Darifenacin Hydrobromide

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

Extended-release tablets 7.5 mg and 15 mg ( 3 ) Darifenacin extended-release tablets 7.5 mg are white to off white colored circular biconvex film coated tablet debossed with “C” on one side and “431” on the other side. Darifenacin extended-release tablets 15 mg are light peach colored circular biconvex film coated tablet debossed with “C” on one side and “432” on the other side.

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. 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 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 )] .

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

Caution should be taken when darifenacin extended-release tablets are 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 extended-release tablets 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 ) 7.1 CYP3A4 Inhibitors The systemic exposure of darifenacin from darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of darifenacin extended-release tablet 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 )] . 7.2 CYP2D6 Inhibitors No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) [see Clinical Pharmacology ( 12.3 )] . 7.3 CYP2D6 Substrates Caution should be taken when darifenacin extended-release tablet 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 )] . 7.4 CYP3A4 Substrates Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology ( 12.3 )] .

7.5 Combination 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 )] .

7.6 Warfarin 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.

7.7 Digoxin 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 )] .

7.8 Other Anticholinergic Agents The concomitant use of darifenacin extended-release tablets 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.

Pregnancy: Darifenacin extended-release tablets should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus ( 8.1 ) Nursing Mothers: It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before darifenacin extended-release tablets are administered to a nursing woman ( 8.3 ) Pediatric Use: The safety and effectiveness of darifenacin extended-release tablets in pediatric patients have not been established ( 8.4 )

8.1 Pregnancy 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 (see Data). 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 2-4% and 15-20%, 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 exposures 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 15 mg (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 (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.

8.2 Lactation Risk Summary There are no data on the presence of darifenacin in human milk, the effects on the breastfed infant, or the effects of darifenacin on milk production. Darifenacin is present in rat milk [see Data]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for darifenacin and any potential adverse effects on the breastfed child from darifenacin or from the underlying maternal conditions. Data After a single oral dose of 14 C radiolabeled darifenacin to lactating rats, darifenacin was detected in maternal milk.

8.4 Pediatric Use The safety and effectiveness of darifenacin extended-release tablets in pediatric patients have not been established.

8.5 Geriatric Use In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with darifenacin extended-release tablets were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n = 207) and younger patients less than 65 years (n = 464). No dose adjustment is recommended for elderly patients [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] .

8.6 Hepatic Impairment Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore darifenacin extended-release tablet is not recommended for use in these patients [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.6 )] . The daily dose of darifenacin extended-release tablet should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B) [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.6 )] . After adjusting for plasma protein binding, unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

8.7 Renal Impairment A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) demonstrated no clear relationship between renal function and darifenacin clearance. No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology ( 12.3 )] .

8.8 Gender No dose adjustment is recommended based on gender [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] .

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.