Solifenacin Succinate

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 )

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) ] .

5 WARNINGS AND PRECAUTIONS Angioedema and Anaphylactic Reactions : Promptly discontinue Solifenacin Succinate Tablets and provide appropriate therapy. ( 5.1 ) Urinary Retention : Solifenacin Succinate Tablets are not recommended for use in patients with clinically significant bladder outlet obstruction. ( 5.2 ) Gastrointestinal Disorders : Solifenacin Succinate Tablets are not recommended for use in patients with decreased gastrointestinal motility. ( 5.3 ) Central Nervous System Effects: Somnolence has been reported with Solifenacin Succinate Tablets. Advise patients not to drive or operate heavy machinery until they know how Solifenacin Succinate Tablets affect them. ( 5.4 ) Controlled Narrow-Angle Glaucoma : Use Solifenacin Succinate Tablets with caution in patients being treated for narrow-angle glaucoma. ( 5.5 ) QT Prolongation in Patients at High Risk of QT Prolongation : Solifenacin Succinate Tablets are not recommended for use in patients at high risk of QT prolongation, including patients with a known history of QT prolongation and patients taking medications known to prolong the QT interval. ( 5.6 ) 5.1 Angioedema and Anaphylactic Reactions Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin succinate. In some cases, angioedema occurred after the first dose, however, cases have been reported to occur hours after the first dose or after multiple doses. Anaphylactic reactions have also been reported in patients treated with solifenacin succinate. Angioedema associated with upper airway swelling and anaphylactic reactions may be life-threatening. Solifenacin Succinate Tablets are contraindicated in patients with a known or suspected hypersensitivity to solifenacin succinate [see Contraindications (4) ] . If involvement of the tongue, hypopharynx, or larynx occurs, promptly discontinue Solifenacin Succinate Tablets andprovide appropriate therapy and/or measures necessary to ensure a patent airway. 5.2 Urinary Retention The use of Solifenacin Succinate Tablets, like other antimuscarinic drugs, in patients with clinically significant bladder outlet obstruction including patients with urinary retention, may result in further urinary retention and kidney injury. The use of Solifenacin Succinate Tablets is not recommended in patients with clinically significant bladder outlet obstruction and is contraindicated in patients with urinary retention [see Contraindications (4) ] . 5.3 Gastrointestinal Disorders The use of Solifenacin Succinate Tablets, like other antimuscarinic drugs, in patients with conditions associated with decreased gastrointestinal motility may result in further decreased gastrointestinal motility. Solifenacin Succinate Tablets are contraindicated in patients with gastric retention [see Contraindications (4) ] . The use of Solifenacin Succinate Tablets is not recommended in patients with conditions associated with decreased gastrointestinal motility. 5.4 Central Nervous System Effects Solifenacin Succinate Tablets are associated with antimuscarinic central nervous system (CNS) adverse reactions [see Adverse Reactions (6.2) ]. A variety of CNS antimuscarinic adverse reactions have been reported, including headache, confusion, hallucinations, and somnolence. Monitor patients for signs of antimuscarinic CNS adverse reactions, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Solifenacin Succinate Tablets affect them. If a patient experiences antimuscarinic CNS adverse reactions, consider dose reduction or drug discontinuation. 5.5 Controlled Narrow-Angle Glaucoma Solifenacin Succinate Tablets should be used with caution in patients being treated for narrow-angle glaucoma [see Contraindications (4) ]. 5.6 QT Prolongation in Patients at High Risk of QT Prolongation In a study of the effect of solifenacin succinate on the QT interval conducted in 76 healthy women [see Clinical Pharmacology (1…

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 )

7 DRUG INTERACTIONS CYP3A4 Inhibitors : Do not exceed the 5 mg dose of Solifenacin Succinate Tablets 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 Tablets greater than 5 mg once daily is not recommended when concomitantly used with strong CYP3A4 inhibitors [see Dosage and Administration (2.4) ] .

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 2-4% and 15-20%, 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.

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 AustarPharma LLC at 1-844-375-5410 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 1-4) [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 2.0 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);…