or greater than the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Desloratadine had no effect on male fertility in rats at 3 mg/kg/day (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD).

Pseudoephedrine

Fertility studies with pseudoephedrine have not been conducted.

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

The clinical efficacy and safety of CLARINEX-D 12 HOUR Extended Release Tablets was evaluated in two 2-week multicenter, randomized parallel group clinical trials involving 1248 subjects 12 to 78 years of age with seasonal allergic rhinitis, 414 of whom received CLARINEX-D 12 HOUR Extended Release Tablets. In the 2 trials, subjects were randomized to receive CLARINEX-D 12 HOUR Extended Release Tablets twice daily, CLARINEX Tablets 5 mg once daily, or sustained-release pseudoephedrine tablet 120 mg twice daily for 2 weeks. The majority of patients were between 18 and <65 years of age with a mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82% Caucasian, 9% Black, 6% Hispanic and 3% Asian/other ethnicity. Primary efficacy variable was twice-daily reflective patient scoring of 4 nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and four non-nasal symptoms (itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate) on a 4 point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic efficacy of CLARINEX-D 12 HOUR Extended Release Tablets, as measured by total symptom score excluding nasal congestion, was significantly greater than pseudoephedrine alone over the 2-week treatment period; and the decongestant efficacy of CLARINEX-D 12 HOUR Extended Release Tablets, as measured by nasal stuffiness/congestion, was significantly greater than CLARINEX (desloratadine alone) over the 2-week treatment period. Primary efficacy variable results from 1 of 2 trials are shown in Table 3.

Table 3: Changes in Symptoms in a 2-Week Clinical Trial in Subjects With Seasonal Allergic Rhinitis
Treatment Group (n) Mean Baseline * (SEM) Change (% Change) from Baseline (SEM) CLARINEX-D 12 HOUR Comparison to Components (P -value)
SEM=Standard Error of the Mean
*
To qualify at Baseline, the sum of the twice-daily diary reflective scores for the 3 days prior to Baseline and the morning of the Baseline visit were to total ≥42 for total nasal symptom score (sum of 4 nasal symptoms of rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and a total of ≥35 for total non-nasal symptoms score (sum of 4 non-nasal symptoms of itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate), and a score of ≥14 for each of the individual symptoms of nasal stuffiness/congestion and rhinorrhea. Each symptom was scored on a 4-point severity scale (0=none, 1=mild, 2=moderate, 3=severe).
Mean reduction in score averaged over the 2-week treatment period.
The comparison of interest is shown bolded.
Total Symptom Score (Excluding Nasal Congestion)
CLARINEX-D 12 HOUR Extended Release Tablets BID (199) 14.18 (0.21) -6.54 (-46.0) (0.30)
Pseudoephedrine tablet 120 mg BID (197) 14.06 (0.21) -5.07 (-35.9) (0.30) P <0.001
CLARINEX 5 mg Tablets QD (197) 14.82 (0.21) -5.09 (-33.5) (0.30) P <0.001
Nasal Stuffiness/Congestion
CLARINEX-D 12 HOUR Extended Release Tablets BID (199) 2.47 (0.027) -0.93 (-37.4) (0.046)
Pseudoephedrine tablet 120 mg BID (197) 2.46 (0.027) -0.75 (-31.2) (0.046) P =0.006
CLARINEX 5 mg Tablets QD (197) 2.50 (0.027) -0.66 (-26.7) (0.046) P <0.001

There were no significant differences in the efficacy of CLARINEX-D 12 HOUR Extended Release Tablets across subgroups of subjects defined by gender, age, or race.

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