Solifenacin Succinate 5 mg Tablet, Coated, 1,000-count — NDC 46708-192-91 (Billing 46708-0192-91)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.

12.2Pharmacodynamics Cardiac Electrophysiology The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Subjects were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin.

Study subjects were female volunteers aged 19 to 79 years. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers those observed upon co-administration of 10 mg solifenacin succinate tablets with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.

The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis. Representative results are shown in Table 2.

Table 2: QTc changes in msec (90%CI) from baseline at T max (relative to placebo) * Drug/Dose Fridericia method (using mean difference) Solifenacin 10 mg 2 (-3, 6) Solifenacin 30 mg 8 (4, 13) *Results displayed are those derived from the parallel design portion of the study and represent the comparison of Group 1 to time-matched placebo effects in Group 2 Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions.

The placebo subtracted mean changes (90% CI) in QTcF for moxifloxacin in the three sessions were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively. The QT interval prolonging effect appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped.

This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

12.3Pharmacokinetics Absorption After oral administration of solifenacin succinate tablets to healthy volunteers, peak plasma levels (C max ) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered. Effect of Food Solifenacin succinate tablets may be administered without regard to meals.

A single 10 mg dose administration of solifenacin succinate tablets with food increased C max and AUC by 4% and 3%, respectively. Distribution Solifenacin is approximately 98% ( in vivo ) bound to human plasma proteins, principally to µ 1 -acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L.

Metabolism Solifenacin is extensively metabolized in the liver. The primary p… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.

12.3Pharmacokinetics Absorption After oral administration of solifenacin succinate tablets to healthy volunteers, peak plasma levels (C max ) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered. Effect of Food Solifenacin succinate tablets may be administered without regard to meals.

A single 10 mg dose administration of solifenacin succinate tablets with food increased C max and AUC by 4% and 3%, respectively. Distribution Solifenacin is approximately 98% ( in vivo ) bound to human plasma proteins, principally to µ 1 -acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L.

Metabolism Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-hydroxylation of tetrahydroisoquinoline ring.

One pharmacologically active metabolite (4R-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing. Excretion Following the administration of 10 mg of 14 C-solifenacin succinate to healthy volunteers, 69.2% of the radioactivity was recovered in the urine and 22.5% in the feces over 26 days.

Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy solifenacin and 4R-hydroxy-N-oxide of solifenacin and in feces 4R-hydroxy solifenacin. The elimination half-life of solifenacin following chronic dosing is approximately 45 to 68 hours.

Drug Interactions Potent CYP3A4 Inhibitors In a crossover study, following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor, ketoconazole 400 mg, once daily for 21 days, the mean C max and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively [see Dosage and Administration (2.4) and Drug Interactions (7.1)] . Warfarin In a crossover study, subjects received a single oral dose of warfarin 25 mg on the 10 th day of dosing with either solifenacin 10 mg or matching placebo once daily for 16 days.

For R -warfarin when it was coadministered with solifenacin, the mean C max increased by 3% and AUC decreased by 2%. For S -warfarin when it was coadministered with solifenacin, the mean C max and AUC increased by 5% and 1%, respectively [see Drug Interactions (7.4)]. Oral Contraceptives In a crossover study, subjects received 2 cycles of 21 days of oral contraceptives containing 30 ug ethinyl estradiol and 150 ug levonorgestrel.

During the second cycle, subjects received additional solifenacin 10 mg or matching placebo once daily for 10 days starting from 12 th day of receipt of oral contraceptives. For ethinyl estradiol when it was administered with solifenacin, the mean C max and AUC increased by 2% and 3%, respectively. For levonorgestrel when it was administered with solifenacin, the mean C max and AUC decreased by 1% [see Drug Interactions (7.5)].

Digoxin In a crossover study, subjects received digoxin (loading dose of 0.25 mg on day 1, followed by 0.125 mg from days 2 to 8) for 8 days. Consecutively, they received solifenacin 10 mg or matching placebo with digoxin 0.125 mg for additional 10 days. When digoxin was coadministered with solifenacin, the mean C max and AUC increased by 13% and 4%, respectively [see Drug Interactions (7.6)].

12.2Pharmacodynamics Cardiac Electrophysiology The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Subjects were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin.

Study subjects were female volunteers aged 19 to 79 years. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers those observed upon co-administration of 10 mg solifenacin succinate tablets with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.

The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis. Representative results are shown in Table 2.

Table 2: QTc changes in msec (90%CI) from baseline at T max (relative to placebo) * Drug/Dose Fridericia method (using mean difference) Solifenacin 10 mg 2 (-3, 6) Solifenacin 30 mg 8 (4, 13) *Results displayed are those derived from the parallel design portion of the study and represent the comparison of Group 1 to time-matched placebo effects in Group 2 Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions.

The placebo subtracted mean changes (90% CI) in QTcF for moxifloxacin in the three sessions were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively. The QT interval prolonging effect appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped.

This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

14 CLINICAL STUDIES Solifenacin succinate tablets were evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in 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 tablets 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 tablets doses and the other two evaluated only the 10 mg dose. All patients completing the 12-week studies were eligible to enter an open label, long term extension study 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 tablets was similar across patient age and gender.

The mean reduction in the number of micturitions per 24 hours was significantly greater with solifenacin succinate tablets 5 mg (2.3; p<0.001) and solifenacin succinate tablets 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 tablets 5 mg (1.5; p<0.001) and solifenacin succinate tablets 10 mg (1.8; p<0.001) treatment groups compared to placebo (1.1). The mean increase in the volume voided per micturition was significantly greater with solifenacin succinate tablets 5 mg (32.3 mL; p<0.001) and solifenacin succinate tablets 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 tablets are reported in Tables 3 through 6. Table 3: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (5 mg and 10 mg daily) and Placebo: Study 1 Parameter Placebo (N=253) Mean (SE) Solifenacin Succinate Tablets 5 mg (N=266) Mean (SE) Solifenacin Succinate Tablets 10 mg (N=264) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) * 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 (0.2) <0.

001 Number of Incontinence Episodes/24 hours † 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] † 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 * Primary endpoint † Secondary endpoint Table 4: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (5 mg and 10 mg daily) and Placebo: Study 2 Parameter Placebo (N=281) Mean (SE) Solifenacin Succinate Tablets 5 mg (N=286) Mean (SE) Solifenacin Succinate Tablets 10 mg (N=290) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) * 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 hours † 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 (0.2) 1.6 (0.18) 0.016 Volume Voided per Micturition [mL] † 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 * Primary endpoint † Secondary endpoint Table 5: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (10 mg daily) and Placebo: Study 3 Parame… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.