Solifenacin Succiate

INDICATIONS AND USAGE 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)

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: 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 ) ].

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 ) 5.1 Angioedema 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. 5.2 Urinary 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 ) ]. 5.3 Gastrointestinal Disorders Solifenacin, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility [ see Contraindications ( 4 ) ]. 5.4 Central 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. 5.5 Controlled Narrow-Angle Glaucoma Solifenacin should be used with caution in patients being treated for narrow-angle glaucoma [ see Contraindications ( 4 ) ]. 5.6 Hepatic 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 ) ]. 5.7 Renal 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 ) ]. 5.8 Patients 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 effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe Solifenacin for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

CONTRAINDICATIONS 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 )

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

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. 6.1 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 drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 and stimulation of salivary secretion. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of 10 mg and 30 mg solifenacin succinate 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. Subjects were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 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 co-administration of 10 mg Solifenacin Succinate Tablets with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG 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 Tmax (relative to placebo)* Drug/Dose Fridericia method (using mean difference) Solifenacin 10 mg 2 (-3,6) Solifenacin 30 mg (4,13) *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 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 appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. 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 to healthy volunteers, peak plasma levels (C max ) of solifenacin are 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, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered. Effect of food Solifenacin may be administered without regard to meals. A single 10 mg dose administration of Solifenacin with food increased C max and AUC by 4% and 3%, respectively. Distribution Solifenacin is approximately 98% ( in vivo ) bound to human plasma proteins, principally to ∝1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L. 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 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, 69.2% of the radioactivity was recovered in the urine and 22.5% 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. The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours. Drug Interactions Potent CYP3A4 Inhibitors In a crossover study, following blockade of CYP3A4 by coadministration of the potent 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 ) ]. 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 10 mg or matching placebo once daily for 16 days. For R-warfarin when it was coadministered with solifenacin, the mean C max increased by 3% and AUC decreased by 2%. For S-warfarin when it was coadministered with solifenacin, the mean C max and AUC increased by 5% and 1%, respectively [ see Drug Interactions ( 7.4 ) ]. Oral Contraceptives In a crossover study, subjects received 2 cycles of 21 days of oral contraceptives containing 30 ug ethinyl estradiol and 150 ug levonorgestrel. During the second cycle, subjects received additional solifenacin 10 mg or matching placebo once daily for 10 days starting from 12 th day of receipt of oral contraceptives. For ethinyl estradiol when it was administered with solifenacin, the mean C max and AUC increased by 2% and 3%, respectively. For levonorgestrel when it was administered with solifenacin, the mean C max and AUC decreased by 1% [ see Drug Interactions ( 7.5 ) ]. 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 10 mg or matching placebo with digoxin 0.125 mg for additional 10 days. When digoxin was coadministered with solifenacin, the mean C max and AUC increased by 13% and 4%, respectively [ see Drug Interactions ( 7.6 ) ].