1 INDICATIONS AND USAGE VESIcare is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. VESIcare is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency (1)
3 DOSAGE FORMS AND STRENGTHS The 5 mg tablets are round, light yellow, debossed with 150. The 10 mg tablets are round, light pink, debossed with 151. Tablets: 5 mg and 10 mg (3)
4 CONTRAINDICATIONS VESIcare is contraindicated in patients with: •urinary retention [see Warnings and Precautions (5.2)], •gastric retention [see Warnings and Precautions (5.3)], •uncontrolled narrow-angle glaucoma [see Warnings and Precautions (5.5)], and •in patients who have demonstrated hypersensitivity to the drug [see Adverse Reactions (6.2)]. •Urinary retention (4, 5.2) •Gastric retention (4, 5.3) •Uncontrolled narrow-angle glaucoma (4, 5.5) •In patients who have demonstrated hypersensitivity to the drug (4, 6.2)
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 VESIcare. Advise patients not to drive or operate heavy machinery until they know how VESIcare affects them (5.4) •Controlled Narrow-Angle Glaucoma: Use with caution in patients being treated for narrow-angle glaucoma (5.5) •QT Prolongation: Use with caution in patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval (5.8) 5.1 Angioedema and Anaphylactic Reactions Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, solifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. Anaphylactic reactions have been reported rarely in patients treated with solifenacin succinate. Solifenacin succinate should not be used in patients with a known or suspected hypersensitivity to solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken. 5.2 Urinary Retention VESIcare, 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 VESIcare, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility [see Contraindications (4)]. 5.4 Central Nervous System Effects VESIcare is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how VESIcare affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 5.5 Controlled Narrow-Angle Glaucoma VESIcare should be used with caution in patients being treated for narrow-angle glaucoma [see Contraindications (4)]. 5.6 Hepatic Impairment VESIcare should be used with caution in patients with hepatic impairment. Doses of VESIcare greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). VESIcare is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)]. 5.7 Renal Impairment VESIcare should be used with caution in patients with renal impairment. Doses of VESIcare greater than 5 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 a study of the effect of solifenacin on the QT interval in 76 healthy women [see Clinical Pharmacology (12.2)] the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval.
6 ADVERSE REACTIONS The most common adverse reactions (> 4% and > placebo) were dry mouth, and constipation at both 5 mg and 10 mg doses; and urinary tract infection, and blurred vision at the 10 mg dose (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc at 1-800-727-7003 or FDA at 1-800-FDA-1088 or http://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. VESIcare has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. Expected adverse reactions of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The incidence of dry mouth and constipation in patients treated with VESIcare was higher in the 10 mg compared to the 5 mg dose group. In the four 12-week double-blind clinical trials, severe fecal impaction, colonic obstruction, and intestinal obstruction were reported in one patient each, all in the VESIcare 10 mg group. Angioneurotic edema has been reported in one patient taking VESIcare 5 mg. Compared to 12 weeks of treatment with VESIcare, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months. The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events, in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with VESIcare 5 or 10 mg once daily for up to 12 weeks. Table 1. Percentages of Patients with Identified Adverse Reactions, Derived from All Adverse Events Exceeding Placebo Rate and Reported by 1% or More Patients for Combined Pivotal Studies Placebo (%) VESIcare 5 mg (%) VESIcare 10 mg (%) Number of Patients 1216 578 1233 GASTROINTESTINAL DISORDERS Dry Mouth 4.2 10.9 27.6 Constipation 2.9 5.4 13.4 Nausea 2.0 1.7 3.3 Dyspepsia 1.0 1.4 3.9 Abdominal Pain Upper 1.0 1.9 1.2 Vomiting NOS 0.9 0.2 1.1 INFECTIONS AND INFESTATIONS Urinary Tract Infection NOS 2.8 2.8 4.8 Influenza 1.3 2.2 0.9 Pharyngitis NOS 1.0 0.3 1.1 NERVOUS SYSTEM DISORDERS Dizziness 1.8 1.9 1.8 EYE DISORDERS Vision Blurred 1.8 3.8 4.8 Dry Eyes NOS 0.6 0.3 1.6 RENAL AND URINARY DISORDERS Urinary Retention 0.6 0 1.4 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema Lower Limb 0.7 0.3 1.1 Fatigue 1.1 1.0 2.1 PSYCHIATRIC DISORDERS Depression NOS 0.8 1.2 0.8 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 0.2 0.2 1.1 VASCULAR DISORDERS Hypertension NOS 0.6 1.4 0.5 6.2 Post-Marketing Experience Because these spontaneously reported events are from the worldwide postmarketing experience, the frequency of events and the role of solifenacin in their causation cannot be reliably determined. The following events have been reported in association with solifenacin use in worldwide postmarketing experience: General : peripheral edema, hypersensitivity reactions, including angioedema with airway obstruction, rash, pruritus, urticaria, and anaphylactic reaction; Central Nervous : headache, confusion, hallucinations, delirium and somnolence; Cardiovascular : QT prolongation; Torsade de Pointes, atrial fibrillation, tachycardia, palpitations; Hepatic : liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase); Renal : renal impairment; Metabolism and nutrition disorders : decreased appetite, hyperkalemia; Dermatologic : exfoliative dermatitis and erythema multiforme; Eye disorders: glaucoma; Gastrointestinal disorders: gastroesophageal reflux disease and ileus; Respiratory, thoracic and mediastinal disorders: dysphonia; Musculoskeletal and connective tissue disorders: muscular weakness;
7 DRUG INTERACTIONS •Inhibitors of CYP3A4 may increase the concentration of VESIcare. (7.1) •Inducers of CYP3A4 may decrease the concentration of VESIcare. (7.2) 7.1 Potent CYP3A4 Inhibitors Following the administration of 10 mg of VESIcare in the presence of 400 mg of ketoconazole, a 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 a 5 mg daily dose of VESIcare 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 VESIcare. In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Therefore, inducers of CYP3A4 may decrease the concentration of solifenacin. 7.3 Drugs Metabolized by Cytochrome P450 At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes. 7.4 Warfarin Solifenacin has no significant effect on the pharmacokinetics of R-warfarin or S-warfarin [see Clinical Pharmacology (12.3)]. 7.5 Oral Contraceptives In the presence of solifenacin there are no significant changes in the plasma concentrations of combined oral contraceptives (ethinyl estradiol/levonorgestrel) [see Clinical Pharmacology (12.3)]. 7.6 Digoxin Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS Pregnancy and Nursing Mothers: VESIcare should be used during pregnancy only if the potential benefit for the mother justifies the potential risk to the fetus. VESIcare should not be administered during nursing (8.1, 8.3) Pediatric Use: The safety and effectiveness of VESIcare in pediatric patients have not been established (8.4) 8.1 Pregnancy Pregnancy Category C There 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, VESIcare 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 VESIcare 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, VESIcare should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue VESIcare in nursing mothers. 8.4 Pediatric Use The safety and effectiveness of VESIcare 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 VESIcare. Multiple dose studies of VESIcare in elderly volunteers (65 to 80 years) showed that Cmax, AUC and t1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years). 8.6 Renal Impairment VESIcare should be used with caution in patients with renal impairment. There is a 2.1-fold increase in AUC and 1.6-fold increase in t1/2 of solifenacin in patients with severe renal impairment. Doses of VESIcare greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min) [see Warnings and Precautions (5.7); Dosage and Administration (2.2)]. 8.7 Hepatic Impairment VESIcare should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of VESIcare greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). VESIcare is not recommended for patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.6); Dosage and Administration (2.3)]. 8.8 Gender The pharmacokinetics of solifenacin is not significantly influenced by gender.