VESICARE LS

VESIcare LS (solifenacin succinate) oral suspension is a muscarinic receptor antagonist. Chemically, solifenacin succinate is a butanedioic acid compound with (1 S )-(3 R )-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1 H )-iso-quinolinecarboxylate (1:1) having an empirical formula of C 23 H 26 N 2 O 2 •C 4 H 6 O 4 , and a molecular weight of 480.55. The structural formula of solifenacin succinate is: Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. VESIcare LS contains 1 mg/mL of solifenacin succinate as an oral suspension (1 mg solifenacin succinate is equivalent to 0.75 mg solifenacin). The inactive ingredients are polacrilin potassium, methylparaben, propylparaben, propylene glycol, simethicone emulsion 30%, carbomer homopolymer Type B, xylitol, acesulfame potassium, natural orange flavor, sodium hydroxide, and purified water. VESIcare LS is a white to off-white color aqueous homogenous oral suspension with an orange flavor. structure of Solifenacin succinate

VESIcare LS ® is indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged 2 years and older. VESIcare LS is a muscarinic antagonist indicated for the treatment of neurogenic detrusor overactivity in pediatric patients aged 2 years and older. ( 1 )

• The recommended once daily dose of VESIcare LS is based on patient weight, refer to Table 1. Dosing should be initiated at the recommended starting dose. Dosage may be titrated to the lowest effective dose but should not exceed the maximum recommended dose. ( 2.1 ) • Instruct patients or their caregivers that patients should take VESIcare LS orally followed by liquid (e.g., water or milk). • Do not exceed the recommended starting dose of VESIcare LS in patients with: • Severe renal impairment creatinine clearance < 30 mL/min/1.73 m 2 . ( 2.2 , 8.6 ) • Moderate hepatic impairment (Child-Pugh B). VESIcare LS is not recommended in patients with severe hepatic impairment (Child-Pugh C). ( 2.3 , 8.7 ) • Concomitant use of strong CYP3A4 inhibitors. ( 2.4 , 7.1 ) 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. Table 1: Once Daily Recommended Dosage According to Patient Body Weight Weight range Starting dose Maximum dose 9 kg to 15 kg 2 mL 4 mL greater than 15 kg to 30 kg 3 mL 5 mL greater than 30 kg to 45 kg 3 mL 6 mL greater than 45 kg to 60 kg 4 mL 8 mL greater than 60 kg 5 mL 10 mL 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 (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 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 )] .

VESIcare LS is contraindicated in patients: • With gastric retention [see Warnings and Precautions ( 5.3 )] , • With uncontrolled narrow-angle glaucoma [see Warnings and Precautions ( 5.5 )] , and • Who have demonstrated hypersensitivity to solifenacin succinate or the inactive ingredients in VESIcare LS oral suspension. Reported adverse reactions have included anaphylaxis and angioedema [see Adverse Reactions ( 6.2 )] . • Gastric retention. ( 4 , 5.3 ) • Uncontrolled narrow-angle glaucoma. ( 4 , 5.5 ) • Hypersensitivity to this product or any of its components. ( 4 , 5.1 , 6.2 )

• Angioedema and Anaphylactic Reactions [see Warnings and Precautions ( 5.1 )] • Urinary Retention [see Warnings and Precautions ( 5.2 )] • Gastrointestinal Disorders [see Warnings and Precautions ( 5.3 )] • Central Nervous System Effects [see Warnings and Precautions ( 5.4 )] • QT Prolongation in Patients at High Risk of QT Prolongation [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (> 2%) were constipation, dry mouth and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 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. 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%. Table 2: Adverse Reactions Reported in ≥ 1% of Neurogenic Detrusor Overactivity (NDO) Patients Aged 2 to 17 Years Taking VESIcare LS Oral Suspension in Studies 1 and 2 Adverse Reaction Percentage (%) of Patients Reporting Adverse Reactions N=95 Constipation 7.4 Dry mouth 3.2 Urinary tract infection 2.1 Abdominal pain 1.1 Urinalysis bacterial test positive 1.1 Somnolence 1.1 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.

CYP3A4 Inhibitors : Do not exceed the recommended starting dose of VESIcare LS with concomitant use of strong CYP3A4 inhibitors. ( 7.1 ) 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 )] .