SOLIFENACIN SUCCINATE

Solifenacin Succinate Tablets (solifenacin succinate) is a muscarinic receptor antagonist. Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)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 pale-yellowish-white crystal 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 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, pregelatinized starch, hypromellose 2910, magnesium stearate, triacetin, polyethylene glycol 3350 and titanium dioxide with yellow ferric oxide and red ferric oxide. structure-solifenacin

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

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: o severe renal impairment [Creatinine Clearance] (CLcr <30 ml/min) ( 2.2 ) o moderate hepatic impairment (Child-Pugh B) ( 2.3 ) o concomitant use of potent CYP3A4 inhibitors ( 2.4 ) Use of Solifenacin Succinate Tablets is not recommended in patients with severe hepatic impairment (Child-Pugh C) ( 2.3 ) 2.1 Dosing Information The recommended 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 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 ); 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 ); 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 ) ].

Solifenacin 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 )

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 AvKARE at 1-855-361-3993 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 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 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 10 mg group. Angioneurotic edema has been reported in one patient taking Solifenacin 5 mg. Compared to 12 weeks of treatment with Solifenacin, 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 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, 5 mg (%) Solifenacin, 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 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, palpitations; Hepatic: liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase); Renal: renal impairment; Metabolism and nutrition disorders: decreased appetite, hyperkalemia; Dermatologic: exfoliative dermatitis and erythema multiforme; Eye disorders: glaucoma; Gastrointestinal disorders: gastroesophageal reflux disease and ileus; Respiratory, thoracic and mediastinal disorders: dysphonia; Musculoskeletal and connective tissue disorders: muscular weakness; To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Inhibitors of CYP3A4 may increase the concentration of Solifenacin ( 7.1 ). Inducers of CYP3A4 may decrease the concentration of Solifenacin ( 7.2 ). 7.1 Potent CYP3A4 Inhibitors Following the administration of 10 mg of Solifenacin in 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 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. 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 ) ].