Darifenacin (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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.

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 extended-release tablet 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 Extended-Release Tablets (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 extended-release tablet 7.5 mg Darifenacin extended-release tablet 15 mg Placebo Darifenacin extended-release tablet 7.5 mg Darifenacin extended-release tablet 15 mg Placebo Darifenacin extended-release tablet 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 15.5
Median 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 10.4
Median 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 4.6
Median 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 extended-release tablets or placebo daily with the option to increase to 15 mg darifenacin extended-release tablets or placebo daily after two weeks.

Table 5: Difference between Darifenacin Extended-Release Tablets(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 extended-release tablet 7.5 mg /15 mg Placebo
No. of Patients Treated 268 127
Urge Incontinence Episodes per Week
Median Baseline 16.0 14.0
Median Change from Baseline -8.2 -6.0
Median Difference to Placebo -1.4*
Micturitions per Day
Median Baseline 9.9 10.4
Median Change from Baseline -1.9 -1.0
Median Difference to Placebo -0.8*
Volume of Urine Passed per Void (mL)
Median Baseline 173.7 177.2
Median Change from Baseline 18.8 6.6
Median Difference to Placebo 13.3*

As seen in Figures 2 a, 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 extended-release tablets 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period.

Figures 2a, 2b, 2c. Median Change from Baseline at Weeks 2, 6, 12 for Number of Urge Incontinence Episodes per Week (Studies 1, 2 and 3)

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