Darifenacin 7.5 mg Tablet, Extended Release, 1,000-count

5 WARNINGS AND PRECAUTIONS Darifenacin should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. ( 5.1 ) Darifenacin should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. ( 5.2 ) Darifenacin 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. Advise patients not to drive or operate heavy machinery until they know how darifenacin affects them. ( 5.5 )

5.1Risk of Urinary Retention Darifenacin should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

5.2Decreased Gastrointestinal Motility Darifenacin should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Darifenacin, 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.

5.3Controlled Narrow-Angle Glaucoma Darifenacin should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.

5.4Angioedema 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.

5.5Central Nervous System Effects Darifenacin 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 darifenacin affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.6Patients with Hepatic Impairment The daily dose of darifenacin should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Darifenacin 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 (>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.

6.1Clinical 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

8.2Constipation 14.8 21.3

6.2Dyspepsia 2.7 8.4

2.6Abdominal Pain 2.4 3.9

0.5Nausea 2.7 1.5

1.5Diarrhea 2.1 0.9

1.8Urogenital Urinary Tract Infection 4.7 4.5

2.6Nervous Dizziness 0.9 2.1

1.3Body as whole Asthenia 1.5 2.7

1.3Eye Dry Eyes 1.5 2.1

0.5Other 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…

7 DRUG INTERACTIONS Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants. ( 7.2 ) The concomitant use of darifenacin with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects of gastrointestinal motility.

( 7.3 )

7.1CYP3A4 Inhibitors The systemic exposure of darifenacin from darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration (2) and Clinical Pharmacology (12.3) ] .

7.2CYP2D6 Inhibitors No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) [see Clinical Pharmacology (12.3) ] .

7.3CYP2D6 Substrates Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants) [see Clinical Pharmacology (12.3) ] .

7.4CYP3A4 Substrates Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology (12.3) ] .

7.5Combination oral contraceptives Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol [see Clinical Pharmacology (12.3) ] .

7.6Warfarin Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state. Standard therapeutic prothrombin time monitoring for warfarin should be continued.

7.7Digoxin Darifenacin (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued [see Clinical Pharmacology (12.3) ] .

7.8Other Anticholinergic Agents The concomitant use of darifenacin with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility.