2.1 Dosing Information

Dosing Information in Pediatric Patients Aged 2 Years and Older

The recommended starting and maximum VESIcare LS oral suspension doses are shown in mL in Table 1. VESIcare LS oral suspension has a concentration of 1 mg/1 mL. The recommended doses are weight-based and are administered once daily. After administration of the recommended starting dose, the dose may be increased to the lowest effective dose but should not exceed the maximum recommended dose.

Evaluate patients periodically for potential dose adjustment.

VESIcare LS oral suspension should be taken once daily. Instruct patients or their caregivers that patients should take VESIcare LS orally followed by liquid (e.g., water or milk). Instruct patients to take any missed doses as soon as they remember, unless more than 12 hours have passed since the missed dose. If more than 12 hours have passed, the missed dose can be skipped, and the next dose should be taken at the usual time.

2.2 Dosing Recommendations in Patients with Renal Impairment

Do not exceed the recommended VESIcare LS oral suspension starting dose in patients with severe renal impairment (CLcr < 30 mL/min/1.73 m2) [see Use in Specific Populations (8.6)].

2.3 Dosing Recommendations in Patients with Hepatic Impairment

Do not exceed the recommended VESIcare LS oral suspension starting dose in patients with moderate hepatic impairment (Child-Pugh B). Do not use VESIcare LS 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 the recommended VESIcare LS oral suspension starting dose when VESIcare LS is 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.

VESIcare LS oral suspension is 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 VESIcare LS oral suspension and provide appropriate therapy and/or measures necessary to ensure a patent airway.

5.2 Urinary Retention

The use of VESIcare LS oral suspension, like other antimuscarinic drugs, in patients with clinically significant bladder outlet obstruction may result in urinary retention. The use of VESIcare LS oral suspension is not recommended in patients with clinically significant bladder outflow obstruction in the absence of clean intermittent catheterization because of the risk of urinary retention.

5.3 Gastrointestinal Disorders

The use of VESIcare LS oral suspension, like other antimuscarinic drugs, in patients with conditions associated with decreased gastrointestinal motility may result in further decreased gastrointestinal motility. VESIcare LS oral suspension is contraindicated in patients with gastric retention [see Contraindications (4)]. The use of VESIcare LS oral suspension is not recommended in patients with conditions associated with decreased gastrointestinal motility.

5.4 Central Nervous System Effects

Solifenacin succinate is 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 VESIcare LS affects them. If a patient experiences antimuscarinic CNS adverse reactions, consider dose reduction or drug discontinuation.

5.5 Controlled Narrow-Angle Glaucoma

VESIcare LS 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 adult women [see Clinical Pharmacology (12.2)], solifenacin succinate 30 mg (three times the largest maximum recommended dose in pediatric 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 VESIcare LS 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.

The safety of VESIcare LS oral suspension was evaluated in two open-label trials (Studies 1 and 2) [see Clinical Studies (14)]. The two studies included 95 pediatric patients aged 2 to 17 years with neurogenic detrusor overactivity (NDO) who were 53% female, 58% White, 34% Asian and 2% Black. Treatment was initiated at the weight-based starting recommended dose and was titrated up or down in 2.5 mg increments over 12 weeks to the lowest effective dose (not to exceed the maximum recommended dose). Subsequent to the dose titration period, patients continued their optimized dose for a 40-week maintenance period (mean exposure duration 301 days, range 1 to 413 days).

The most commonly reported adverse reactions were constipation, dry mouth, urinary tract infection, abdominal pain, urinalysis bacterial test positive, and somnolence. The incidence of adverse reactions was similar between patients taking the starting recommended dose and patients taking the maximum recommended dose with the exception of constipation, which was reported, in 8.5% of patients taking the maximum recommended dose compared to 0% of patients taking the starting recommended dose.

Table 2 lists the adverse reactions reported in Studies 1 and 2 at an incidence equal to or greater than 1%.

Adverse reactions reported in ≥ 1% of solifenacin succinate-treated adult patients and at an incidence greater than in placebo-treated adult patients in clinical adult trials were:

Gastrointestinal disorders: dry mouth, constipation, nausea, dyspepsia, upper abdominal pain, vomiting

Infections and infestations: urinary tract infection, influenza, pharyngitis

Nervous system disorders: dizziness

Eye disorders: blurred vision, dry eyes

Renal and urinary disorders: urinary retention

General disorders and administration site conditions: lower limb edema, fatigue

Psychiatric disorders: depression

Respiratory, thoracic and mediastinal disorders: cough

Vascular disorders: hypertension

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of solifenacin succinate. 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 VESIcare LS greater than the starting dose 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 or adolescents 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 VESIcare LS and any potential adverse effects on the breastfed child from VESIcare LS or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of VESIcare LS have been established in pediatric patients aged 2 years and older for the treatment of neurogenic detrusor overactivity (NDO) and the information on this use is discussed throughout the labeling. The safety and effectiveness of VESIcare LS have not been established in pediatric patients less than 2 years of age.

8.6 Renal Impairment

Solifenacin plasma concentrations are greater in adults with severe renal impairment compared to adults 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 VESIcare LS oral suspension in pediatric patients 2 years of age and older with severe renal impairment (CLcr < 30 mL/min/1.73 m2) is the starting dose [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 adults with moderate hepatic impairment compared to adults 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 VESIcare LS oral suspension in pediatric patients 2 years of age and older with moderate hepatic impairment (Child-Pugh B) is the starting dose [see Dosage and Administration (2.3)] and VESIcare LS oral suspension is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

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

12.3 Pharmacokinetics

Absorption

After oral administration of VESIcare LS in pediatric patients with neurogenic detrusor overactivity (NDO) aged 2 to 17 years, peak plasma concentrations (Cmax) of solifenacin were reached within 2 to 6 hours after administration (tmax) and, at steady-state, the dose-normalized Cmax ranged from 2.5 - 29 ng/mL/mg. The absolute bioavailability of solifenacin in adults is approximately 90%, with plasma concentrations of solifenacin proportional to the dose administered.

Effect of Food

Food intake did not significantly affect the Cmax and AUC of solifenacin following oral administration of VESIcare LS.

Distribution

Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to α1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a median steady-state volume of distribution of 211 L in pediatric neurogenic detrusor overactivity (NDO) patients from 2 to 17 years old.

Elimination

The median elimination half-life of solifenacin is approximately 26 hours in pediatric neurogenic detrusor overactivity (NDO) patients 2 years of age and older.

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 adult 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

Patients with Renal Impairment

In studies with solifenacin succinate 10 mg in adults, there was a 2.1-fold increase in AUC and a 1.6-fold increase in t1/2 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 in adults, there was a 2-fold increase in the t1/2 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 has not been studied in patients with severe hepatic impairment.

Drug Interaction Studies

Interaction studies have only been performed in adults. In pediatric patients 2 years of age and older, metabolism via CYP3A4 is the major route of elimination and the metabolic capacity of the liver is similar.

Strong CYP3A4 Inhibitors

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

CYP3A4 Inducers

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

Warfarin

In a crossover study in adults, subjects received a single oral dose of warfarin 25 mg on the 10th 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 Cmax increased by 3% and AUC decreased by 2%. For S-warfarin, when it was coadministered with solifenacin succinate, the mean Cmax and AUC increased by 5% and 1%, respectively.

Oral Contraceptives

In a crossover study in adults, 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 12th day of receipt of oral contraceptives. For ethinyl estradiol, when it was administered with solifenacin succinate, the mean Cmax and AUC increased by 2% and 3%, respectively. For levonorgestrel, when it was administered with solifenacin succinate, the mean Cmax and AUC decreased by 1%.

Digoxin

In a crossover study in adults, 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 Cmax 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.