Darifenacin

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 affects 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 affects 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 tablet should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin extended-release tablet has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population [see Dosage and Administration ( 2 ) Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .

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 Cipla Limited, India at 1-866-604-3268 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 tablet was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with darifenacin extended-release tablet. 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 tablet 7.5 mg N = 337 Darifenacin extended- release tablet 15 mg N = 334 Placebo N = 338 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 tablet 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 tablet 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 greater than 3% of patients treated with darifenacin extended-release tablets and greater than placebo. Table 2: Number (%) of Adverse Reactions, Derived from All Adverse Events Reported in greater than 3% of Patients Treated with Darifenacin Extended-Release Tablets, and More Frequent with Darifenacin Extended-Release Tablets than Placebo, in Study 4 Adverse Reaction Darifenacin extended-release tablet 7.5 mg/15 mg N = 268 Placebo N = 127 Constipation 56 (20.9%) 10 (7.9%) Dry Mouth 50 (18.7%) 11 (8.7%) Headache 18 (6.7%) 7 (5.5%) Dyspepsia 12 (4.5%) 2 (1.6%) Nausea 11 (4.1%) 2 (1.6%) Urinary Tract Infection 10 (3.7%) 4 (3.1%) Accidental Injury 8 (3.0%) 3 (2.4%) Flu Syndrome 8 (3.0%) 3 (2.4%) 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

<table width="100%"><caption>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</caption><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Botrule" align="center"><content styleCode="bold">Body System</content></th><th styleCode="Botrule" align="center"><content styleCode="bold">Adverse Reaction</content></th><th colspan="3" styleCode="Botrule"><content styleCode="bold"> % of Subjects</content></th></tr></thead><tbody><tr><td styleCode="Botrule" align="center"><paragraph> </paragraph></td><td styleCode="Botrule" align="center"><paragraph> </paragraph></td><td styleCode="Botrule"><paragraph><content styleCode="bold">Darifenacin extended-release tablet</content> <content styleCode="bold">7.5 mg</content> <content styleCode="bold">N = 337</content></paragraph></td><td styleCode="Botrule"><paragraph><content styleCode="bold">Darifenacin extended-</content> <content styleCode="bold">release tablet</content> <content styleCode="bold">15 mg</content> <content styleCode="bold">N = 334</content></paragraph></td><td styleCode="Botrule"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">N = 338</content></paragraph></td></tr><tr><td align="center"><paragraph>Digestive</paragraph></td><td align="center"><paragraph>Dry Mouth</paragraph></td><td><paragraph>20.2</paragraph></td><td><paragraph>35.3</paragraph></td><td><paragraph>8.2</paragraph></td></tr><tr><td><paragraph> </paragraph></td><td align="center"><paragraph>Constipation</paragraph></td><td><paragraph>14.8</paragraph></td><td><paragraph>21.3</paragraph></td><td><paragraph>6.2</paragraph></td></tr><tr><td><paragraph> </paragraph></td><td align="center"><paragraph>Dyspepsia</paragraph></td><td><paragraph>2.7</paragraph></td><td><paragraph>8.4</paragraph></td><td><paragraph>2.6</paragraph></td></tr><tr><td><paragraph> </paragraph></td><td align="center"><paragraph>Abdominal Pain</paragraph></td><td><paragraph>2.4</paragraph></td><td><paragraph>3.9</paragraph></td><td><paragraph>0.5</paragraph></td></tr><tr><td><paragraph> </paragraph></td><td align="center"><paragraph>Nausea</paragraph></td><td><paragraph>2.7</paragraph></td><td><paragraph>1.5</paragraph></td><td><paragraph>1.5</paragraph></td></tr><tr><td><paragraph> </paragraph></td><td align="center"><paragraph>Diarrhea</paragraph></td><td><paragraph>2.1</paragraph></td><td><paragraph>0.9</paragraph></td><td><paragraph>1.8</paragraph></td></tr><tr><td align="center"><paragraph>Urogenital</paragraph></td><td align="center"><paragraph>Urinary Tract Infection</paragraph></td><td><paragraph>4.7</paragraph></td><td><paragraph>4.5</paragraph></td><td><paragraph>2.6</paragraph></td></tr><tr><td align="center"><paragraph>Nervous</paragraph></td><td align="center"><paragraph>Dizziness</paragraph></td><td><paragraph>0.9</paragraph></td><td><paragraph>2.1</paragraph></td><td><paragraph>1.3</paragraph></td></tr><tr><td align="center"><paragraph>Body as a Whole</paragraph></td><td align="center"><paragraph>Asthenia</paragraph></td><td><paragraph>1.5</paragraph></td><td><paragraph>2.7</paragraph></td><td><paragraph>1.3</paragraph></td></tr><tr><td styleCode="Botrule" align="center"><paragraph>Eye</paragraph></td><td styleCode="Botrule" align="center"><paragraph>Dry Eyes</paragraph></td><td styleCode="Botrule"><paragraph>1.5</paragraph></td><td styleCode="Botrule"><paragraph>2.1</paragraph></td><td styleCode="Botrule"><paragraph>0.5</paragraph></td></tr></tbody></table>

<table width="100%"><caption>Table 2: Number (%) of Adverse Reactions, Derived from All Adverse Events Reported in greater than 3% of Patients Treated with Darifenacin Extended-Release Tablets, and More Frequent with Darifenacin Extended-Release Tablets than Placebo, in Study 4 </caption><col width="34%" align="left" valign="middle"/><col width="33%" align="left" valign="middle"/><col width="33%" align="left" valign="middle"/><thead><tr><th styleCode="Botrule"><content styleCode="bold">Adverse Reaction</content></th><th styleCode="Botrule"><content styleCode="bold">Darifenacin extended-release </content> <content styleCode="bold">tablet 7.5 mg/15 mg</content> <content styleCode="bold">N = 268</content></th><th styleCode="Botrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">N = 127</content></th></tr></thead><tbody><tr><td valign="top"><paragraph>Constipation</paragraph></td><td valign="top"><paragraph>56 (20.9%)</paragraph></td><td valign="top"><paragraph>10 (7.9%)</paragraph></td></tr><tr><td valign="top"><paragraph>Dry Mouth</paragraph></td><td valign="top"><paragraph>50 (18.7%)</paragraph></td><td valign="top"><paragraph>11 (8.7%)</paragraph></td></tr><tr><td valign="top"><paragraph>Headache</paragraph></td><td valign="top"><paragraph>18 (6.7%)</paragraph></td><td valign="top"><paragraph>7 (5.5%)</paragraph></td></tr><tr><td valign="top"><paragraph>Dyspepsia</paragraph></td><td valign="top"><paragraph>12 (4.5%)</paragraph></td><td valign="top"><paragraph>2 (1.6%)</paragraph></td></tr><tr><td valign="top"><paragraph>Nausea</paragraph></td><td valign="top"><paragraph>11 (4.1%)</paragraph></td><td valign="top"><paragraph>2 (1.6%)</paragraph></td></tr><tr><td valign="top"><paragraph>Urinary Tract Infection</paragraph></td><td valign="top"><paragraph>10 (3.7%)</paragraph></td><td valign="top"><paragraph>4 (3.1%)</paragraph></td></tr><tr><td valign="top"><paragraph>Accidental Injury</paragraph></td><td valign="top"><paragraph>8 (3.0%)</paragraph></td><td valign="top"><paragraph>3 (2.4%)</paragraph></td></tr><tr><td styleCode="Botrule" valign="top"><paragraph>Flu Syndrome</paragraph></td><td styleCode="Botrule" valign="top"><paragraph>8 (3.0%)</paragraph></td><td styleCode="Botrule" valign="top"><paragraph>3 (2.4%)</paragraph></td></tr></tbody></table>