Solifenacin Succinate 5 mg Tablet, Film Coated, 30-count — NDC 51407-471-30 (Billing 51407-0471-30)

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.

12.2Pharmacodynamics Cardiac Electrophysiology The effect of 10 mg and 30 mg solifenacin succinate (three times the maximum recommended dose) 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 [see Warnings and Precautions (5.6) ]. After receiving placebo and moxifloxacin sequentially, subjects were randomized to one of two treatment groups. One group (n=51) completed 3 additional sequential periods of dosing with solifenacin succinate 10 mg, 20 mg, 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 coadministration of 10 mg solifenacin succinate with strong CYP3A4 inhibitors (e.g., ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline ECG 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) 1 Drug/Dose Fridericia method (using mean difference) 1. 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. Solifenacin succinate 10 mg 2 (-3,6) Solifenacin succinate 30 mg 8 (4,13) 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 of the highest solifenacin succinate dose (three times the maximum therapeutic dose) studied was not as large as that of the positive control moxifloxacin at its recommended dose. However, the confidence intervals overlapped, and 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 in healthy volunteers, peak plasma concentrations (C max ) of solifenacin were reached within 3 to 8 hours after administration and, at steady-state, ranged from 32.3 ng/mL to 62.9 ng/mL for the 5 mg and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, with plasma concentrations of solifenacin proportional to the dose administered. Effect of Food Solifenacin succinate may be administered without regard to meals.

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

Elimination The elimination half-life (t 1/2 ) of solifenacin following chronic dosi… [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.

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

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

Elimination The elimination half-life (t 1/2 ) of solifenacin following chronic dosing is approximately 45 to 68 hours. 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 the 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% of the radioactivity was recovered in the urine and 23% 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. Specific Populations Geriatric Patients Multiple dose studies of solifenacin succinate in geriatric volunteers (65 to 80 years) showed that C max , AUC and t 1/2 values of solifenacin were 20 to 25% higher compared to the younger adult volunteers (18 to 55 years). [see Use in Specific Populations (8.5) ].

Patients with Renal Impairment In studies with solifenacin succinate 10 mg, there was a 2.1-fold increase in AUC and a 1.6-fold increase in t 1/2 of solifenacin in patients with severe renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ]. Patients with Hepatic Impairment In studies with solifenacin succinate 10 mg, there was a 2-fold increase in the t 1/2 and a 35% increase in AUC of solifenacin in patients with moderate hepatic impairment compared to subjects with normal hepatic function [see Use in Specific Populations (8.7) ].

Solifenacin succinate has not been studied in patients with severe hepatic impairment. Drug Interaction Studies Strong CYP3A4 Inhibitors In a crossover study, following blockade of CYP3A4 by coadministration of the strong 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) ]. CYP3A4 Inducers Because solifenacin is a substrate of CYP3A4, inducers of CYP3A4 may decrease the concentration of solifenacin.

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 succinate 10 mg or matching placebo once daily for 16 days. For R -warfarin, when it was coadministered with solifenacin succinate, the mean C max increased by 3% and AUC decreased by 2%. For S -warfarin, when it was coadministered with so… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology The effect of 10 mg and 30 mg solifenacin succinate (three times the maximum recommended dose) 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 [see Warnings and Precautions (5.6) ]. After receiving placebo and moxifloxacin sequentially, subjects were randomized to one of two treatment groups. One group (n=51) completed 3 additional sequential periods of dosing with solifenacin succinate 10 mg, 20 mg, 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 coadministration of 10 mg solifenacin succinate with strong CYP3A4 inhibitors (e.g., ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline ECG 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) 1 Drug/Dose Fridericia method (using mean difference) 1. 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. Solifenacin succinate 10 mg 2 (-3,6) Solifenacin succinate 30 mg 8 (4,13) 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 of the highest solifenacin succinate dose (three times the maximum therapeutic dose) studied was not as large as that of the positive control moxifloxacin at its recommended dose. However, the confidence intervals overlapped, and this study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

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 mg 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) 1. Primary endpoint 2.

Secondary endpoint 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 hours 2 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) <

0.01Volume 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 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) 1. Primary endpoint 2. Secondary endpoint 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 hours 2 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 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) 1.

Primary endpoint 2. Secondary endpoint Urinary Frequency (N… [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.

13.2Animal 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.