ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (>4% and >placebo) were dry mouth, and constipation at both 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 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 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 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 succinate tablets was higher in the 10 mg compared to the 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 has been reported in one patient taking solifenacin succinate tablets 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. The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 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 succinate tablets 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 Succinate Tablets 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 1.7 3.3 Dyspepsia 1.4 3.9 Abdominal Pain Upper 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 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 1.4 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema Lower Limb 0.7 0.3 1.1 Fatigue 1.1 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, and palpitations; Hepatic: liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), and GGT (gamma-glutamyl transferase); Renal: renal impairment; Metabolism and nutrition disorders: decreased appetite and hyperkalemia;Dermatologic: exfoliative dermatitis, erythema multiforme, and dry skin;Eye disorders: glaucoma; Gastrointestinal disorders: gastroesophageal reflux disease, ileus, abdominal pain, and dysgeusia;Respiratory, thoracic and mediastinal disorders: dysphonia and nasal dryness; Musculoskeletal and connective tissue disorders: muscular weakness.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Solifenacin is 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 ElectrophysiologyThe 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 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 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed 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 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 beats/minute, respectively. Because 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 (-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 to time-matched placebo effects in Group Moxifloxacin was included as positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 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. AbsorptionAfter oral administration of solifenacin succinate tablets to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within to hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.Effect of Food Solifenacin succinate tablets may be administered without regard to meals. single 10 mg dose administration of solifenacin succinate tablets with food increased Cmax and AUC by 4% and 3%, respectively.Distribution Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to u1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having 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.ExcretionFollowing the administration of 10 mg of 14C-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 to 68 hours.Drug Interactions Potent CYP3A4 Inhibitors In crossover study, following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor, ketoconazole 400 mg, once daily for 21 days, the mean Cmax 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 crossover study, subjects received single oral dose of warfarin 25 mg on the 10th 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 Cmax increased by 3% and AUC decreased by 2%. For S-warfarin when it was coadministered with solifenacin, the mean Cmax and AUC increased by 5% and 1%, respectively [see Drug Interactions (7.4)]. Oral Contraceptives In crossover study, subjects received 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 12thday of receipt of oral contraceptives. For ethinyl estradiol when it was administered with solifenacin, the mean Cmax and AUC increased by 2% and 3%, respectively. For levonorgestrel when it was administered with solifenacin, the mean Cmax and AUC decreased by 1% [see Drug Interactions (7.5)]. Digoxin In crossover study, subjects received digoxin (loading dose of 0.25 mg on day 1, followed by 0.125 mg from days to 8) for 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 Cmax and AUC increased by 13% and 4%, respectively [see Drug Interactions (7.6)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Solifenacin succinate tablets were evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in patients having symptoms of urinary frequency, urgency, and/or urge or mixed incontinence (with 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 tablets and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the and 10 mg solifenacin succinate tablets doses and the other two evaluated only the 10 mg dose. All patients completing the 12-week studies were eligible to enter an open label, long term extension study and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with 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 tablets was similar across patient age and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with solifenacin succinate tablets mg (2.3; p<0.001) and solifenacin succinate tablets 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 tablets mg (1.5; p<0.001) and solifenacin succinate tablets 10 mg (1.8; p<0.001) treatment groups compared to placebo (1.1). The mean increase in the volume voided per micturition was significantly greater with solifenacin succinate tablets mg (32.3 mL; p<0.001) and solifenacin succinate tablets 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 tablets are reported in Tables through 6. Table 3: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (5 mg and 10 mg daily) and Placebo: Study 1ParameterPlacebo (N=253) Mean (SE)Solifenacin Succinate Tablets mg (N=266) Mean (SE)Solifenacin Succinate Tablets 10 mg (N=264) Mean (SE)Urinary Frequency (Number of Micturitions/24 hours) Baseline Reduction 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 (0.2)<0. 001 Number of Incontinence Episodes/24 hours+ Baseline Reduction 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]+ Baseline Increase 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 Primary endpoint Secondary endpoint Table 4: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (5 mg and 10 mg daily) and Placebo: Study 2Parameter Placebo (N=281) Mean (SE)Solifenacin Succinate Tablets mg (N=286) Mean (SE)Solifenacin Succinate Tablets 10 mg (N=290) Mean (SE)Urinary Frequency (Number of Micturitions/24 hours) Baseline Reduction 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+ Baseline Reduction value vs. placebo 3.2 (0.24)1.3 (0.19) 2.6 (0.18)1.6 (0.16)<0.01 2.8 (0.2)1.6 (0.18)0.016 Volume Voided per Micturition [mL]+ BaselineIncrease 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 Primary endpoint Secondary endpoint Table 5: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (10 mg daily) and Placebo: Study 3ParameterPlacebo(N=309)Mean (SE)Solifenacin Succinate Tablets 10 mg (N=306) Mean (SE)Urinary Frequency (Number of Micturitions/24 hours) Baseline Reduction value vs. placebo 11.5 (0.18)1.5 (0.15) 11.7 (0.18)3 (0.15)<0. 001 Number of Incontinence Episodes/24 hours+ Baseline Reduction value vs. placebo (0.2)1.1 (0.16) 3.1 (0.22)2 (0.19)<0.001 Volume Voided per Micturition [mL]+ Baseline Increase value vs. placebo 190.3 (5.48)2.7 (3.15) 183.5 (4.97)47.2 (3.79)<0.001 Primary endpoint Secondary endpoint Table 6: Mean Change from Baseline to Endpoint for Solifenacin Succinate Tablets (10 mg daily) and Placebo: Study ParameterPlacebo(N=295)Mean (SE)Solifenacin Succinate Tablets 10 mg (N=298) Mean (SE)Urinary Frequency (Number of Micturitions/24 hours) BaselineReductionP 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+ BaselineReductionP value vs. placebo 2.9 (0.18)1.2 (0.15) 2.9 (0.17)2 (0.15)<0.001 Volume Voided per Micturition [mL]+ BaselineIncreaseP value vs. placebo 175.7 (4.44)13 (3.45) 174.1 (4.15)46.4 (3.73)<0.001 Primary endpoint Secondary endpoint.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. mg tablet taken once daily, and if well tolerated may be increased to 10 mg once daily (2.1). Do not exceed mg tablet once daily in patients with:severe renal impairment [Creatinine Clearance] (CLcr <30 mL/min) (2.2).moderate hepatic impairment (Child-Pugh B) (2.3). concomitant use of potent CYP3A4 inhibitors (2.4). Use of solifenacin succinate tablet is not recommended in patients with severe hepatic impairment (Child-Pugh C) (2.3).. mg tablet taken once daily, and if well tolerated may be increased to 10 mg once daily (2.1). Do not exceed mg tablet once daily in patients with:severe renal impairment [Creatinine Clearance] (CLcr <30 mL/min) (2.2).moderate hepatic impairment (Child-Pugh B) (2.3). concomitant use of potent CYP3A4 inhibitors (2.4). severe renal impairment [Creatinine Clearance] (CLcr <30 mL/min) (2.2).. moderate hepatic impairment (Child-Pugh B) (2.3). concomitant use of potent CYP3A4 inhibitors (2.4).. Use of solifenacin succinate tablet is not recommended in patients with severe hepatic impairment (Child-Pugh C) (2.3).. 2.1 Dosing Information. The recommended dose of solifenacin succinate tablet is mg once daily. If the 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 (CLcr <30 mL/min), daily dose of solifenacin succinate tablets greater than mg is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6)].. 2.3 Dose Adjustment in Patients with Hepatic Impairment. For patients with moderate hepatic impairment (Child-Pugh B), daily dose of solifenacin succinate tablets greater than 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) and Use in Specific Populations (8.7)]. 2.4 Dose Adjustment in Patients Taking CYP3A4 Inhibitors. When administered with potent CYP3A4 inhibitors such as ketoconazole, daily dose of solifenacin succinate tablets greater than mg is not recommended [see Drug Interactions (7.1)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Inhibitors of CYP3A4 may increase the concentration of solifenacin succinate tablets (7.1).Inducers of CYP3A4 may decrease the concentration of solifenacin succinate tablets (7.2).. Inhibitors of CYP3A4 may increase the concentration of solifenacin succinate tablets (7.1).. Inducers of CYP3A4 may decrease the concentration of solifenacin succinate tablets (7.2).. 7.1 Potent CYP3A4 Inhibitors. Following the administration of 10 mg of solifenacin succinate tablets in the presence of 400 mg of ketoconazole, potent inhibitor of CYP3A4, the mean Cmax and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively. Therefore, it is recommended not to exceed 5 mg daily dose of solifenacin succinate tablets 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 succinate tablets. In vitro drug metabolism studies have shown that solifenacin is 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients should be informed that antimuscarinic agents such as solifenacin succinate tablets have been associated with constipation and blurred vision. Patients should be advised to contact their physician if they experience severe abdominal pain or become constipated for or more days. Because solifenacin succinate tablets may cause blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drugs effect on the patients vision has been determined. Heat prostration (due to decreased sweating) can occur when anticholinergic drugs, such as solifenacin succinate tablets, are used in hot environment. Patients should read the patient leaflet entextd Patient Information solifenacin succinate tablets before starting therapy with solifenacin succinate tablets. Patients should be informed that solifenacin may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue solifenacin therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe 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 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 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed 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 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 beats/minute, respectively. Because 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 (-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 to time-matched placebo effects in Group Moxifloxacin was included as positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter oral administration of solifenacin succinate tablets to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within to hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the and 10 mg solifenacin succinate tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.Effect of Food Solifenacin succinate tablets may be administered without regard to meals. single 10 mg dose administration of solifenacin succinate tablets with food increased Cmax and AUC by 4% and 3%, respectively.Distribution Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to u1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having 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.ExcretionFollowing the administration of 10 mg of 14C-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 to 68 hours.Drug Interactions Potent CYP3A4 Inhibitors In crossover study, following blockade of CYP3A4 by coadministration of the potent CYP3A4 inhibitor, ketoconazole 400 mg, once daily for 21 days, the mean Cmax 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 crossover study, subjects received single oral dose of warfarin 25 mg on the 10th 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 Cmax increased by 3% and AUC decreased by 2%. For S-warfarin when it was coadministered with solifenacin, the mean Cmax and AUC increased by 5% and 1%, respectively [see Drug Interactions (7.4)]. Oral Contraceptives In crossover study, subjects received 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 12thday of receipt of oral contraceptives. For ethinyl estradiol when it was administered with solifenacin, the mean Cmax and AUC increased by 2% and 3%, respectively. For levonorgestrel when it was administered with solifenacin, the mean Cmax and AUC decreased by 1% [see Drug Interactions (7.5)]. Digoxin In crossover study, subjects received digoxin (loading dose of 0.25 mg on day 1, followed by 0.125 mg from days to 8) for 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 Cmax and AUC increased by 13% and 4%, respectively [see Drug Interactions (7.6)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women.Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin succinate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Solifenacin (SOE-li-FEN-a-sin) Succinate (SUX-i-nate) TabletsRead the Patient Information that comes with solifenacin succinate tablets before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.What is solifenacin succinate tablet Solifenacin succinate tablet is prescription medicine for adults used to treat the following symptoms due to condition called overactive bladder: Urge urinary incontinence: strong need to urinate with leaking or wetting accidents Urgency: strong need to urinate right away Frequency: urinating oftenIt is not known if solifenacin succinate tablets are safe and effective in children. Who should not take solifenacin succinate tablets Do not take solifenacin succinate tablets if you: are not able to empty your bladder (urinary retention) have delayed or slow emptying of your stomach (gastric retention) have an eye problem called uncontrolled narrow-angle glaucoma are allergic to solifenacin succinate or any of the ingredients in solifenacin succinate tablets. See end of this leaflet for complete list of ingredients.What should tell my doctor before taking solifenacin succinate tablets Before you take solifenacin succinate tablets, tell your doctor if you:o have any stomach or intestinal problems or problems with constipation have trouble emptying your bladder or you have weak urine stream have an eye problem called narrow angle glaucoma have liver problems have kidney problems have rare heart problem called QT prolongation are pregnant or plan to become pregnant. It is not known if solifenacin succinate tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if solifenacin succinate tablets passes into your breast milk. You and your doctor should decide if you will take solifenacin succinate tablets or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Solifenacin succinate tablets may affect the way other medicines work, and other medicines may affect how solifenacin succinate tablet works. How should take solifenacin succinate tablets Take solifenacin succinate tablets exactly as your doctor tells you to take it. You should take solifenacin succinate tablets tablet time day. You should take solifenacin succinate tablets with water and swallow the tablet whole. You can take solifenacin succinate tablets with or without food. If you miss dose of solifenacin succinate tablets, begin taking solifenacin succinate tablets again the next day. Do not take doses of solifenacin succinate tablets the same day. If you take too much solifenacin succinate tablets, call your doctor or go to the nearest hospital emergency room right away.What should avoid while taking solifenacin succinate tablets Solifenacin succinate tablets can cause blurred vision or drowsiness. Do not drive or operate heavy machinery until you know how solifenacin succinate tablet affects you. What are the possible side effects of solifenacin succinate tablets Solifenacin succinate tablets may cause serious side effects including: Serious allergic reaction. Stop taking solifenacin succinate tablets and get medical help right away if you have: hives, skin rash or swelling severe itching swelling of your face, mouth or tongue trouble breathingThe most common side effects of solifenacin succinate tablets include: dry mouth constipation. Call your doctor if you get severe stomach area (abdominal) pain or become constipated for or more days. urinary tract infection blurred vision heat exhaustion or heat-stroke. This can happen when solifenacin succinate tablets is used in hot environments. Symptoms may include: decreased sweating dizziness tiredness nausea increase in body temperature Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of solifenacin succinate tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.How should store solifenacin succinate tablets Store solifenacin succinate tablets at 25oC (77oF) with excursions permitted from 15oC to 30oC (59F to 86oF). Keep the bottle closed. Safely throw away medicine that is out of date or no longer need. Keep solifenacin succinate tablets and all medicines out of the reach of children.General information about the safe and effective use of solifenacin succinate tabletsMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use solifenacin succinate tablets for condition for which it was not prescribed. Do not give solifenacin succinate tablets to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about solifenacin succinate tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about solifenacin succinate tablets that is written for health professionals. What are the ingredients in solifenacin succinate tablets Active ingredient: solifenacin succinate Inactive ingredients: lactose monohydrate, hypromellose, corn starch, magnesiun stearate,titanium dioxide, polyethylene glycol, talc, iron oxide yellow with D&C Yellow 10 Aluminum Lake (5 mg solifenacin succinate tablet) or iron oxide red (10 mg solifenacin succinate tablet).What is overactive bladder Overactive bladder occurs when you cannot control your bladder contractions. When these muscle contractions happen too often or cannot be controlled you can get symptoms of overactive bladder, which are urinary frequency, urinary urgency, and urinary incontinence (leakage). This Patient Information has been approved by the U.S. Food and Drug Administration Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal 389350, Gujarat, India.Revised: 05/2019.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy and Nursing Mothers: Solifenacin succinate tablets should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. Solifenacin succinate tablets should not be administered during nursing (8.1, 8.3).Pediatric Use: The safety and effectiveness of solifenacin succinate tablets in pediatric patients have not been established (8.4).. 8.1 Pregnancy. Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women.Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, solifenacin succinate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.2 Labor and Delivery. The effect of solifenacin succinate tablets on labor and delivery in humans has not been studied. There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality. 8.3 Nursing Mothers. After oral administration of 14C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD]. Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period. It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, solifenacin succinate tablets should not be administered during nursing. decision should be made whether to discontinue nursing or to discontinue solifenacin succinate tablets in nursing mothers.. 8.4 Pediatric Use. The safety and effectiveness of solifenacin succinate tablets in pediatric patients have not been established.. 8.5 Geriatric Use. In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients >=65 years and 189 patients >=75 years) and younger patients (1188 patients <65 years) treated with solifenacin succinate tablets. Multiple dose studies of solifenacin succinate tablets in elderly volunteers (65 to 80 years) showed that Cmax, AUC and t1/2 values were 20 to 25% higher as compared to the younger volunteers (18 to 55 years).. 8.6 Renal Impairment. Solifenacin succinate tablets should be used with caution in patients with renal impairment. There is 2.1-fold increase in AUC and 1.6-fold increase in t1/2 of solifenacin in patients with severe renal impairment. Doses of solifenacin succinate tablets greater than mg are not recommended in patients with severe renal impairment (CLcr <30 mL/min) [see Warnings and Precautions (5.7) and Dosage and Administration (2.2)]. 8.7 Hepatic Impairment. Solifenacin succinate tablets should be used with caution in patients with reduced hepatic function. There is 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of solifenacin succinate tablets greater than mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin succinate tablets are not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.6) and Dosage and Administration (2.3)]. 8.8 Gender. The pharmacokinetics of solifenacin is not significantly influenced by gender.

WARNINGS AND PRECAUTIONS SECTION.

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 succinate tablets. Advise patients not to drive or operate heavy machinery until they know how solifenacin succinate tablets 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 known history of QT prolongation or patients who are taking medications known to prolong the QT interval (5.8). 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 succinate tablets. Advise patients not to drive or operate heavy machinery until they know how solifenacin succinate tablets 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 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 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 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 succinate tablets, 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 succinate tablets, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility [see Contraindications (4)]. 5.4 Central Nervous System Effects. Solifenacin succinate tablets are associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. 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 affect them. If patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.. 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 Hepatic Impairment. Solifenacin succinate tablets should be used with caution in patients with hepatic impairment. Doses of solifenacin succinate tablets greater than mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin succinate tablets are 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 succinate tablets should be used with caution in patients with renal impairment. Doses of solifenacin succinate tablets greater than mg are not recommended in patients with severe renal impairment (CLcr <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 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 succinate tablets for patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.