SOLIFENACIN: 8,324 Adverse Event Reports & Safety Profile

Solifenacin succinate tablets are a muscarinic receptor antagonist. Chemically, solifenacin succinate is a butanedioic acid compound with 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 3(R)-quinuclidinyl ester Monosuccinate 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 g/mol. The structural formula of solifenacin succinate is: Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble or soluble in water, glacial acetic acid, dimethyl sulfoxide; soluble in methanol, very slightly soluble in acetone and ethanol. Each solifenacin succinate tablet contains 5 or 10 mg of solifenacin succinate and is formulated for oral administration. In addition to the active ingredient solifenacin succinate, the tablets also contain the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, talc, titanium dioxide and triacetin.

The

5 mg tablets contain the colorants iron oxide yellow and FD&C yellow# 6.

The

10 mg tablets contain the colorants iron oxide yellow and FD&C Red# 40. chemical-structure

AND USAGE Solifenacin succinate tablets are indicated for the treatment of adults with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Solifenacin succinate tablets are a muscarinic antagonist indicated for the treatment of adults with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1 )

AND ADMINISTRATION

• 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 &lt; 30 mL/min/1.73 m 2 ) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

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) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 )]</span> .

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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

Solifenacin succinate tablets are contraindicated in patients:

• With urinary retention [ see Warnings and Precautions ( 5.2 ) ],
• 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 solifenacin succinate tablets. Reported adverse reactions have included anaphylaxis and angioedema [ see Adverse Reactions ( 6.2 ) ].
• Urinary retention ( 4 , 5.2 ).
• 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 ).

REACTIONS

• 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) <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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.

AND PRECAUTIONS

• Angioedema and Anaphylactic Reactions : Promptly discontinue Solifenacin Succinate Tablets and provide appropriate therapy. ( 5.1 )
• Urinary Retention : Solifenacin Succinate Tablets are not recommended for use in patients with clinically significant bladder outlet obstruction. ( 5.2 )
• Gastrointestinal Disorders : Solifenacin Succinate Tablets are not recommended for use 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 affect them. ( 5.4 )
• Controlled Narrow-Angle Glaucoma : Use Solifenacin Succinate Tablets with caution in patients being treated for narrow-angle glaucoma. ( 5.5 )
• QT Prolongation in Patients at High Risk of QT Prolongation : Solifenacin Succinate Tablets are not recommended for use in patients at high risk of QT prolongation, including patients with a known history of QT prolongation and patients taking medications known to prolong the QT interval. ( 5.6 )

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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> , 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.

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).

7.1 Potent CYP3A4 Inhibitors Following the administration of 10 mg of solifenacin succinate tablets in the presence of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, the mean C max 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 solifenacin succinate tablets when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]</span>. 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 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

7.6 Digoxin Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.