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)] .

5.1 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 and provide 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 ( 12.2)] , solifenacin succinate 30 mg (three times the largest maximum recommended dose in adult patients) was associated with a mean increase in the Fridericia-corrected QT interval of 8 msec (90% CI, 4, 13). The QT prolonging effect appeared less with solifenacin succinate 10 mg than with solifenacin succinate 30 mg, and the effect of solifenacin succinate 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose.

The use of Solifenacin Succinate Tablets is not recommended in patients at high risk of QT prolongation, including patients with a known history of QT prolongation and patients who are taking medications known to prolong the QT interval.

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.

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);

Renal and urinary disorders: renal impairment, urinary retention;

Metabolism and nutrition disorders: decreased appetite, hyperkalemia;

Skin and subcutaneous tissue disorders: exfoliative dermatitis, erythema multiforme, dry skin;

Eye disorders: glaucoma;

Gastrointestinal disorders: gastroesophageal reflux disease, ileus, vomiting, abdominal pain, dysgeusia, sialadenitis;

Respiratory, thoracic and mediastinal disorders: dysphonia, nasal dryness;

Musculoskeletal and connective tissue disorders: muscular weakness.

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.

8.2 Lactation

Risk Summary

There is no information on the presence of solifenacin in human milk, the effects on the breastfed child, or the effects on milk production. Solifenacin is present in mouse milk [see Data] . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Solifenacin Succinate Tablets and any potential adverse effects on the breastfed child from Solifenacin Succinate Tablets or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of Solifenacin Succinate Tablets have not been established in pediatric patients.

8.5 Geriatric Use

In placebo-controlled clinical studies, similar safety and effectiveness were observed between geriatric patients (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger adult patients (1188 patients < 65 years) treated with Solifenacin Succinate Tablets  [see Clinical Pharmacology ( 12.3)] .

8.6 Renal Impairment

Solifenacin plasma concentrations are greater in patients with severe renal impairment compared to subjects with normal renal function [see Clinical Pharmacology ( 12.3)] . Because increased solifenacin plasma concentrations increase the risk of antimuscarinic adverse reactions, the maximum recommended dose of Solifenacin Succinate Tablets in patients with severe renal impairment (CL cr < 30 mL/min/1.73 m 2) is 5 mg once daily [see Dosage and Administration ( 2.2)] . The recommended dose in patients with mild or moderate renal impairment is the same as in patients with normal renal function.

8.7 Hepatic Impairment

Solifenacin plasma concentrations are greater in patients with moderate hepatic impairment compared to subjects with normal hepatic function [see Clinical Pharmacology ( 12.3)] . Because increased solifenacin plasma concentrations increase the risk of antimuscarinic adverse reactions, the maximum recommended dose of Solifenacin Succinate Tablets in patients with moderate hepatic impairment (Child-Pugh B) is 5 mg once daily [see Dosage and Administration ( 2.3)] and Solifenacin Succinate Tablets are not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

8.8 Gender

The pharmacokinetics of solifenacin is not significantly influenced by gender.

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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of 10 mg and 30 mg solifenacin succinate (three times the maximum recommended dose) 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 [see Warnings and Precautions ( 5.6)]. After receiving placebo and moxifloxacin sequentially, subjects were randomized to one of two treatment groups. One group (n=51) completed 3 additional sequential periods of dosing with solifenacin succinate 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 coadministration of 10 mg Solifenacin Succinate Tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline ECG 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.

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 of the highest solifenacin succinate dose (three times the maximum therapeutic dose) studied was not as large as that of the positive control moxifloxacin at its recommended dose. However, the confidence intervals overlapped, and 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 Succinate Tablets in healthy volunteers, peak plasma concentrations (C max) of solifenacin were 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 Succinate Tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, with plasma concentrations of solifenacin proportional to the dose administered.

Effect of Food

Solifenacin Succinate Tablets may be administered without regard to meals. A single 10 mg dose administration of Solifenacin Succinate Tablets with food increased C maxand AUC of solifenacin by 4% and 3%, respectively.

Distribution

Solifenacin is approximately 98% ( in vivo) bound to human plasma proteins, principally to α 1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600 L.

Elimination

The elimination half-life (t 1/2) of solifenacin following chronic dosing is approximately 45-68 hours.

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 the 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 14C-solifenacin succinate to healthy volunteers, 69% of the radioactivity was recovered in the urine and 23% 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.

Specific Populations

Geriatric Patients

Multiple dose studies of Solifenacin Succinate Tablets in geriatric volunteers (65 to 80 years) showed that C max, AUC and t 1/2 values of solifenacin were 20-25% higher compared to the younger adult volunteers (18 to 55 years). [See Use in Specific Populations ( 8.5)] .



Patients with Renal Impairment

In studies with solifenacin succinate 10 mg, there was a 2.1-fold increase in AUC and a 1.6-fold increase in t 1/2 of solifenacin in patients with severe renal impairment compared to subjects with normal renal function [see Use in Specific Populations ( 8.6)] .



Patients with Hepatic Impairment

In studies with solifenacin succinate 10 mg, there was a 2-fold increase in the t 1/2 and a 35% increase in AUC of solifenacin in patients with moderate hepatic impairment compared to subjects with normal hepatic function [see Use in Specific Populations ( 8.7)] . Solifenacin Succinate Tablets have not been studied in patients with severe hepatic impairment.

Drug Interaction Studies

Strong CYP3A4 Inhibitors

In a crossover study, following blockade of CYP3A4 by coadministration of the strong 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)] .



CYP3A4 Inducers

Because solifenacin is a substrate of CYP3A4, inducers of CYP3A4 may decrease the concentration of solifenacin.



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 succinate 10 mg or matching placebo once daily for 16 days. For R-warfarin, when it was coadministered with solifenacin succinate, the mean C max increased by 3% and AUC decreased by 2%. For S-warfarin, when it was coadministered with solifenacin succinate, the mean C max and AUC increased by 5% and 1%, respectively.



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 succinate 10 mg or matching placebo once daily for 10 days starting from the 12 th day of receipt of oral contraceptives. For ethinyl estradiol, when it was administered with solifenacin succinate, the mean C max and AUC increased by 2% and 3%, respectively. For levonorgestrel, when it was administered with solifenacin succinate, the mean C max and AUC decreased by 1%.



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 succinate 10 mg or matching placebo with digoxin 0.125 mg for an additional 10 days. When digoxin was coadministered with solifenacin succinate, the mean C max and AUC increased by 13% and 4%, respectively.



Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies demonstrated that, at therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No increase in tumors was found following the administration of solifenacin succinate to male and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times, respectively, of the exposure at the maximum recommended human dose [MRHD] of 10 mg), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (< 1 times the exposure at the MRHD).

Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood lymphocytes with or without metabolic activation or in the in vivo micronucleus test in rats.

Solifenacin succinate had no effect on reproductive function, fertility, or early embryonic development of the fetus in male and female mice treated with 250 mg/kg/day (13 times the exposure at the MRHD) of solifenacin succinate, and in male rats treated with 50 mg/kg/day (< 1 times the exposure at the MRHD) and female rats treated with 100 mg/kg/day (1.7 times the exposure at the MRHD) of solifenacin succinate.

13.2 Animal Toxicology and/or Pharmacology

Juvenile Animal Toxicology Data

Dose-related increased mortality without preceding clinical signs occurred in juvenile mice treated before weaning for a duration of 12 weeks, from day 10 after birth, with doses that achieved a pharmacological effect. Animals dosed from postnatal day 10 onwards had higher mortality compared to the mortality in adult mice. No increased frequency in mortality was observed in juvenile mice that were treated after weaning for a duration of 4 weeks, from day 21 after birth onwards. Plasma exposure at postnatal day 10 was higher than in adult mice; the systemic exposure at postnatal day 21 was comparable to the systemic exposure in adult mice.