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

Darifenacin is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

( 1 )

6 ADVERSE REACTIONS The most frequently reported adverse reactions (>3 percent) for darifenacin are: constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Polygen Pharmaceuticals Inc.

at 1-888-291-7337 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 was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin.

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 7.5 mg daily and 15 mg daily, respectively.

In all long-term trials combined, 1,216 and 672 patients received treatment with darifenacin for at least 24 and 52 weeks, respectively.

In Studies 1, 2 and 3 combined, the serious adverse reactions to darifenacin were urinary retention and constipation.

In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0 percent, 0.9 percent, and 0 percent of patients treated with darifenacin 7.5 mg daily, darifenacin 15 mg daily and placebo, respectively.

Constipation leading to study discontinuation occurred in 0.6 percent, 1.2 percent, and 0.3 percent of patients treated with darifenacin 7.5 mg daily, darifenacin 15 mg daily and placebo, respectively.

Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2 percent or more of patients treated with 7.5 mg or 15 mg darifenacin, 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 ≥2 Percent of Patients Treated with Darifenacin Extended-Release Tablets and More Frequent with Darifenacin than with Placebo in Studies 1, 2, and 3 Body System Adverse Reaction Percentage of Subjects Darifenacin 7.5 mg N = 337 Darifenacin 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 whole Asthenia 1.5 2.7 1.3 Eye Dry Eyes 1.5 2.1 0.5 Other adverse reactions reported by 1 percent to 2 percent of darifenacin-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 was administered in accordance with dosing recommendations [see Dosage and Administration (2) ] .

All patients initially received placebo or darifenacin 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to darifenacin 15 mg if needed.

In this study, the most commonly reported adverse reactions were also constipation and dry mouth.

Table 2 lists the identified adverse reactions, derived from all adverse events reported in >3 percent of patients treated with darifenacin and greater than placebo.

Table 2: Number (Percent) of Adverse Reactions, Derived from All Adverse Events Reported in >3 Percent of Patients Treated with Darifenacin Extended-Release Tablets, and More Frequent with Darifenacin than Placebo, in Study 4 Adverse Reaction Darifenacin 7.5 mg/15 mg N = 268 Placebo N = 127 Constipation 56 (20.9 percent) 10 (7.9 percent) Dry Mouth 50 (18.7 percent) 11 (8.7 percent) Headache 18 (6.7 percent) 7 (5.5 percent) Dyspepsia 12 (4.5 percent) 2 (1.6 percent) Nausea 11 (4.1 percent) 2 (1.6 percent) Urinary Tract Infection 10 (3.7 percent) 4 (3.1 percent) Accidental Injury 8 (3.0 percent) 3 (2.4 percent) Flu Syndrome 8 (3.0 percent) 3 (2.4 percent) 6.2 Post Marketing Experience The following adverse reactions have been reported during post approval use of darifenacin extended-release tablets (darifenacin).

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

Dermatologic: erythema multiforme, interstitial granuloma annulare General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction Central Nervous: confusion, hallucinations and somnolence Cardiovascular: palpitations and syncope