Solifenacin Succinate

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

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 tablet is not recommended in patients with severe hepatic impairment (Child-Pugh C) (2.3). 2.1 Dosing Information The recommended dose of solifenacin succinate tablet 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 tablets should be taken with water and swallowed whole. Solifenacin succinate tablets 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 tablets 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 tablets greater than 5 mg is not recommended. Use of solifenacin succinate tablets 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 tablets greater than 5 mg is not recommended [see Drug Interactions (7.1)] .

3 DOSAGE FORMS AND STRENGTHS The 5 mg tablets are creamish to light yellow, round, film-coated tablets, debossed with “L” on one side and “431” on other side. The 10 mg tablets are light pink, round, film-coated tablets, debossed with “L” on one side and “432” on other side. Tablets: 5 mg and 10 mg. (3)

4 CONTRAINDICATIONS Solifenacin succinate tablets are contraindicated in patients: With urinary retention [see Warnings and Precautions (5.2)], With gastric retention [see Warnings and Precautions (5.3)], With uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.5)], and Who have demonstrated hypersensitivity to solifenacin succinate or the inactive ingredients in solifenacin succinate tablets. Reported adverse reactions have included anaphylaxis and angioedema [see Adverse Reactions (6.2)]. Urinary retention. (4, 5.2) Gastric retention. (4, 5.3) Uncontrolled narrow-angle glaucoma. (4, 5.5) Hypersensitivity to this product or any of its components. (4, 5.1, 6.2)

6 ADVERSE REACTIONS The most common adverse reactions (>4% in solifenacin succinate tablets-treated patients and >placebo-treated patients) 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 Alembic Pharmaceuticals Limited at 1-866-210-9797 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 tablets have been evaluated for safety in 1811 adult patients in four randomized, placebo-controlled trials (Studies 1 to 4) [see Clinical Studies (14)] . 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 tablets was higher in the 10 mg dose group 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 tablets 10 mg group. Angioneurotic edema was reported in one patient taking solifenacin succinate tablets 5 mg. Compared to 12 weeks of treatment with solifenacin succinate tablets, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months in Study 5 [see Clinical studies (14)]. The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, in the four randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with solifenacin succinate tablets 5 or 10 mg once daily for up to 12 weeks. Table 1: Adverse Reactions Reported by ≥ 1% of Patients and Exceeding Placebo in Studies 1, 2, 3 and 4 Placebo (%) Solifenacin Succinate Tablets 5 mg (%) Solifenacin Succinate Tablets 10 mg (%) Number of Patients 1216 578 1233 GASTROINTESTINAL DISORDERS Dry Mouth 4.2 10.9 27.6 Constipation 2.9 5.4 13.4 Nausea 2 1.7 3.3 Dyspepsia 1 1.4 3.9 Abdominal Pain Upper 1 1.9 1.2 Vomiting NOS 0.9 0.2 1.1 INFECTIONS AND INFESTATIONS Urinary Tract Infection NOS 2.8 2.8 4.8 Influenza 1.3 2.2 0.9 Pharyngitis NOS 1 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 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 Postmarketing Experience The following adverse reactions have been identified during post-approval use of solifenacin succinate in the U.S. and/or outside of the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions : peripheral edema, hypersensitivity reactions (including angioedema with airway obstruction, rash, pruritus, urticaria, anaphylactic reaction); Nervous system disorders : dizziness, headache, confusion, hallucinations, delirium, somnolence; Cardiac disorders : QT prolongation, Torsade de Pointes, atrial fibrillation, tachycardia, palpitations; Hepatobiliary disorders : liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl trans …

7 DRUG INTERACTIONS Inhibitors of CYP3A4 may increase the concentration of solifenacin succinate tablets (7.1). Inducers of CYP3A4 may decrease the concentration of solifenacin succinate tablets (7.2). 7.1 Potent CYP3A4 Inhibitors Following the administration of 10 mg of solifenacin succinate tablets 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 tablets 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 tablets. 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)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies with the use of solifenacin succinate in pregnant women to inform a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes. No adverse developmental outcomes were observed in animal reproduction studies with oral administration of solifenacin succinate to pregnant mice during the period of organogenesis at a dose resulting in 1.2 times the systemic exposure at the maximum recommended human dose (MRHD) of 10 mg/day. However, administration of doses 3.6 times and greater than the MRHD during organogenesis produced maternal toxicity in the pregnant mice and resulted in developmental toxicity and reduced fetal body weights in offspring [see Data] . In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of 14 C-solifenacin succinate to pregnant mice resulted in the recovery of radiolabel in the fetus indicating that solifenacin-related product can cross the placental barrier. In pregnant mice, administration of solifenacin succinate at a dose of 250 mg/kg/day (7.9 times the systemic exposure at the MRHD of 10 mg), resulted in an increased incidence of cleft palate and increased maternal lethality. Administration of solifenacin succinate to pregnant mice during organogenesis at greater than or equal to 3.6 times (100 mg/kg/day and greater) the systemic exposure at the MRHD, resulted in reduced fetal body weights and reduced maternal body weight gain. No embryo-fetal toxicity or teratogenicity was observed in fetuses from pregnant mice treated with solifenacin succinate at a dose of 30 mg/kg/day (1.2 times the systemic exposure at the MRHD). Administration of solifenacin succinate to pregnant rats and rabbits at a dose of 50 mg/kg/day (<1 times and 1.8 times the systemic exposure at the MRHD, respectively), resulted in no findings of embryo-fetal toxicity. Oral pre- and post-natal administration of solifenacin succinate at 100 mg/kg/day (3.6 times the systemic exposure at the MRHD) during the period of organogenesis through weaning, resulted in reduced peripartum and postnatal survival, reduced body weight gain by the pups, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring (F2 generation) exposed to maternal doses of 250 mg/kg/day. There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected systemic exposure at the MRHD. 8.2 Lactation Risk Summary There is no information on the presence of solifenacin in human milk, the effects on the breastfed child, or the effects on milk production. Solifenacin is present in mouse milk [see Data] . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for solifenacin succinate tablets and any potential adverse effects on the breastfed child from solifenacin succinate tablets or from the underlying maternal condition. Data Animal Data Oral administration of 14 C-solifenacin succinate to lactating mice resulted in the recovery of radioactivity in maternal milk. Lactating female mice orally administered solifenacin succinate at a maternally toxic dose of 100 mg/kg/day (3.6 times the systemic exposure at the MRHD) had increased postpartum pup mortality, pups with reduced body weights, or delays in the onset of reflex and physical development. Pups from lactating dams orally administered solifenacin succinate at a dose of 30 mg/kg/day (1.2 times the systemic exposure at the MRHD) had no discernible adverse findings. The concentrations of solifenacin in animal milk does not necessarily predict the concentration of drug in human …

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.

11 DESCRIPTION Solifenacin succinate tablets are 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 off white powder. It is freely soluble in water, methanol, acetic acid and dimethyl sulfoxide. Each solifenacin succinate tablet contains 5 mg 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: lactose monohydrate, hypromellose, corn starch, magnesium stearate,titanium dioxide, polyethylene glycol, talc, iron oxide yellow with D&C Yellow #10 Aluminum Lake (5 mg solifenacin succinate tablet) or iron oxide red (10 mg solifenacin succinate tablet). Structure

10 OVERDOSAGE Overdosage with solifenacin succinate tablets can potentially result in severe antimuscarinic effects and should be treated accordingly. The highest dose ingested in an accidental overdose of solifenacin succinate was 280 mg (28 times the maximum dosage) in a 5-hour period. This case was associated with mental status changes. Some cases reported a decrease in the level of consciousness. Intolerable antimuscarinic adverse reactions (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 tablets, treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.

16 HOW SUPPLIED/STORAGE AND HANDLING Solifenacin succinate tablets 5 mg are creamish to light yellow, round, film-coated tablets, debossed with “L” on one side and “431” on other side. They are supplied as follows: NDC 62332-192-30 Bottle of 30 NDC 62332-192-90 Bottle of 90 NDC 62332-192-91 Bottle of 1000 NDC 62332-192-08 Carton of 80 (10 x 8) unit-dose tablets Solifenacin succinate tablets 10 mg are light pink, round, film-coated tablets, debossed with “L” on one side and “432” on other side. They are supplied as follows: NDC 62332-193-30 Bottle of 30 NDC 62332-193-90 Bottle of 90 NDC 62332-193-91 Bottle of 1000 NDC 62332-193-08 Carton of 80 (10 x 8) unit-dose tablets Store at 25oC (77oF) with excursions permitted from 15oC to 30oC (59°F to 86oF) [see USP Controlled Room Temperature].