ADVERSE REACTIONS SECTION.

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 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 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, 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, and combined, the serious adverse reactions to darifenacin were urinary retention and constipation.In Studies 1, and combined, dry mouth leading to study discontinuation occurred in percent, 0.9 percent, and 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 lists the rates of identified adverse reactions, derived from all reported adverse events in percent or more of patients treated with 7.5 mg or 15 mg darifenacin, and greater than placebo in Studies 1, 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 3Body SystemAdverse ReactionPercentage of SubjectsDarifenacin7.5 mgN 337Darifenacin15 mgN 334PlaceboN=388DigestiveDry 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 UrogenitalUrinary Tract Infection 4.7 4.5 2.6 NervousDizziness 0.9 2.1 1.3 Body as wholeAsthenia 1.5 2.7 1.3 EyeDry Eyes 1.5 2.1 0.5 Other adverse reactions reported by percent to 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 was 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 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 4Adverse ReactionDarifenacin 7.5 mg/15 mg = 268Placebo = 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) (5.5 percent) Dyspepsia 12 (4.5 percent) (1.6 percent) Nausea 11 (4.1 percent) (1.6 percent) Urinary Tract Infection 10 (3.7 percent) (3.1 percent) Accidental Injury (3.0 percent) (2.4 percent) Flu Syndrome (3.0 percent) (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 population of uncertain size, it is not always possible to reliably estimate frequency or establish 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Darifenacin is competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion.In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.. 12.2 Pharmacodynamics. In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after darifenacin treatment. These findings are consistent with an antimuscarinic action on the urinary bladder.ElectrophysiologyThe effect of six-day treatment of 15 mg and 75 mg darifenacin on QT/QTc interval was evaluated in multiple-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44 percent male, 56 percent female) aged 18 to 65. Subjects included 18 percent poor metabolizer (PMs) and 82 percent extensive metabolizer (EMs). The QT interval was measured over 24-hour period both pre-dosing and at steady-state. The 75 mg darifenacin dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of darifenacin in the presence of potent CYP3A4 inhibitor. At the doses studied, darifenacin did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, darifenacin 15 mg and 75 mg doses demonstrated mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with darifenacin was no different from placebo.. 12.3 Pharmacokinetics. AbsorptionAfter oral administration of darifenacin to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.Figure 1: Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3.Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 PhenotypeDarifenacin 7.5 mg (N 68 EM, PM)Darifenacin 15 mg (N 102 EM, 17 PM)AUC2 (ngoh/mL) Cm x (ng/mL) Ca g (ng/mL) Tm x (h) t1 /2 (h) AUC2 (ngoh/mL) Cm x (ng/mL) Ca g (ng/mL) Tm x (h) t1 /2 (h) EM 29.24 (15.47) 2.01 (1.04) 1.22 (0.64) 6.49 (4.19) 12.43 (5.64)a 88.90 (67.87) 5.76 (4.24) 3.70 (2.83) 7.61 (5.06) 12.05 (12.37)b PM 67.56 (13.13) 4.27 (0.98) 2.81 (0.55) 5.20 (1.79) 19.95c 157.71 (77.08) 9.99 (5.09) 6.58 (3.22) 6.71 (3.58) 7.40d aN 25; bN 8; cN 2; dN 1; AUC2 = Area under the plasma concentration versus time curve for 24h; Cm x Maximum observed plasma concentration; Ca g Average plasma concentration at steady-state; Tm x Time of occurrence of Cm x; t1 2 Terminal elimination half-life. Regarding EM and PM [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism (12.3)]. The mean oral bioavailability of darifenacin in EMs at steady-state is estimated to be 15 percent and 19 percent for mg and 15 mg tablets, respectively.Effect of FoodFollowing single dose administration of darifenacin with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22 percent and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from darifenacin.DistributionDarifenacin is approximately 98 percent bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L.MetabolismDarifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows:(i) monohydroxylation in the dihydrobenzofuran ring; (ii) dihydrobenzofuran ring opening; (iii) N-dealkylation of the pyrrolidine nitrogen.The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin.Variability in MetabolismA subset of individuals (approximately percent Caucasians and percent African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively.ExcretionFollowing administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60 percent of the radioactivity was recovered in the urine and 40 percent in the feces. Only small percentage of the excreted dose was unchanged darifenacin (3 percent). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 19 hours.Drug-Drug Interactions Effects of Other Drugs on DarifenacinDarifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics [see Drug Interactions (7)].CYP3A4 Inhibitors: In drug interaction study, when 7.5 mg once daily dose of darifenacin was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n 10) and 55.4 ng/mL for one PM subject (n 1). Mean AUC increased to 143 and 939 ngoh/mL for EMs and for one PM subject, respectively. When 15 mg daily dose of darifenacin was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n 3) and one PM subject (n 1), respectively. Mean AUC increased to 1,110 and 931 ngoh/mL for EMs and for one PM subject, respectively [see Dosage and Administration (2) and Drug Interactions (7.1)].The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128 percent and 95 percent higher, respectively, in the presence of moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88 percent and 84 percent, respectively [see Drug Interactions (7.1)]. The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine, mixed CYP P450 enzyme inhibitor.CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33 percent higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see Drug Interactions (7.2)].Effects of Darifenacin on Other DrugsIn Vitro Studies: Based on in vitro human microsomal studies, darifenacin is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations. In Vivo Studies: The potential for clinical doses of darifenacin to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies. CYP2D6 Substrates: The mean Cmax and AUC of imipramine, CYP2D6 substrate, were increased by 57 percent and 70 percent, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260 percent [see Drug Interactions (7.3)]. CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with single oral dose of midazolam 7.5 mg resulted in 17 percent increase in midazolam exposure. Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg). Warfarin: Darifenacin had no significant effect on prothrombin time when single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state [see Drug Interactions (7.6)]. Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in 16 percent increase in digoxin exposure [see Drug Interactions (7.7)]. Pharmacokinetics in Special Populations Age: population pharmacokinetic analysis of patient data indicated trend for clearance of darifenacin to decrease with age (6 percent per decade relative to median age of 44). Following administration of darifenacin 15 mg once daily, darifenacin exposure at steady-state was approximately 12 percent to 19 percent higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations (8.5)]. Pediatric: The pharmacokinetics of darifenacin has not been studied in the pediatric population [see Use in Specific Populations (8.4)]. Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were approximately 57 percent to 79 percent and 61 percent to 73 percent higher in females than in males, respectively [see Use in Specific Populations (8.8)]. Renal Impairment: study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given darifenacin 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance [see Use in Specific Populations (8.7)]. Hepatic Impairment: Darifenacin pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. 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. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Dosage and Administration (2), Warning and Precautions (5.5) and Use in Specific Population (8.6)].. Image.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Darifenacin extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinary incontinence per week. The majority of patients were white (94 percent) and female (84 percent), with mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were >=65 years of age. These characteristics were well balanced across treatment groups. The study population was inclusive of both naive patients who had not received prior pharmacotherapy for overactive bladder (60 percent) and those who had (40 percent).Table shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily darifenacin for 12 weeks. significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies. Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition.Table 4: Difference Between Darifenacin (7.5 mg, 15 mg) and Placebo for the Week 12 Change from Baseline (Studies 1, and 3)Study 1Study 2Study 3Darifenacin 7.5 mgDarifenacin 15 mgPlaceboDarifenacin 7.5 mgDarifenacin 15 mgPlaceboDarifenacin 15 mgPlaceboNo. of Patients Entered 229 115 164 108 107 109 112 115 Urge Incontinence Episodes per WeekMedian Baseline 16.3 17 16.6 14 17.3 16.1 16.2 15.5 Median Change from Baseline -9 -10.4 -7.6 -8.1 -10.4 -5.9 -11.4 -9 Median Difference to Placebo -1.5 -2.1 -2.8 -4.3 -2.4 Micturitions per DayMedian Baseline 10.1 10.1 10.1 10.3 11 10.1 10.5 10.4 Median Change from Baseline -1.6 -1.7 -0.8 -1.7 -1.9 -1.1 -1.9 -1.2 Median Difference to Placebo -0.8 -0.9 -0.5 -0.7 -0.5 Volume of Urine Passed per Void (mL)Median Baseline 160.2 151.8 162.4 161.7 157.3 162.2 155 147.1 Median Change from Baseline 14.9 30.9 7.6 16.8 23.6 7.1 26.7 4.6 Median Difference to Placebo 9.1 20.7 9.2 16.6 20.1 Indicates statistically significant difference versus placebo (p<0.05, Wilcoxon rank-sum test)Table shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg darifenacin or placebo daily with the option to increase to 15 mg darifenacin or placebo daily after two weeks.Table 5: Difference between Darifenacin (7.5 mg/15 mg) and Placebo for the Week 12 Change from Baseline (Study 4)Indicates statistically significant difference versus placebo (p<0.05, Wilcoxon rank-sum test) Darifenacin7.5 mg /15 mgPlaceboNo. of Patients Treated268 127 Urge Incontinence Episodes per WeekMedian Baseline 16.0 14.0 Median Change from Baseline -8.2 -6.0 Median Difference to Placebo -1.4 Micturitions per DayMedian Baseline 9.9 10.4 Median Change from Baseline -1.9 -1.0 Median Difference to Placebo -0.8 Volume of Urine Passed per Void (mL)Median Baseline 173.7 177.2 Median Change from Baseline 18.8 6.6 Median Difference to Placebo 13.3 As seen in Figures a, and c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with darifenacin 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period.Figures 2a, 2b, 2c. Median Change from Baseline at Weeks 2, 6, 12 for Number of Urge Incontinence Episodes per Week (Studies 1, and 3). Image. Image. Image.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have 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). Caution should be taken when darifenacin is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have 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). 7.1 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 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 is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have 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 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 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 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 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter oral administration of darifenacin to healthy volunteers, peak plasma concentrations of darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.Figure 1: Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3.Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 PhenotypeDarifenacin 7.5 mg (N 68 EM, PM)Darifenacin 15 mg (N 102 EM, 17 PM)AUC2 (ngoh/mL) Cm x (ng/mL) Ca g (ng/mL) Tm x (h) t1 /2 (h) AUC2 (ngoh/mL) Cm x (ng/mL) Ca g (ng/mL) Tm x (h) t1 /2 (h) EM 29.24 (15.47) 2.01 (1.04) 1.22 (0.64) 6.49 (4.19) 12.43 (5.64)a 88.90 (67.87) 5.76 (4.24) 3.70 (2.83) 7.61 (5.06) 12.05 (12.37)b PM 67.56 (13.13) 4.27 (0.98) 2.81 (0.55) 5.20 (1.79) 19.95c 157.71 (77.08) 9.99 (5.09) 6.58 (3.22) 6.71 (3.58) 7.40d aN 25; bN 8; cN 2; dN 1; AUC2 = Area under the plasma concentration versus time curve for 24h; Cm x Maximum observed plasma concentration; Ca g Average plasma concentration at steady-state; Tm x Time of occurrence of Cm x; t1 2 Terminal elimination half-life. Regarding EM and PM [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism (12.3)]. The mean oral bioavailability of darifenacin in EMs at steady-state is estimated to be 15 percent and 19 percent for mg and 15 mg tablets, respectively.Effect of FoodFollowing single dose administration of darifenacin with food, the AUC of darifenacin was not affected, while the Cmax was increased by 22 percent and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from darifenacin.DistributionDarifenacin is approximately 98 percent bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L.MetabolismDarifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows:(i) monohydroxylation in the dihydrobenzofuran ring; (ii) dihydrobenzofuran ring opening; (iii) N-dealkylation of the pyrrolidine nitrogen.The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of darifenacin.Variability in MetabolismA subset of individuals (approximately percent Caucasians and percent African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of darifenacin in PMs will be principally mediated via CYP3A4. The darifenacin ratios (PM versus EM) for Cmax and AUC following darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively.ExcretionFollowing administration of an oral dose of 14C-darifenacin solution to healthy volunteers, approximately 60 percent of the radioactivity was recovered in the urine and 40 percent in the feces. Only small percentage of the excreted dose was unchanged darifenacin (3 percent). Estimated darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of darifenacin following chronic dosing is approximately 13 to 19 hours.Drug-Drug Interactions Effects of Other Drugs on DarifenacinDarifenacin metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics [see Drug Interactions (7)].CYP3A4 Inhibitors: In drug interaction study, when 7.5 mg once daily dose of darifenacin was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean darifenacin Cmax increased to 11.2 ng/mL for EMs (n 10) and 55.4 ng/mL for one PM subject (n 1). Mean AUC increased to 143 and 939 ngoh/mL for EMs and for one PM subject, respectively. When 15 mg daily dose of darifenacin was given with ketoconazole, mean darifenacin Cmax increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n 3) and one PM subject (n 1), respectively. Mean AUC increased to 1,110 and 931 ngoh/mL for EMs and for one PM subject, respectively [see Dosage and Administration (2) and Drug Interactions (7.1)].The mean Cmax and AUC of darifenacin following 30 mg once daily dosing at steady-state were 128 percent and 95 percent higher, respectively, in the presence of moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, moderate CYP3A4 inhibitor and darifenacin 30 mg once daily at steady-state increased darifenacin Cmax and AUC by 88 percent and 84 percent, respectively [see Drug Interactions (7.1)]. The mean Cmax and AUC of darifenacin following 30 mg once daily at steady-state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine, mixed CYP P450 enzyme inhibitor.CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33 percent higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see Drug Interactions (7.2)].Effects of Darifenacin on Other DrugsIn Vitro Studies: Based on in vitro human microsomal studies, darifenacin is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations. In Vivo Studies: The potential for clinical doses of darifenacin to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies. CYP2D6 Substrates: The mean Cmax and AUC of imipramine, CYP2D6 substrate, were increased by 57 percent and 70 percent, respectively, in the presence of steady-state darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260 percent [see Drug Interactions (7.3)]. CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with single oral dose of midazolam 7.5 mg resulted in 17 percent increase in midazolam exposure. Combination Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg). Warfarin: Darifenacin had no significant effect on prothrombin time when single dose of warfarin 30 mg was co-administered with darifenacin (30 mg daily) at steady-state [see Drug Interactions (7.6)]. Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in 16 percent increase in digoxin exposure [see Drug Interactions (7.7)]. Pharmacokinetics in Special Populations Age: population pharmacokinetic analysis of patient data indicated trend for clearance of darifenacin to decrease with age (6 percent per decade relative to median age of 44). Following administration of darifenacin 15 mg once daily, darifenacin exposure at steady-state was approximately 12 percent to 19 percent higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations (8.5)]. Pediatric: The pharmacokinetics of darifenacin has not been studied in the pediatric population [see Use in Specific Populations (8.4)]. Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Darifenacin Cmax and AUC at steady-state were approximately 57 percent to 79 percent and 61 percent to 73 percent higher in females than in males, respectively [see Use in Specific Populations (8.8)]. Renal Impairment: study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given darifenacin 15 mg once daily to steady-state demonstrated no clear relationship between renal function and darifenacin clearance [see Use in Specific Populations (8.7)]. Hepatic Impairment: Darifenacin pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given darifenacin 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. However, protein binding of darifenacin was affected by moderate hepatic impairment. 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. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Dosage and Administration (2), Warning and Precautions (5.5) and Use in Specific Population (8.6)].

SPL PATIENT PACKAGE INSERT SECTION.

FDA-Approved Patient Labeling. Darifenacin (DAR-i-FEN-a-s in) Extended-Release TabletsRead this Patient Information leaflet about darifenacin extended-release tablets before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.What are darifenacin extended-release tabletsDarifenacin extended-release tablets are prescription medicine for adults used to treat the following symptoms due to condition called overactive bladder:Urge urinary incontinence: strong need to urinate with leaking or wetting accidentsUrgency: strong need to urinate right awayFrequency: urinating oftenIt is unknown if darifenacin extended-release tablets are safe and effective in children.Who should not take darifenacin extended-release tabletsDo not take darifenacin extended-release tablets if you:are not able to empty your bladder (urinary retention)have delayed or slow emptying of your stomach (gastric retention)have an eye problem called uncontrolled narrow-angle glaucomaWhat should tell my healthcare provider before starting darifenacin extended-release tabletsBefore starting darifenacin extended-release tablets, tell your doctor if you:have trouble emptying your bladder or if you have weak urine streamhave any stomach or intestinal problems, or problems with constipationhave liver problemshave any other medical conditionsare pregnant or are planning to become pregnant. It is not known if darifenacin can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if darifenacin passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take darifenacin extended-release tablets.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Darifenacin extended-release tablets and certain other medicines may affect each other, causing side effects.Especially tell your healthcare provider if you take a:antifungal medicine ketoconazole (Nizoral(R)) or itraconazole (Sporanox(R))antibiotic medicine clarithromycin (Biaxin(R))anti-HIV medicine ritonavir (Norvir(R)) or nelfinavir (Viracept(R))medicine to treat depression nefazadone (Serzone(R))medicine to treat an abnormal heartbeat flecainide (Tambocor(R))antipsychotic medicine thioridazine (Mellaril(R))medicine to treat depression called tricyclic antidepressantKnow all the medicines you take. Keep list of them with you to show your doctor and pharmacist each time you get new medicine.How should take darifenacin extended-release tabletsTake darifenacin extended-release tablets exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take darifenacin extended-release tablets time daily with water.Darifenacin extended-release tablets should be swallowed whole. Do not chew, cut or crush darifenacin extended-release tablet.Darifenacin extended-release tablets may be taken with or without food.If you take too much darifenacin extended-release tablets call your doctor or go to the nearest hospital emergency room right away.What should avoid while taking darifenacin extended-release tabletsDarifenacin extended-release tablets can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how darifenacin extended-release tablets affect you.What are the possible side effects of darifenacin extended-release tabletsDarifenacin extended-release tablets may cause serious side effects including:Serious allergic reaction. Stop taking darifenacin extended-release tablets and get medical help right away if you have:hives, skin rash or swellingsevere itchingswelling of your face, mouth or tonguetrouble breathing The most common side effects with darifenacin extended-release tablets are:constipationdry mouthheadacheheartburnnauseaurinary tract infectionblurred visionheat exhaustion or heat-stroke. This can happen when darifenacin extended-release tablets are used in hot environments. Symptoms of heat exhaustion may include: decreased sweatingdizzinesstirednessnauseaincrease body temperature Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of darifenacin extended-release tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store darifenacin extended-release tabletsStore darifenacin extended-release tablets at room temperature, at 77 (25 C).Keep darifenacin extended-release tablets out of the light.Keep darifenacin extended-release tablets and all medicines out of the reach of children.General information about darifenacin extended-release tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use darifenacin extended-release tablets for condition for which it was not prescribed. Do not give darifenacin extended-release tablets to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about darifenacin extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about darifenacin extended-release tablets that is written for health professionals.What are the ingredients in darifenacin extended-release tabletsActive ingredient: darifenacin Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide.The 15 mg tablet also contains iron oxide red and iron oxide yellow.The brands listed are the trademarks of their respective owners.Manufactured and Distributed by:Polygen Pharmaceuticals Inc.,Edgewood, NY 11717, USA. Urge urinary incontinence: strong need to urinate with leaking or wetting accidents. Urgency: strong need to urinate right away. Frequency: urinating often. are not able to empty your bladder (urinary retention). have delayed or slow emptying of your stomach (gastric retention). have an eye problem called uncontrolled narrow-angle glaucoma. have trouble emptying your bladder or if you have weak urine stream. have any stomach or intestinal problems, or problems with constipation. have liver problems. have any other medical conditions. are pregnant or are planning to become pregnant. It is not known if darifenacin can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if darifenacin passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take darifenacin extended-release tablets.. antifungal medicine ketoconazole (Nizoral(R)) or itraconazole (Sporanox(R)). antibiotic medicine clarithromycin (Biaxin(R)). anti-HIV medicine ritonavir (Norvir(R)) or nelfinavir (Viracept(R)). medicine to treat depression nefazadone (Serzone(R)). medicine to treat an abnormal heartbeat flecainide (Tambocor(R)). antipsychotic medicine thioridazine (Mellaril(R)). medicine to treat depression called tricyclic antidepressant. Take darifenacin extended-release tablets exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take darifenacin extended-release tablets time daily with water.. Darifenacin extended-release tablets should be swallowed whole. Do not chew, cut or crush darifenacin extended-release tablet.. Darifenacin extended-release tablets may be taken with or without food.. If you take too much darifenacin extended-release tablets call your doctor or go to the nearest hospital emergency room right away.. Serious allergic reaction. Stop taking darifenacin extended-release tablets and get medical help right away if you have:hives, skin rash or swellingsevere itchingswelling of your face, mouth or tonguetrouble breathing hives, skin rash or swelling. severe itching. swelling of your face, mouth or tongue. trouble breathing. constipation. dry mouth. headache. heartburn. nausea. urinary tract infection. blurred vision. heat exhaustion or heat-stroke. This can happen when darifenacin extended-release tablets are used in hot environments. Symptoms of heat exhaustion may include: decreased sweatingdizzinesstirednessnauseaincrease body temperature decreased sweating. dizziness. tiredness. nausea. increase body temperature. Store darifenacin extended-release tablets at room temperature, at 77 (25 C).. Keep darifenacin extended-release tablets out of the light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Darifenacin 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 is administered to nursing woman. (8.3)Pediatric Use: The safety and effectiveness of darifenacin in pediatric patients have not been established. (8.4). Pregnancy: Darifenacin 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 is administered to nursing woman. (8.3). Pediatric Use: The safety and effectiveness of darifenacin in pediatric patients have not been established. (8.4). 8.1 Pregnancy. Pregnancy Category There are no studies of darifenacin in pregnant women. 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 rats, there was delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of darifenacin was shown to increase post-implantation loss, with no effect level at nine times (10 mg/kg/day) the AUC at the MRHD. Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of darifenacin, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD. Because animal reproduction studies are not always predictive of human response, darifenacin should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.. 8.3 Nursing Mothers. Darifenacin is excreted into the milk of rats. It is not known whether darifenacin is excreted into human milk and therefore caution should be exercised before darifenacin is administered to nursing woman.. 8.4 Pediatric Use. The safety and effectiveness of darifenacin in pediatric patients have not been established.. 8.5 Geriatric Use. In the fixed-dose, placebo-controlled, clinical studies, 30 percent of patients treated with darifenacin 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 <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 is not recommended for use in these patients [see Dosage and Administration (2) and Warnings and Precautions (5.6)]. The daily dose of darifenacin 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. 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)].

WARNINGS AND PRECAUTIONS SECTION.

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). 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). 5.1 Risk of Urinary Retention. Darifenacin should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.. 5.2 Decreased 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.. 5.3 Controlled 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.. 5.4 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 patent airway should be promptly provided.. 5.5 Central Nervous System Effects. Darifenacin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6.2)]. 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 patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.. 5.6 Patients 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)].