Clarinex-D 12 Hour desloratadine and pseudoephedrine sulfate 2.5 mg; 120 mg Tablet, Extended Release, 100-count — NDC 78206-120-01 (Billing 78206-0120-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Desloratadine is a long acting tricyclic histamine antagonist with selective H 1 -receptor histamine antagonist activity. Receptor binding data indicate that at a concentration of 2 to 3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H 1 receptor. Desloratadine inhibited histamine release from human mast cells in vitro .

Results of a radiolabeled tissue distribution study in rats and a radioligand H 1 -receptor-binding study in guinea pigs showed that desloratadine does not readily cross the blood brain barrier. The clinical significance of this finding is unknown. Pseudoephedrine sulfate is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa.

Pseudoephedrine sulfate 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.

12.2Pharmacodynamics 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 QT c : 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 QT c 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 (QT c ) by both Bazett's and Fridericia methods. Using the QT c (Bazett), there was a mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo.

Using QT c (Fridericia) there was a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

12.3Pharmacokinetics Absorption: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (T max ) for desloratadine occurred at approximately 4 to 5 hours post dose and mean peak plasma concentrations (C max ) 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 (C max and AUC) of desloratadine. For pseudoephedrine, the mean T max occurred at 6 to 7 hours post dose and mean peak plasma concentrations (C max ) 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 (C max 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 (C… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Desloratadine is a long acting tricyclic histamine antagonist with selective H 1 -receptor histamine antagonist activity. Receptor binding data indicate that at a concentration of 2 to 3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H 1 receptor. Desloratadine inhibited histamine release from human mast cells in vitro .

Results of a radiolabeled tissue distribution study in rats and a radioligand H 1 -receptor-binding study in guinea pigs showed that desloratadine does not readily cross the blood brain barrier. The clinical significance of this finding is unknown. Pseudoephedrine sulfate is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa.

Pseudoephedrine sulfate 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.

12.3Pharmacokinetics Absorption: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (T max ) for desloratadine occurred at approximately 4 to 5 hours post dose and mean peak plasma concentrations (C max ) 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 (C max and AUC) of desloratadine. For pseudoephedrine, the mean T max occurred at 6 to 7 hours post dose and mean peak plasma concentrations (C max ) 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 (C max 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 (C max ) and area under the concentration-time curve AUC 0-12 hrs of approximately 1.7 ng/mL and 16 ng∙hr/mL were observed, respectively.

For pseudoephedrine, mean steady-state peak plasma concentrations (C max ) and AUC 0-12 hrs 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 Ext… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 QT c : 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 QT c 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 (QT c ) by both Bazett's and Fridericia methods. Using the QT c (Bazett), there was a mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo.

Using QT c (Fridericia) there was a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

14 CLINICAL STUDIES

14.1Seasonal 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 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). (SEM) Change (% Change) from Baseline Mean reduction in score averaged over the 2-week treatment period. (SEM) CLARINEX-D 12 HOUR Comparison to Components The comparison of interest is shown bolded.

( P -value) SEM=Standard Error of the Mean 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.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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/m 2 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/m 2 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.