1 INDICATIONS AND USAGE

Enablex (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

2 DOSAGE AND ADMINISTRATION

The recommended starting dose of Enablex is 7.5mg once daily. Based upon individual response, the dose may be increased to 15mg once daily, as early as two weeks after starting therapy.

Enablex should be taken once daily with water. Enablex 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 (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of Enablex should not exceed 7.5mg. Enablex is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings & Precautions (5.5), Drug Interactions (7.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Enablex extended-release tablets 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse.

Enablex extended-release tablets 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.

4 CONTRAINDICATIONS

Enablex is contraindicated in patients with, or at risk for, the following conditions:

• urinary retention
• gastric retention, or
• uncontrolled narrow-angle glaucoma.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Urinary Retention

Enablex 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

Enablex should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Enablex, 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

Enablex 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 Patients with Hepatic Impairment

The daily dose of Enablex should not exceed 7.5mg for patients with moderate hepatic impairment (Child-Pugh B). Enablex 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

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 Enablex was eva luated in controlled clinical trials in a total of 8,830patients, 6,001 of whom were treated with Enablex. Of this total, 1,069patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334patients received Enablex 7.5mg daily and 15mg daily, respectively. In all long-term trials combined, 1,216 and 672patients received treatment with Enablex for at least 24 and 52weeks, respectively.

In Studies 1, 2 and 3 combined, the serious adverse reactions to Enablex 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 Enablex 7.5mg daily, Enablex 15mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Enablex 7.5mg daily, Enablex 15mg daily and placebo, respectively.

Table1 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 Enablex, and greater than placebo in Studies1, 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.

Other adverse reactions reported by 1% to 2% of Enablex-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.

Study4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which Enablex was administered in accordance with dosing recommendations [seeDosage and Administration (2)]. All patients initially received placebo or Enablex 7.5mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Enablex 15mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table2 lists the identified adverse reactions, derived from all adverse events reported in >3% of patients treated with Enablex and greater than placebo.

6.2 Post Marketing Experience

The following adverse reactions have been identified during post approval use of Enablex extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: hypersensitivity reactions, including angioedema with airway obstruction

Central Nervous: confusion and hallucinations

Cardiovascular: palpitations

7 DRUG INTERACTIONS

7.1 CYP3A4 Inhibitors

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

7.2 CYP2D6 Inhibitors

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

7.3 CYP2D6 Substrates

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

7.4 CYP3A4 Substrates

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

7.5 Combination oral contraceptives

Darifenacin (10mg 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 30mg was co-administered with darifenacin (30mg 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 Enablex 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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 30mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg . At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13times the AUC. Dystocia was observed in dams at approximately 17times 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 a 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 (3mg/kg/day) the AUC at the MRHD).

Because animal reproduction studies are not always predictive of human response, Enablex 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 Enablex is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of Enablex in pediatric patients have not been established.

8.5 Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Enablex were over 65years of age. No overall differences in safety or efficacy were observed between patients over 65 years (n=207) and younger patients <65years (n=464). No dose adjustment is recommended for elderly patients [seeClinical Pharmacology (12.3) and Clinical Studies (14)].

8.6 Hepatic Impairment

Subjects with severe hepatic impairment (Child PughC) have not been studied, therefore Enablex is not recommended for use in these patients [see Dosage and Administration (2) and Warnings and Precautions (5.5)]. The daily dose of Enablex should not exceed 7.5mg once daily for patients with moderate hepatic impairment (Child PughB) [see Dosage and Administration (2) and Warnings and Precautions (5.5)]. After adjusting for plasma protein binding, unbound darifenacin exposure was