Solifenacin Succinate

6 ADVERSE REACTIONS The most common adverse reactions (> 4% in solifenacin succinate-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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 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 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 10 mg group. Angioneurotic edema was 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 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 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 5 mg (%) Solifenacin Succinate 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 2.0 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 Urinary Tract 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 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 transferase); Renal and urinary disorders : renal impairment, urinary retention; Metabolism and nutrition disorders : decreased appetite, hyperkalemia; Skin and subcutaneous tissue disorders : exfoliative dermatitis, erythema multiforme, dry skin; Eye disorders : glaucoma; Gastrointestinal disorders : gastroesophageal reflux disease, ileus, vomiting, abdominal pain, dysgeusia, sialadenitis; Respiratory, thoracic and mediastinal disorders : dysphonia, nasal dryness; Musculoskeletal and connective tissue disorders : muscular weakness.

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 )

11 DESCRIPTION Solifenacin succinate is a muscarinic receptor antagonist. Chemically, solifenacin succinate is a butanedioic acid compound 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 molecular 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 pale-yellowish-white crystals or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Each solifenacin succinate tablet contains 5 mg or 10 mg of solifenacin succinate and is for oral administration. In addition to the active ingredient solifenacin succinate, each solifenacin succinate tablet also contains the following inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, talc, and titanium dioxide. In addition, the 5 mg tablets also contain yellow iron oxide and the 10 mg tablets contain red iron oxide. Chemical Structure

2 DOSAGE AND ADMINISTRATION 5 mg tablet taken orally once daily, and if well tolerated may be increased to 10 mg once daily. ( 2.1 ) Do not exceed the 5 mg dose of solifenacin succinate tablets in patients with: Severe renal impairment creatinine clearance < 30 mL/min/1.73 m 2 . ( 2.2 , 8.6 ) Moderate hepatic impairment (Child-Pugh B). Solifenacin succinate tablets are not recommended in patients with severe hepatic impairment (Child-Pugh C). ( 2.3 , 8.7 ) Concomitant use of strong CYP3A4 inhibitors. ( 2.4 , 7.1 ) 2.1 Dosing Information The recommended oral dose of solifenacin succinate tablets 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 Dosing Recommendations in Patients with Renal Impairment Do not exceed 5 mg once daily in patients with severe renal impairment (CL cr < 30 mL/min/1.73 m 2 ) [see Use in Specific Populations (8.6) ] . 2.3 Dosing Recommendations in Patients with Hepatic Impairment Do not exceed 5 mg once daily in patients with moderate hepatic impairment (Child-Pugh B). Do not use solifenacin succinate tablets in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7) ] . 2.4 Dosing Recommendations in Patients Taking CYP3A4 Inhibitors Do not exceed 5 mg once daily when solifenacin succinate tablets are administered with strong CYP3A4 inhibitors such as ketoconazole [see Drug Interactions (7.1) ] .

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

10 OVERDOSAGE Overdosage with solifenacin succinate 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, treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.

7 DRUG INTERACTIONS CYP3A4 Inhibitors : Do not exceed the 5 mg dose of solifenacin succinate with concomitant use of strong CYP3A4 inhibitors. ( 7.1 ) 7.1 Strong CYP3A4 Inhibitors Solifenacin is a substrate of CYP3A4. Concomitant use of ketoconazole, a strong CYP3A4 inhibitor, significantly increased the exposure of solifenacin [see Clinical Pharmacology (12.3) ] . The dosage of solifenacin succinate greater than 5 mg once daily is not recommended when concomitantly used with strong CYP3A4 inhibitors [see Dosage and Administration (2.4) ] .

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. 12.2 Pharmacodynamics 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, 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 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 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. Drug/Dose Fridericia method (using mean difference) 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. 12.3 Pharmacokinetics 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 to 62.9 ng/mL for the 5 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 α 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 solifenacin succinate, the mean C max and AUC increased by 5% and 1%, respectively. 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 succinate 10 mg or matching placebo once daily for 10 days starting from the 12 th day of receipt of oral contraceptives. For ethinyl estradiol, when it was administered with solifenacin succinate, the mean C max and AUC increased by 2% and 3%, respectively. For levonorgestrel, when it was administered with solifenacin succinate, the mean C max and AUC decreased by 1%. 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 succinate 10 mg or matching placebo with digoxin 0.125 mg for an additional 10 days. When digoxin was coadministered with solifenacin succinate, the mean C max and AUC increased by 13% and 4%, respectively. Drugs Metabolized by Cytochrome P450 Enzymes In vitro studies demonstrated that, at therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.

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.

12.2 Pharmacodynamics 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, 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 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 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. Drug/Dose Fridericia method (using mean difference) 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.

12.3 Pharmacokinetics 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 to 62.9 ng/mL for the 5 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 α 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 solifenacin succinate, the mean C max and AUC increased by 5% and 1%, respectively. 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 succinate 10 mg or matching placebo once daily for 10 days starting from the 12 th day of receipt of oral contraceptives. For ethinyl estradiol, when it was administered with solifenacin succinate, the mean C max and AUC increased by 2% and 3%, respectively. For levonorgestrel, when it was administered with solifenacin succinate, the mean C max and AUC decreased by 1%. 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 succinate 10 mg or matching placebo with digoxin 0.125 mg for an additional 10 days. When digoxin was coadministered with solifenacin succinate, the mean C max and AUC increased by 13% and 4%, respectively. Drugs Metabolized by Cytochrome P450 Enzymes In vitro studies demonstrated that, at therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.

20230404

2

3 DOSAGE FORMS AND STRENGTHS The 5 mg tablets are light yellow colored, round shaped, biconvex, film-coated tablets debossed with ‘CC’ on one side and ‘31’ on the other side. The 10 mg tablets are light pink colored, round shaped, biconvex, film-coated tablets debossed with ‘CC’ on one side and ‘32’ on the other side. Tablets: 5 mg and 10 mg. (3)

Solifenacin Succinate Solifenacin Succinate SOLIFENACIN SUCCINATE SOLIFENACIN SILICON DIOXIDE STARCH, CORN HYPROMELLOSE 2910 (5 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 4000 TALC TITANIUM DIOXIDE FERRIC OXIDE YELLOW Light Yellow Biconvex CC;31 Solifenacin Succinate Solifenacin Succinate SOLIFENACIN SUCCINATE SOLIFENACIN SILICON DIOXIDE STARCH, CORN HYPROMELLOSE 2910 (5 MPA.S) HYPROMELLOSE 2910 (6 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 4000 TALC TITANIUM DIOXIDE FERRIC OXIDE RED Light Pink Biconvex CC;32

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

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

ANDA206817

Solifenacin Succinate

Solifenacin Succinate

65862-878

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 5 mg (30 Tablet Bottle) NDC 65862-878-30 Rx only Solifenacin Succinate Tablets 5 mg ONCE-DAILY AUROBINDO 30 Tablets PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 5 mg (30 Tablet Bottle)

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Angioedema and Anaphylactic Reactions Inform patients that angioedema and anaphylactic reactions have been reported in patients treated with solifenacin succinate. Angioedema and anaphylactic reactions may be life-threatening. Advise patients to promptly discontinue solifenacin succinate therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing [see Contraindications (4) and Warnings and Precautions (5.1) ] . Urinary Retention Inform patients that solifenacin succinate may cause urinary retention in patients with conditions associated with bladder outlet obstruction [see Warnings and Precautions (5.2) ] . Gastrointestinal Disorders Inform patients that solifenacin succinate may cause further decrease in gastrointestinal motility in patients with conditions associated with decreased gastrointestinal motility. Solifenacin succinate has been associated with constipation and dry mouth. Advise patients to contact their health care providers if they experience severe abdominal pain or become constipated for 3 or more days [see Warnings and Precautions (5.3) ] . Central Nervous System Effects Because solifenacin succinate, like other antimuscarinic agents, may cause central nervous system effects or blurred vision, advise patients to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effect on the patient has been determined [see Warnings and Precautions (5.4) ] . Narrow-Angle Glaucoma Inform patients that solifenacin succinate, like other antimuscarinics, may cause worsening of the glaucoma condition in patients with narrow-angle glaucoma [see Warnings and Precautions (5.5) ] . Dry Skin Inform patients that solifenacin succinate, like other antimuscarinics, may cause dry skin due to decreased sweating. Heat prostration due to decreased sweating can occur when solifenacin succinate is used in a hot environment [see Adverse Reactions (6.2) ] . Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad–500 032, India Revised: 03/2023

14 CLINICAL STUDIES Solifenacin succinate was evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in adult patients having symptoms of urinary frequency, urgency, and/or urge or mixed incontinence (with a predominance of urge). Entry criteria required that patients have symptoms of overactive bladder for ≥ 3 months duration. These studies involved 3027 patients (1811 on solifenacin succinate and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg solifenacin succinate doses (Studies 1 and 2) and the other two evaluated only the 10 mg dose (Studies 3 and 4). All patients completing the 12-week studies were eligible to enter an open-label, long-term extension study (Study 5) and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with a mean age of 58 years. The primary endpoint in all four trials was the mean change from baseline to 12 weeks in number of micturitions/24 hours. Secondary endpoints included mean change from baseline to 12 weeks in number of incontinence episodes/24 hours, and mean volume voided per micturition. The efficacy of solifenacin succinate was similar across patient age groups and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with solifenacin succinate 5 mg (2.3; p < 0.001) and solifenacin succinate 10 mg (2.7; p < 0.001) compared to placebo (1.4). The mean reduction in the number of incontinence episodes per 24 hours was significantly greater with solifenacin succinate 5 mg (1.5; p < 0.001) and solifenacin succinate 10 mg (1.8; p < 0.001) treatment groups compared to the placebo treatment group (1.1). The mean increase in the volume voided per micturition was significantly greater with solifenacin succinate 5 mg (32.3 mL; p < 0.001) and solifenacin succinate 10 mg (42.5 mL; p < 0.001) compared with placebo (8.5 mL). The results for the primary and secondary endpoints in the four individual 12-week clinical studies of solifenacin succinate are reported in Tables 3 through 6. Table 3: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 1 1. Primary endpoint 2. Secondary endpoint Parameter Placebo (N=253) Mean (SE) Solifenacin Succinate 5 mg (N=266) Mean (SE) Solifenacin Succinate 10 mg (N=264) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) 1 Baseline Reduction P value vs. placebo 12.2 (0.26) 1.2 (0.21) 12.1 (0.24) 2.2 (0.18) < 0.001 12.3 (0.24) 2.6 (0.20) < 0.001 Number of Incontinence Episodes/24 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) < 0.01 Volume Voided per Micturition [mL] 2 Baseline Increase P value vs. placebo 143.8 (3.37) 7.4 (2.28) 149.6 (3.35) 32.9 (2.92) < 0.001 147.2 (3.15) 39.2 (3.11) < 0.001 Table 4: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 2 1. Primary endpoint 2. Secondary endpoint Parameter Placebo (N=281) Mean (SE) Solifenacin Succinate 5 mg (N=286) Mean (SE) Solifenacin Succinate 10 mg (N=290) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) 1 Baseline Reduction P value vs. placebo 12.3 (0.23) 1.7 (0.19) 12.1 (0.23) 2.4 (0.17) < 0.001 12.1 (0.21) 2.9 (0.18) < 0.001 Number of Incontinence Episodes/24 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 1. Primary endpoint 2. Secondary endpoint Parameter Placebo (N=309) Mean (SE) Solifenacin Succinate 10 mg (N=306) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) 1 Baseline Reduction P value vs. placebo 11.5 (0.18) 1.5 (0.15) 11.7 (0.18) 3.0 (0.15) < 0.001 Number of Incontinence Episodes/24 hours 2 Baseline Reduction P value vs. placebo 3.0 (0.20) 1.1 (0.16) 3.1 (0.22) 2.0 (0.19) < 0.001 Volume Voided per Micturition [mL] 2 Baseline Increase P value vs. placebo 190.3 (5.48) 2.7 (3.15) 183.5 (4.97) 47.2 (3.79) < 0.001 Table 6: Mean Changes from Baseline to Week 12 in Efficacy Endpoints in Study 4 1. Primary endpoint 2. Secondary endpoint Parameter Placebo (N=295) Mean (SE) Solifenacin Succinate 10 mg (N=298) Mean (SE) Urinary Frequency (Number of Micturitions/24 hours) 1 Baseline Reduction P value vs. placebo 11.8 (0.18) 1.3 (0.16) 11.5 (0.18) 2.4 (0.15) < 0.001 Number of Incontinence Episodes/24 hours 2 Baseline Reduction P value vs. placebo 2.9 (0.18) 1.2 (0.15) 2.9 (0.17) 2.0 (0.15) < 0.001 Volume Voided per Micturition [mL] 2 Baseline Increase P value vs. placebo 175.7 (4.44) 13.0 (3.45) 174.1 (4.15) 46.4 (3.73) < 0.001

8.5 Geriatric Use In placebo-controlled clinical studies, similar safety and effectiveness were observed between geriatric patients (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger adult patients (1188 patients < 65 years) treated with solifenacin succinate [see Clinical Pharmacology (12.3) ] .

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 and any potential adverse effects on the breastfed child from solifenacin succinate 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 milk.

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

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 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 and any potential adverse effects on the breastfed child from solifenacin succinate 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 milk. 8.4 Pediatric Use The safety and effectiveness of solifenacin succinate tablets have not been established in pediatric patients. 8.5 Geriatric Use In placebo-controlled clinical studies, similar safety and effectiveness were observed between geriatric patients (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger adult patients (1188 patients < 65 years) treated with solifenacin succinate [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment Solifenacin plasma concentrations are greater in patients with severe renal impairment compared to subjects with normal renal function [see Clinical Pharmacology (12.3) ] . Because increased solifenacin plasma concentrations increase the risk of antimuscarinic adverse reactions, the maximum recommended dose of solifenacin succinate in patients with severe renal impairment (CL cr < 30 mL/min/1.73 m 2 ) is 5 mg once daily [see Dosage and Administration (2.2) ] . The recommended dose in patients with mild or moderate renal impairment is the same as in patients with normal renal function. 8.7 Hepatic Impairment Solifenacin plasma concentrations are greater in patients with moderate hepatic impairment compared to subjects with normal hepatic function [see Clinical Pharmacology (12.3) ] . Because increased solifenacin plasma concentrations increase the risk of antimuscarinic adverse reactions, the maximum recommended dose of solifenacin succinate in patients with moderate hepatic impairment (Child-Pugh B) is 5 mg once daily [see Dosage and Administration (2.3) ] and solifenacin succinate is not recommended for use in patients with severe hepatic impairment (Child-Pugh C). 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 colored, round shaped, biconvex, film-coated tablets debossed with ‘CC’ on one side and ‘31’ on the other side. Bottles of 30 NDC 65862-878-30 Bottles of 90 NDC 65862-878-90 Bottles of 1,000 NDC 65862-878-99 3 x 10 Unit-dose Tablets NDC 65862-878-03 Solifenacin Succinate Tablets 10 mg are light pink colored, round shaped, biconvex, film-coated tablets debossed with ‘CC’ on one side and ‘32’ on the other side. Bottles of 30 NDC 65862-879-30 Bottles of 90 NDC 65862-879-90 Bottles of 1,000 NDC 65862-879-99 3 x 10 Unit-dose Tablets NDC 65862-879-03 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].