Darifenacin

1 INDICATIONS AND USAGE Darifenacin extended-release tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. Darifenacin extended-release tablets are a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency ( 1 )

12.1 Mechanism of Action Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play a role in cholinergically mediated functions, including contractions of the urinary bladder smooth muscle. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M 3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M 3 compared to M 1 and M 5 , respectively, and 59-fold greater affinity for M 3 compared to both M 2 and M 4 ). M 3 receptors are involved in contraction of human bladder.

2 DOSAGE AND ADMINISTRATION The recommended starting dose of darifenacin extended-release tablets is 7.5 mg orally once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy. Darifenacin extended-release tablets should be taken orally once daily with water. Darifenacin extended-release tablets may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed. For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of darifenacin extended-release tablets should not exceed 7.5 mg. Darifenacin extended-release tablets are not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings and Precautions (5.6), Drug Interactions (7.1) , Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . The recommended starting dose of darifenacin extended-release tablets is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy ( 2 ) The daily dose of darifenacin extended-release tablets should not exceed 7.5 mg in the following patients: Patients with moderate hepatic impairment (Child-Pugh B) ( 2 , 8.6 ) Patients taking potent CYP3A4 inhibitors ( 2 , 7.1 ) Darifenacin extended-release tablets are not recommended for use in patients with severe hepatic impairment (Child-Pugh C) ( 2 , 8.6 ) Darifenacin extended-release tablets may be taken with or without food. The tablet should be swallowed whole with water and not chewed, divided or crushed ( 2 )

6 ADVERSE REACTIONS The most frequently reported adverse reactions (greater than 3%) for darifenacin extended-release tablets are: constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 darifenacin extended-release tablets was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin extended-release tablets. Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received darifenacin extended-release tablets 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with darifenacin extended-release tablets for at least 24 and 52 weeks, respectively. In Studies 1, 2 and 3 combined, the serious adverse reactions to darifenacin extended-release tablets were urinary retention and constipation. In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with darifenacin extended-release tablets 7.5 mg daily, darifenacin extended-release tablets 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with darifenacin extended-release tablets 7.5 mg daily, darifenacin extended-release tablets 15 mg daily and placebo, respectively. Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg darifenacin extended-release tablets, and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment. Table 1: Incidence of Identified Adverse Reactions, Derived from All Adverse Events Reported in greater than or equal to 2% of Patients Treated with Darifenacin Extended-Release Tablets and More Frequent with Darifenacin Extended-Release Tablets than with Placebo in Studies 1, 2, and 3 Body System Adverse Reaction % of Subjects Darifenacin Extended-Release Tablets 7.5 mg N = 337 Darifenacin Extended-Release Tablets 15 mg N = 334 Placebo N = 388 Digestive Dry Mouth 20.2 35.3 8.2 Constipation 14.8 21.3 6.2 Dyspepsia 2.7 8.4 2.6 Abdominal Pain 2.4 3.9 0.5 Nausea 2.7 1.5 1.5 Diarrhea 2.1 0.9 1.8 Urogenital Urinary Tract Infection 4.7 4.5 2.6 Nervous Dizziness 0.9 2.1 1.3 Body as a Whole Asthenia 1.5 2.7 1.3 Eye Dry Eyes 1.5 2.1 0.5 Other adverse reactions reported by 1% to 2% of darifenacin extended-release tablets -treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis. Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which darifenacin extended-release tablets was administered in accordance with dosing recommendations [see Dosage and Administration (2) ] . All patients initially received placebo or darifenacin extended-release tablets 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to darifenacin extended-release tablets 15 mg if needed. In this study, the most commonly r

5 WARNINGS AND PRECAUTIONS Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention ( 5.1 ) Darifenacin extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention ( 5.2 ) Darifenacin extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks ( 5.3 ) Central Nervous System Effects: Somnolence has been reported with darifenacin extended-release tablets. Advise patients not to drive or operate heavy machinery until they know how darifenacin extended-release tablets affect them ( 5.5 ) 5.1 Risk of Urinary Retention Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. 5.2 Decreased Gastrointestinal Motility Darifenacin extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Darifenacin extended-release tablets, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis. 5.3 Controlled Narrow-Angle Glaucoma Darifenacin extended-release tablets should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks. 5.4 Angioedema Angioedema of the face, lips, tongue, and/or larynx have been reported with darifenacin. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, darifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. 5.5 Central Nervous System Effects Darifenacin extended-release tablets are 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 darifenacin extended-release tablets affect them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered. 5.6 Patients with Hepatic Impairment The daily dose of darifenacin extended-release tablets should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin extended-release tablets have not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore are not recommended for use in this patient population [see Dosage and Administration (2) Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

4 CONTRAINDICATIONS Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions: urinary retention gastric retention, or uncontrolled narrow-angle glaucoma. Darifenacin extended-release tablets are contraindicated in patients with, or at risk for, the following conditions ( 4 ): urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma.

10 OVERDOSAGE Overdosage with antimuscarinic agents, including darifenacin extended-release tablets, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Darifenacin extended-release tablets have been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision.