Solifenacin Succinate

6 ADVERSE REACTIONS The most common adverse reactions (> 4% and > placebo) were dry mouth, and constipation at both 5 mg and 10 mg doses; and urinary tract infection, and blurred vision at the 10 mg dose ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Solifenacin succinate has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. Expected adverse reactions of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The incidence of dry mouth and constipation in patients treated with solifenacin succinate was higher in the 10 mg compared to the 5 mg dose group. In the four 12-week double-blind clinical trials, severe fecal impaction, colonic obstruction, and intestinal obstruction were reported in one patient each, all in the solifenacin succinate 10 mg group. Angioneurotic edema has been reported in one patient taking solifenacin succinate 5 mg. Compared to 12 weeks of treatment with solifenacin succinate, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months. The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events, in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with solifenacin succinate 5 or 10 mg once daily for up to 12 weeks. TABLE 1: Percentages of Patients with Identified Adverse Reactions, Derived from All Adverse Events Exceeding Placebo Rate and Reported by 1% or More Patients for Combined Pivotal Studies Placebo (%) Solifenacin succinate 5 mg (%) Solifenacin succinate 10 mg (%) Name of Patients 1216 578 1233 GASTROINTESTINAL DISORDERS Dry Mouth 4.2 10.9 27.6 Constipation 2.9 5.4 13.4 Nausea 2.0 1.7 3.3 Dyspepsia 1.0 1.4 3.9 Abdominal Pain Upper 1.0 1.9 1.2 Vomiting NOS 0.9 0.2 1.1 INFECTIONS AND INFESTATIONS Unrinary Track Infection NOS 2.8 2.8 4.8 Influenza 1.3 2.2 0.9 Pharyngitis NOS 1.0 0.3 1.1 NERVOUS SYSTEM DISORDERS Dizziness 1.8 1.9 1.8 EYE DISORDERS Vision Blurred 1.8 3.8 4.8 Dry Eyes NOS 0.6 0.3 1.6 RENAL AND URINARY DISORDERS Urinary Retention 0.6 0 1.4 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema Lower Limb 0.7 0.3 1.1 Fatigue 1.1 1.0 2.1 PSYCHIATRIC DISORDERS Depression NOS 0.8 1.2 0.8 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 0.2 0.2 1.1 VASCULAR DISORDERS Hypertension NOS 0.6 1.4 0.5 6.2 Post-Marketing Experience Because these spontaneously reported events are from the worldwide postmarketing experience, the frequency of events and the role of solifenacin in their causation cannot be reliably determined. The following events have been reported in association with solifenacin use in worldwide postmarketing experience: General : peripheral edema, hypersensitivity reactions, including angioedema with airway obstruction, rash, pruritus, urticaria, and anaphylactic reaction; Central Nervous : headache, confusion, hallucinations, delirium, and somnolence; Cardiovascular : QT prolongation, Torsade de Pointes, atrial fibrillation, tachycardia, and palpitations; Hepatic : liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), and GGT (gamma-glutamyl transferase); Renal : renal impairment; Metabolism and nutrition disorders : decreased appetite and hyperkalemia; Dermatologic : exfoliative dermatitis, erythema multiforme, and dry skin; Eye disorders : glaucoma; Gastrointestinal disorders : gastroesophageal reflux disease, ileus, abdominal pain, and dysgeusia; Respiratory, thoracic and mediastinal disorders : dysphonia and nasal dryness; Musculoskeletal and connective tissue disorders : muscular weakness.

4 CONTRAINDICATIONS Solifenacin succinate is contraindicated in patients with: • urinary retention [see Warnings and Precautions (5.2) ] , • gastric retention [see Warnings and Precautions (5.3) ], • uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.5) ] , and • in patients who have demonstrated hypersensitivity to the drug [see Adverse Reactions (6.2) ] . • Urinary retention ( 4 , 5.2 ). • Gastric retention ( 4 , 5.3 ). • Uncontrolled narrow-angle glaucoma ( 4 , 5.5 ). • In patients who have demonstrated hypersensitivity to the drug ( 4 , 6.2 ).

11 DESCRIPTION Solifenacin succinate is a muscarinic receptor antagonist. Chemically, solifenacin succinate is butanedioic acid, compounded with (1 S )-(3 R )-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1 H )-iso-quinolinecarboxylate (1:1) having an empirical formula of C 23 H 26 N 2 O 2 ∙C 4 H 6 O 4 , and a molecular weight of 480.55. The structural formula of solifenacin succinate is: Solifenacin succinate is a white to light yellow powder. It is freely soluble at room temperature in water, and ethanol. Each solifenacin succinate tablet contains 5 or 10 mg of solifenacin succinate and is formulated for oral administration. In addition to the active ingredient solifenacin succinate, each solifenacin succinate tablet also contains the following inert ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 8000, talc, and titanium dioxide with yellow ferric oxide (5 mg solifenacin succinate tablet) or red ferric oxide (10 mg solifenacin succinate tablet). Chemical Structure

2 DOSAGE AND ADMINISTRATION • 5 mg tablet taken once daily, and if well tolerated may be increased to 10 mg once daily ( 2.1 ). • Do not exceed 5 mg tablet once daily in patients with: • severe renal impairment [Creatinine Clearance] (CL cr < 30 mL/min) ( 2.2 ). • moderate hepatic impairment (Child-Pugh B) ( 2.3 ). • concomitant use of potent CYP3A4 inhibitors ( 2.4 ). • Use of solifenacin succinate is not recommended in patients with severe hepatic impairment (Child-Pugh C) ( 2.3 ). 2.1 Dosing Information The recommended dose of solifenacin succinate is 5 mg once daily. If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily. Solifenacin succinate should be taken with water and swallowed whole. Solifenacin succinate can be administered with or without food. 2.2 Dose Adjustment in Patients with Renal Impairment For patients with severe renal impairment (CL cr < 30 mL/min), a daily dose of solifenacin succinate greater than 5 mg is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6) ] . 2.3 Dose Adjustment in Patients with Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh B), a daily dose of solifenacin succinate greater than 5 mg is not recommended. Use of solifenacin succinate in patients with severe hepatic impairment (Child-Pugh C) is not recommended [see Warnings and Precautions (5.6) and Use in Specific Populations (8.7) ] . 2.4 Dose Adjustment in Patients Taking CYP3A4 Inhibitors When administered with potent CYP3A4 inhibitors such as ketoconazole, a daily dose of solifenacin succinate greater than 5 mg is not recommended [see Drug Interactions (7.1) ] .

1 INDICATIONS AND USAGE Solifenacin succinate is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Solifenacin succinate is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency ( 1 ).

10 OVERDOSAGE Overdosage with solifenacin succinate can potentially result in severe anticholinergic effects and should be treated accordingly. The highest dose ingested in an accidental overdose of solifenacin succinate was 280 mg in a 5-hour period. This case was associated with mental status changes. Some cases reported a decrease in the level of consciousness. Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg daily (5 times the maximum recommended therapeutic dose) and resolved within 7 days following discontinuation of drug. In the event of overdose with solifenacin succinate, treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.

7 DRUG INTERACTIONS • Inhibitors of CYP3A4 may increase the concentration of solifenacin succinate ( 7.1 ). • Inducers of CYP3A4 may decrease the concentration of solifenacin succinate ( 7.2 ). 7.1 Potent CYP3A4 Inhibitors Following the administration of 10 mg of solifenacin succinate in the presence of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, the mean C max and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively. Therefore, it is recommended not to exceed a 5 mg daily dose of solifenacin succinate when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . The effects of weak or moderate CYP3A4 inhibitors were not examined. 7.2 CYP3A4 Inducers There were no in vivo studies conducted to evaluate the effect of CYP3A4 inducers on solifenacin succinate. In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Therefore, inducers of CYP3A4 may decrease the concentration of solifenacin. 7.3 Drugs Metabolized by Cytochrome P450 At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes. 7.4 Warfarin Solifenacin has no significant effect on the pharmacokinetics of R -warfarin or S -warfarin [see Clinical Pharmacology (12.3) ] . 7.5 Oral Contraceptives In the presence of solifenacin there are no significant changes in the plasma concentrations of combined oral contraceptives (ethinyl estradiol/levonorgestrel) [see Clinical Pharmacology (12.3) ] . 7.6 Digoxin Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects [see Clinical Pharmacology (12.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism 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. 12.2 Pharmacodynamics 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 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 Tmax (relative to placebo) 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 Drug/Dose Fridericia method (using mean difference) Solifenacin 10 mg 2 (-3,6) Solifenacin 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 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. 12.3 Pharmacokinetics Absorption After oral administration of solifenacin succinate 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 may be administered without regard to meals. A single 10 mg dose administration of solifenacin succinate 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 ∝ 1 -acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L. 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 45-68 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 mcg ethinyl estradiol and 150 mcg 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) ] .

12.1 Mechanism 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.

12.2 Pharmacodynamics 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 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 Tmax (relative to placebo) 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 Drug/Dose Fridericia method (using mean difference) Solifenacin 10 mg 2 (-3,6) Solifenacin 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 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.

12.3 Pharmacokinetics Absorption After oral administration of solifenacin succinate 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 may be administered without regard to meals. A single 10 mg dose administration of solifenacin succinate 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 ∝ 1 -acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L. 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 45-68 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 mcg ethinyl estradiol and 150 mcg 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) ] .

20200601

2

3 DOSAGE FORMS AND STRENGTHS The 5 mg tablets are light yellow, round, film coated tablets debossed with 'SG' on one side and '427' on other side. The 10 mg tablets are light pink, round, film coated tablets debossed with 'SG' on one side and '428' on other side. Tablets: 5 mg and 10 mg ( 3 ).

Solifenacin Succinate Solifenacin Succinate Solifenacin Succinate Solifenacin STARCH, CORN HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 8000 TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW SG;427 Solifenacin Succinate Solifenacin Succinate Solifenacin Succinate Solifenacin STARCH, CORN HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 8000 TALC TITANIUM DIOXIDE FERRIC OXIDE RED SG;428

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 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.

ANDA211657

Solifenacin Succinate

Solifenacin Succinate

71205-986

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label NDC 71205-986-30 Rx Only Solifenacin Succinate Tablets 5 mg ONCE DAILY 30 Tablets 71205-986-30

Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 Manufactured for: Westminster Pharmaceuticals, LLC Nashville, TN 37217 Rev. 09/19

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients should be informed that antimuscarinic agents such as solifenacin succinate have been associated with constipation and blurred vision. Patients should be advised to contact their physician if they experience severe abdominal pain or become constipated for 3 or more days. Because solifenacin succinate may cause blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effect on the patient's vision has been determined. Heat prostration (due to decreased sweating) can occur when anticholinergic drugs, such as solifenacin succinate, are used in a hot environment. Patients should read the patient leaflet entitled "Patient Information solifenacin succinate" before starting therapy with solifenacin succinate. Patients should be informed that solifenacin may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue solifenacin therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.

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 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 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 was similar across patient age 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 placebo (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 Change from Baseline to Endpoint for Solifenacin Succinate (5 mg and 10 mg daily) and Placebo: Study 1 Parameter Placebo Solifenacin succinate 5 mg Solifenacin succinate 10 mg (N=253) Mean (SE) (N=266) Mean (SE) (N=264) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) Primary endpoint Baseline 12.2 (0.26) 12.1 (0.24) 12.3 (0.24) Reduction 1.2 (0.21) 2.2 (0.18) 2.6 (0.20) P value vs. placebo < 0.001 < 0.001 Number of Incontinence Episodes/24 hours Secondary endpoint Baseline 2.7 (0.23) 2.6 (0.22) 2.6 (0.23) Reduction 0.8 (0.18) 1.4 (0.15) 1.5 (0.18) P value vs. placebo < 0.01 < 0.01 Volume Voided per Micturition [mL] Baseline 143.8 (3.37) 149.6 (3.35) 147.2 (3.15) Increase 7.4 (2.28) 32.9 (2.92) 39.2 (3.11) P value vs. placebo < 0.001 < 0.001 Table 4: Mean Change from Baseline to Endpoint for Solifenacin Succinate (5 mg and 10 mg daily) and Placebo: Study 2 Parameter Placebo Solifenacin succinate 5 mg Solifenacin succinate 10 mg (N=281) Mean (SE) (N=286) Mean (SE) (N=290) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) Primary endpoint Baseline 12.3 (0.23) 12.1 (0.23) 12.1 (0.21) Reduction 1.7 (0.19) 2.4 (0.17) 2.9 (0.18) P value vs. placebo < 0.001 < 0.001 Number of Incontinence Episodes/24 hours Secondary endpoint Baseline 3.2 (0.24) 2.6 (0.18) 2.8 (0.20) Reduction 1.3 (0.19) 1.6 (0.16) 1.6 (0.18) P value vs. placebo < 0.01 0.016 Volume Voided per Micturition [mL] Baseline 147.2 (3.18) 148.5 (3.16) 145.9 (3.42) Increase 11.3 (2.52) 31.8 (2.94) 36.6 (3.04) P value vs. placebo < 0.001 < 0.001 Table 5: Mean Change from Baseline to Endpoint for Solifenacin Succinate (10 mg daily) and Placebo: Study 3 Parameter Placebo Solifenacin succinate 10 mg (N=309) Mean (SE) (N=306) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) Primary endpoint Baseline 11.5 (0.18) 11.7 (0.18) Reduction 1.5 (0.15) 3.0 (0.15) P Value vs. placebo < 0.001 Number of Incontinence Episodes/24 hours Secondary endpoint Baseline 3.0 (0.20) 3.1 (0.22) Reduction 1.1 (0.16) 2.0 (0.19) P value vs. placebo < 0.001 Volume Voided per Micturition [mL] Baseline 190.3 (5.48) 183.5 (4.97) Increase 2.7 (3.15) 47.2 (3.79) P value vs. placebo < 0.001 Table 6: Mean Change from Baseline to Endpoint for Solifenacin Succinate (10 mg daily) and Placebo: Study 4 Parameter Placebo Solifenacin succinate 10 mg (N=295) Mean (SE) (N=298) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) Primary endpoint Baseline 11.8 (0.18) 11.5 (0.18) Reduction 1.3 (0.16) 2.4 (0.15) P value vs. placebo < 0.001 Number of Incontinence Episodes/24 hours Secondary endpoint Baseline 2.9 (0.18) 2.9 (0.17) Reduction 1.2 (0.15) 2.0 (0.15) P value vs. placebo < 0.001 Volume Voided per Micturition [mL] Baseline 175.7 (4.44) 174.1 (4.15) Increase 13.0 (3.45) 46.4 (3.73) P value vs. placebo < 0.001

8.5 Geriatric Use In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients < 65 years) treated with solifenacin succinate. Multiple dose studies of solifenacin succinate in elderly volunteers (65 to 80 years) showed that C max , AUC and t 1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years).

8.2 Labor and Delivery The effect of solifenacin succinate on labor and delivery in humans has not been studied. There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality.

8.3 Nursing Mothers After oral administration of 14 C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD]. Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period. It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, solifenacin succinate should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue solifenacin succinate in nursing mothers.

8.4 Pediatric Use The safety and effectiveness of solifenacin succinate in pediatric patients have not been established.

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14 C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (< 1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin succinate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14 C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (< 1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin succinate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8 USE IN SPECIFIC POPULATIONS Pregnancy and Nursing Mothers: Solifenacin succinate should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Solifenacin succinate should not be administered during nursing ( 8.1 , 8.3 ). Pediatric Use: The safety and effectiveness of solifenacin succinate in pediatric patients have not been established ( 8.4 ). 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14 C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (< 1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin succinate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.2 Labor and Delivery The effect of solifenacin succinate on labor and delivery in humans has not been studied. There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality. 8.3 Nursing Mothers After oral administration of 14 C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD]. Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period. It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, solifenacin succinate should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue solifenacin succinate in nursing mothers. 8.4 Pediatric Use The safety and effectiveness of solifenacin succinate in pediatric patients have not been established. 8.5 Geriatric Use In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients < 65 years) treated with solifenacin succinate. Multiple dose studies of solifenacin succinate in elderly volunteers (65 to 80 years) showed that C max , AUC and t 1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years). 8.6 Renal Impairment Solifenacin succinate should be used with caution in patients with renal impairment. There is a 2.1-fold increase in AUC and 1.6-fold increase in t 1/2 of solifenacin in patients with severe renal impairment. Doses of solifenacin succinate greater than 5 mg are not recommended in patients with severe renal impairment (CL cr < 30 mL/min) [see Warnings and Precautions (5.7) and Dosage and Administration (2.2) ] . 8.7 Hepatic Impairment Solifenacin succinate should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t 1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of solifenacin succinate greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin succinate is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.6) and Dosage and Administration (2.3) ] . 8.8 Gender The pharmacokinetics of solifenacin is not significantly influenced by gender.

16 HOW SUPPLIED/STORAGE AND HANDLING Solifenacin succinate tablets, 5 mg, are light yellow, round, film coated tablets debossed with 'SG' on one side and '427' on other side. They are supplied as follows: NDC 71205-986-30 bottles of 30 NDC 71205-986-60 bottles of 60 NDC 71205-986-90 bottles of 90 Solifenacin succinate tablets, 10 mg, are light pink, round, film coated tablets debossed with 'SG' on one side and '428' on other side. They are supplied as follows: • NDC 71205-987-30 bottles of 30 NDC 71205-987-60 bottles of 60 NDC 71205-987-90 bottles of 90 Store at 25°C (77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from moisture.

Store at 25°C (77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from moisture.