Solifenacin Succinate (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No increase in tumors was found following the administration of solifenacin succinate to male and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times, respectively, of the exposure at the maximum recommended human dose [MRHD] of 10 mg), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times the exposure at the MRHD).

Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood lymphocytes with or without metabolic activation or in the in vivo micronucleus test in rats.

Solifenacin succinate had no effect on reproductive function, fertility, or early embryonic development of the fetus in male and female mice treated with 250 mg/kg/day (13 times the exposure at the MRHD) of solifenacin succinate, and in male rats treated with 50 mg/kg/day (<1 times the exposure at the MRHD) and female rats treated with 100 mg/kg/day (1.7 times the exposure at the MRHD) of solifenacin succinate.

13.2 Animal Toxicology and/or Pharmacology

Juvenile Animal Toxicology Data

Dose-related increased mortality without preceding clinical signs occurred in juvenile mice treated before weaning for a duration of 12 weeks, from day 10 after birth, with doses that achieved a pharmacological effect. Animals dosed from postnatal day 10 onwards had higher mortality compared to the mortality in adult mice. No increased frequency in mortality was observed in juvenile mice that were treated after weaning for a duration of 4 weeks, from day 21 after birth onwards. Plasma exposure at postnatal day 10 was higher than in adult mice; the systemic exposure at postnatal day 21 was comparable to the systemic exposure in adult mice.

14 CLINICAL STUDIES

Solifenacin succinate was evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in adult patients having symptoms of urinary frequency, urgency, and/or urge or mixed incontinence (with a predominance of urge). Entry criteria required that patients have symptoms of overactive bladder for ≥3 months duration. These studies involved 3027 patients (1811 on solifenacin succinate and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg solifenacin succinate doses (Studies 1 and 2) and the other two evaluated only the 10 mg dose (Studies 3 and 4). All patients completing the 12-week studies were eligible to enter an open-label, long-term extension study (Study 5) and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with a mean age of 58 years.

The primary endpoint in all four trials was the mean change from baseline to 12 weeks in number of micturitions/24 hours. Secondary endpoints included mean change from baseline to 12 weeks in number of incontinence episodes/24 hours, and mean volume voided per micturition.

The efficacy of solifenacin succinate was similar across patient age groups and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with solifenacin succinate 5 mg (2.3; p<0.001) and solifenacin succinate 10 mg (2.7; p<0.001) compared to placebo (1.4). The mean reduction in the number of incontinence episodes per 24 hours was significantly greater with solifenacin succinate 5 mg (1.5; p<0.001) and solifenacin succinate 10 mg (1.8; p<0.001) treatment groups compared to the placebo treatment group (1.1). The mean increase in the volume voided per micturition was significantly greater with solifenacin succinate 5 mg (32.3 mL; p<0.001) and solifenacin succinate 10 mg (42.5 mL; p<0.001) compared with placebo (8.5 mL).

The results for the primary and secondary endpoints in the four individual 12-week clinical studies of solifenacin succinate are reported in Tables 3 through 6.

Table 3: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 1

Parameter

Placebo

(N=253)

Mean (SE)

Solifenacin Succinate

5 mg

(N=266)

Mean (SE)

Solifenacin Succinate

10 mg

(N=264)

Mean (SE)

Urinary Frequency (Number of Micturitions/24 hours)1

Baseline
Reduction
P value vs. placebo

12.2 (0.26)

1.2 (0.21)

12.1 (0.24)

2.2 (0.18)

< 0.001

12.3 (0.24)

2.6 (0.20)

< 0.001

Number of Incontinence Episodes/24 hours2

Baseline
Reduction
P value vs. placebo

2.7 (0.23)

0.8 (0.18)

2.6 (0.22)

1.4 (0.15)

< 0.01

2.6 (0.23)

1.5 (0.18)

< 0.01

Volume Voided per Micturition [mL]2

Baseline
Increase
P value vs. placebo

143.8 (3.37)

7.4 (2.28)

149.6 (3.35)

32.9 (2.92)

< 0.001

147.2 (3.15)

39.2 (3.11)

< 0.001

1 Primary endpoint

2 Secondary endpoint

Table 4: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 2

Parameter Placebo
(N=281)
Mean (SE)
Solifenacin Succinate 5 mg (N=286)
Mean (SE)
Solifenacin Succinate 10 mg (N=290)
Mean (SE)
Urinary Frequency (Number of Micturitions/24 hours)1
Baseline
Reduction
P value vs. placebo
12.3 (0.23)
1.7 (0.19)
12.1 (0.23)
2.4 (0.17)
< 0.001
12.1 (0.21)
2.9 (0.18)
< 0.001
Number of Incontinence Episodes/24 hours2
Baseline
Reduction
P value vs. placebo
3.2 (0.24)
1.3 (0.19)
2.6 (0.18)
1.6 (0.16)
< 0.01
2.8 (0.20)
1.6 (0.18)
0.016
Volume Voided per Micturition [mL]2
Baseline
Increase
P value vs. placebo
147.2 (3.18)
11.3 (2.52)
148.5 (3.16)
31.8 (2.94)
< 0.001
145.9 (3.42)
36.6 (3.04)
< 0.001

1 Primary endpoint

2 Secondary endpoint

Table 5: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 3

Parameter Placebo
(N=309)
Mean (SE)
Solifenacin Succinate 10 mg (N=306)
Mean (SE)

Urinary Frequency (Number of Micturitions/24 hours)1

Baseline
Reduction
P value vs. placebo

11.5 (0.18)

1.5 (0.15)

11.7 (0.18)

3 (0.15)

< 0.001

Number of Incontinence Episodes/24 hours2

Baseline
Reduction
P value vs. placebo

3 (0.20)

1.1 (0.16)

3.1 (0.22)

2 (0.19)

< 0.001

Volume Voided per Micturition [mL]2

Baseline
Increase
P value vs. placebo

190.3 (5.48)

2.7 (3.15)

183.5 (4.97)

47.2 (3.79)

< 0.001

1 Primary endpoint

2 Secondary endpoint

Table 6: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 4

Parameter

Placebo

(N=295)

Mean (SE)

Solifenacin Succinate 10 mg (N=298)

Mean (SE)

Urinary Frequency (Number of Micturitions/24 hours)1

Baseline
Reduction
P value vs. placebo

11.8 (0.18)

1.3 (0.16)

11.5 (0.18)

2.4 (0.15)

< 0.001

Number of Incontinence Episodes/24 hours2

Baseline
Reduction
P value vs. placebo

2.9 (0.18)

1.2 (0.15)

2.9 (0.17)

2 (0.15)

< 0.001

Volume Voided per Micturition [mL]2

Baseline
Increase
P value vs. placebo

175.7 (4.44)

13 (3.45)

174.1 (4.15)

46.4 (3.73)

< 0.001

1 Primary endpoint

2 Secondary endpoint

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