Solifenacin Succinate solifenacin succiate 5 mg Tablet, Film Coated, 90-count

5 WARNINGS AND PRECAUTIONS Angioedema and anaphylactic reactions: Reports of angioedema of the face, lips and/or larynx, in some cases occurring after the first dose, have been described. Anaphylactic reactions have been reported rarely ( 5.1 ) Urinary Retention: Administer with caution to patients with clinically significant bladder outflow obstruction ( 5.2 ) Gastrointestinal Disorders: Use with caution in patients with decreased gastrointestinal motility ( 5.3 ) Central Nervous System Effects: Somnolence has been reported with Solifenacin.

Advise patients not to drive or operate heavy machinery until they know how Solifenacin affects them ( 5.4 ) Controlled Narrow-Angle Glaucoma: Use with caution in patients being treated for narrow-angle glaucoma ( 5.5 ) QT Prolongation: Use with caution in patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval ( 5.8 )

5.1Angioedema and Anaphylactic Reactions Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses.

Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, solifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. Anaphylactic reactions have been reported rarely in patients treated with solifenacin succinate.

Solifenacin succinate should not be used in patients with a known or suspected hypersensitivity to solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.

5.2Urinary Retention Solifenacin, like other anticholinergic drugs, should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [ see Contraindications ( 4 ) ].

5.3Gastrointestinal Disorders Solifenacin, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility [ see Contraindications ( 4 ) ].

5.4Central Nervous System Effects Solifenacin is associated with anticholinergic central nervous system (CNS) effects [ see Adverse Reactions ( 6.2 ) ]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose.

Advise patients not to drive or operate heavy machinery until they know how Solifenacin Succinate Tablets affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.5Controlled Narrow-Angle Glaucoma Solifenacin should be used with caution in patients being treated for narrow-angle glaucoma [ see Contraindications ( 4 ) ].

5.6Hepatic Impairment Solifenacin should be used with caution in patients with hepatic impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin is not recommended for patients with severe hepatic impairment (Child-Pugh C) [ see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.7 ) ].

5.7Renal Impairment Solifenacin should be used with caution in patients with renal impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with severe renal impairment (CL cr <30 mL/min) [ see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 ) ].

5.8Patients with Congenital or Acquired QT Prolongation In a study of the effect of solifenacin on the QT interval in 76 healthy women [ see Clinical Pharmacology ( 12.2 ) ] the QT prolonging…

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 AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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

27.6Constipation 2.9 5.4

13.4Nausea 2.0 1.7

3.3Dyspepsia 1.0 1.4

3.9Abdominal Pain Upper 1.0 1.9

1.2Vomiting NOS 0.9 0.2

1.1INFECTIONS AND INFESTATIONS Urinary Tract Infection NOS 2.8 2.8

4.8Influenza 1.3 2.2

0.9Pharyngitis NOS 1.0 0.3

1.1NERVOUS SYSTEM DISORDERS Dizziness 1.8 1.9

1.8EYE DISORDERS Vision Blurred 1.8 3.8

4.8Dry Eyes NOS 0.6 0.3

1.6RENAL AND URINARY DISORDERS Urinary Retention 0.6 0

1.4GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema Lower Limb 0.7 0.3

1.1Fatigue 1.1 1.0

2.1PSYCHIATRIC DISORDERS Depression NOS 0.8 1.2

0.8RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 0.2 0.2

1.1VASCULAR DISORDERS Hypertension NOS 0.6 1.4 0.5

6.2Post-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: dysphon…

7 DRUG INTERACTIONS Inhibitors of CYP3A4 may increase the concentration of Solifenacin ( 7.1 ). Inducers of CYP3A4 may decrease the concentration of Solifenacin ( 7.2 ).

7.1Potent 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.

7.2CYP3A4 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.

7.3Drugs Metabolized by Cytochrome P450 At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.

7.4Warfarin Solifenacin has no significant effect on the pharmacokinetics of R-warfarin or S-warfarin [ see Clinical Pharmacology ( 12.3 ) ].

7.5Oral 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 ) ].

7.6Digoxin Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects [ see Clinical Pharmacology ( 12.3 ) ].