Darifenacin 15 mg Tablet, Extended Release, 30-count — NDC 72162-2571-3 (Billing 72162-2571-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play a role in cholinergically mediated functions, including contractions of the urinary bladder smooth muscle. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M 3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M 3 compared to M 1 and M 5 , respectively, and 59-fold greater affinity for M 3 compared to both M 2 and M 4 ).

M 3 receptors are involved in contraction of human bladder.

12.2Pharmacodynamics In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after darifenacin extended-release tablet treatment. These findings are consistent with an antimuscarinic action on the urinary bladder. Electrophysiology The effect of a six-day treatment of 15 mg and 75 mg darifenacin on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65.

Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg darifenacin extended-release tablets dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor.

At the doses studied, darifenacin did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with darifenacin was no different from placebo.

12.3Pharmacokinetics Absorption After oral administration of darifenacin extended-release tablets to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1. Figure 1 Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs* *Includes 95 EMs and 6 PMs for 7.5 mg; 104 EMs and 10 PMs for 15 mg.

A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3. Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype Darifenacin 7.5 mg (N = 68 EM, 5 PM) Darifenacin 15 mg (N = 102 EM, 17 PM) A UC 24 (ng•h/mL) C max (ng/mL) C a v g (ng/mL) T max (h) t 1/2 (h) A UC 24 (ng•h/mL) C max (ng/mL) C a v g (ng/mL) T max (h) t 1/2 (h) EM 29.24 2.01 1.22 6.49 12.43 88.90 5.76 3.70 7.61 12.05 (15.47) (1.04) (0.64) (4.19) (5.64) a (67.87) (4.24) (2.83) (5.06) (12.37) b PM 67.56 4.27 2.81 5.20 19.95 c 157.71 9.99 6.58 6.71 7.40 d (13.13) (0.98) (0.55) (1.79) - (77.08) (5.09) (3.22) (3.58) - a N = 25; b N = 8; c N = 2; d N = 1; AUC 24 = Area under the plasma concentration versus time curve for 24h; C max = Maximum observed plasma concentration; C avg = Average plasma concentration at steady-s… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play a role in cholinergically mediated functions, including contractions of the urinary bladder smooth muscle. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M 3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M 3 compared to M 1 and M 5 , respectively, and 59-fold greater affinity for M 3 compared to both M 2 and M 4 ).

M 3 receptors are involved in contraction of human bladder.

12.3Pharmacokinetics Absorption After oral administration of darifenacin extended-release tablets to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1. Figure 1 Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs* *Includes 95 EMs and 6 PMs for 7.5 mg; 104 EMs and 10 PMs for 15 mg.

A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3. Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype Darifenacin 7.5 mg (N = 68 EM, 5 PM) Darifenacin 15 mg (N = 102 EM, 17 PM) A UC 24 (ng•h/mL) C max (ng/mL) C a v g (ng/mL) T max (h) t 1/2 (h) A UC 24 (ng•h/mL) C max (ng/mL) C a v g (ng/mL) T max (h) t 1/2 (h) EM 29.24 2.01 1.22 6.49 12.43 88.90 5.76 3.70 7.61 12.05 (15.47) (1.04) (0.64) (4.19) (5.64) a (67.87) (4.24) (2.83) (5.06) (12.37) b PM 67.56 4.27 2.81 5.20 19.95 c 157.71 9.99 6.58 6.71 7.40 d (13.13) (0.98) (0.55) (1.79) - (77.08) (5.09) (3.22) (3.58) - a N = 25; b N = 8; c N = 2; d N = 1; AUC 24 = Area under the plasma concentration versus time curve for 24h; C max = Maximum observed plasma concentration; C avg = Average plasma concentration at steady-state; T max = Time of occurrence of Cmax; t 1/2 = Terminal elimination half-life.

Regarding EM and PM [see Clincal Pharmacology, Pharmacokinetics, Variability in Metabolism (12.3)]. The mean oral bioavailability of darifenacin extended-release tablets in EMs at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. Effect of Food Following single dose administration of darifenacin extended-release tablets with food, the AUC of darifenacin was not affected, while the C max was increased by 22% and T max was shortened by 3.3 hours.

There is no effect of food on multiple-dose pharmacokinetics from darifenacin extended-release tablets. Distribution Darifenacin is approximately 98 % bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L.

Metabolism Darifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows: (i) monohydroxylation in the dihydrobenzofuran ring; (ii) dihydrobenzofuran ring opening; (iii) N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin. Variability in Metabolism A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs).

The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for C max and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively. Excretion Following administration of an oral dose of 14 C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces.

Only a small percentage of the excreted dose was unchanged darifenacin (3%). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 1… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after darifenacin extended-release tablet treatment. These findings are consistent with an antimuscarinic action on the urinary bladder. Electrophysiology The effect of a six-day treatment of 15 mg and 75 mg darifenacin on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44% male, 56% female) aged 18 to 65.

Subjects included 18% poor metabolizers (PMs) and 82% extensive metabolizers (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg darifenacin extended-release tablets dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of a potent CYP3A4 inhibitor.

At the doses studied, darifenacin did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with darifenacin was no different from placebo.

14 CLINICAL STUDIES Darifenacin extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinary incontinence per week.

The majority of patients were white (94%) and female (84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were greater than or equal to 65 years of age . These characteristics were well balanced across treatment groups.

The study population was inclusive of both naïve patients who had not received prior pharmacotherapy for overactive bladder (60%) and those who had (40%). Table 4 shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily darifenacin for 12 weeks. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies.

Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition. Table 4: Difference Between Darifenacin (7.5 mg, 15 mg) and Placebo for the Week 12 Change from Baseline (Studies 1, 2 and 3) *Indicates statistically significant difference versus placebo (p less than 0.05, Wilcoxon rank-sum test) Study 1 Study 2 Study 3 Darifenacin 7.5 mg Darifenacin 15 mg Placebo Darifenacin 7.5 mg Darifenacin 15 mg Placebo Darifenacin 15 mg Placebo No. of Patients Entered 229 115 164 108 107 109 112 115 Urge Incontinence Episodes per Week Median Baseline 16.3 17.0 16.6 14.0 17.3 16.1 16.2

15.5Median Change from Baseline -9.0 -10.4 -7.6 -8.1 -10.4 -5.9 -11.4 -9.0 Median Difference to Placebo -1.5* -2.1* - -2.8* -4.3* - -2.4* - Micturitions per Day Median Baseline 10.1 10.1 10.1 10.3 11.0 10.1 10.5

10.4Median Change from Baseline -1.6 -1.7 -0.8 -1.7 -1.9 -1.1 -1.9 -1.2 Median Difference to Placebo -0.8* -0.9* - -0.5 -0.7* - -0.5 - Volume of Urine Passed per Void (mL) Median Baseline 160.2 151.8 162.4 161.7 157.3 162.2 155.0 147.1 Median Change from Baseline 14.9 30.9 7.6 16.8 23.6 7.1 26.7

4.6Median Difference to Placebo 9.1* 20.7* - 9.2 16.6* - 20.1* - Table 5 shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg darifenacin or placebo daily with the option to increase to 15 mg darifenacin or placebo daily after two weeks. Table 5: Difference between Darifenacin (7.5 mg/15 mg) and Placebo for the Week 12 Change from Baseline (Study 4) *Indicates statistically significant difference versus placebo (p less than 0.05, Wilcoxon rank-sum test) Darifenacin 7.5 mg /15 mg Placebo No. of Patients Treated 268 127 Urge Incontinence Episodes per Week Median Baseline Median Change from Baseline Median Difference to Placebo 16.0 -8.2 -1.4* 14.0 -6.0 - Micturitions per Day Median Baseline Median Change from Baseline Median Difference to Placebo 9.9 -1.9 -0.8* 10.4 -1.0 - Volume of Urine Passed per Void (mL) Median Baseline 173.7 177.2 Median Change from Baseline Median Difference to Placebo 18.8 13.3 * 6.6 - As seen in Figures 2a, 2b and 2c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with darifenacin 7.5 mg and 15 mg once daily compared to placebo.

Further, these effects were sustained throughout the 12-week treatme… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated free plasma AUC reached at the maximum recommended human dose (the AUC at the MRHD) of 15 mg and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at the MRHD in female rats and approximately eight times the AUC at the MRHD in male rats.

Mutagenesis Darifenacin was not genotoxic in the bacterial mutation assay (Ames test), the Chinese hamster ovary assay, the human lymphocyte assay, or the in vivo mouse bone marrow cytogenetics assay. Impairment of Fertility There was no evidence for effects on fertility in male or female rats treated at oral doses associated with up to approximately 78 times (50 mg/kg/day) the AUC at the MRHD.