Darifenacin

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.

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) . 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 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 is 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

Darifenacin extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention 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 should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks 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

5.1Risk 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.

5.2Decreased 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.

5.3Controlled 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.

5.4Angioedema 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

extended-release tablets are associated with anticholinergic central nervous system (CNS) effects . 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.

5.6Patients 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 is not recommended for use in this patient population .

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 is contraindicated in patients with, or at risk for, the following conditions: urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma.

8.1Pregnancy Risk Summary There

are no available data on darifenacin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal studies, darifenacin was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 and 28 times the maximum recommended human dose (MRHD) of 15 mg, respectively. Effects on embryofetal development were observed following administration of darifenacin during pregnancy (dilated ureter and/or kidney pelvis in rabbits at about 9 times the MRHD, post-implantation loss in rabbits at about 28 times, and delayed ossification in rats at about 59 times) and during pregnancy and lactation (developmental delays in rats at about 17 times the MRHD), which was associated with maternal toxicity . Dystocia was observed in rat dams at about 17 times the MRHD. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data Embryofetal development studies were conducted with oral darifenacin in female rats (0, 3, 10, and 50 mg/kg/day) and rabbits (0, 3, 10, and 30 mg/kg/day) during the period of organogenesis (gestation days 6 to 17 in the rat and gestation days 6 to 18 in the rabbit). Darifenacin was not teratogenic in rats and rabbits at plasma exposure of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg. At approximately 59 times the MRHD in pregnant rats there was a delay in the ossification of the sacral and caudal vertebrae (associated with a decrease in maternal and pup body weight gains) which was not observed at an exposure approximately 13 times the AUC at the MRHD. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups.

In pregnant rabbits, an exposure of darifenacin approximately 28 times the AUC at the MRHD of 15mg (30 mg/kg/day) was shown to increase post-implantation loss (associated with decreased maternal body weight gain), with a no effect level at 10 mg/kg/day (9 times the AUC at the MRHD). Dilated ureter and/or kidney pelvis was also observed in offspring at this highest dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at the mid dose of 10 mg/kg/day (9 times the MRHD). No effect was observed at the lowest dose of 3 mg/kg/day (approximately 2.8 times the AUC at the MRHD).

A pre- and post-natal development study was conducted with oral darifenacin in female rats (0, 3, 10, and 50 mg/kg/day) throughout gestation and lactation. Decreased body weight gain and dystocia were observed in dams at 10 mg/kg/day) throughout gestation and lactation. Decreased body weight and dystocia were observed in dams at 10 mg/kg/day (approximately 17 times the MRHD) and above.

Slight developmental delays (surface righting reflex, incisor eruption, eyelid opening, vaginal opening, preputial separation) were observed in pups at these doses. At 5 times the AUC at the MRHD (3 mg/kg/day), there were no effects on dams or pups.

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 To report SUSPECTED ADVERSE REACTIONS, contact TORRENT PHARMA INC. at 1-800-912-9561 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 %, 0.9 %, and 0 % 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 %, 1.2 %, and 0.3 % 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 % 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 greater than or equal to 2 % of Patients Treated with Darifenacin Extended-Release Tablets and More Frequent with Darifenacin than with Placebo in Studies 1, 2, and 3 Body System A d v er se Reaction % age 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 a Whole Asthenia

1.5 2.7

1.3Eye Dry Eyes

1.5 2.1

0.5Other

adverse reactions reported by 1% to 2% 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 . 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 greater than 3% of patients treated with darifenacin 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 than Placebo, in Study 4 A d v er se Reaction Darifenacin 7.5 mg/15 mg Placebo N = 268 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 %)

6.2Post Marketing Experience The

following adverse reactions have been reported during post-approval use of darifenacin extended-release tablets. 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