Jane S. Ricciuti, RPh, MS

Disclosures

January 20, 2005

In This Article

Genitourinary Agents

Enablex
(darifenacin) Extended-Release Tablets

Manufacturer: Novartis

Drug Approval Classification: Original New Drug Application (Approval Date: 12/22/04)

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

Dosing: The recommended starting dose of darifenacin is 7.5 mg once daily. Depending on individual response, the dose may be increased to 15 mg once daily, as early as 2 weeks after starting therapy. Darifenacin should be taken once daily with liquid. It may be taken with or without food and should be swallowed whole and not chewed, divided, or crushed.

For patients with moderate hepatic impairment or when coadministered with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, and nefazodone), the daily dose of darifenacin should not exceed 7.5 mg. Darifenacin is not recommended for use in patients with severe hepatic impairment.

Clinical Summary: Darifenacin is a potent muscarinic receptor antagonist. Darifenacin was evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in 3 randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and 1 randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). The majority of patients were white (94%) and female (84%), with a mean age of 58 years (range 19 to 93 years). Thirty-three percent of patients were > 65 years of age. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes, was observed in all 3 studies. Reductions in the number of incontinence episodes per week were observed within the first 2 weeks in patients treated with darifenacin compared with placebo. These effects were sustained throughout the 12-week treatment period.

Adverse Effects: In all fixed-dose phase 3 studies combined, 3.3% of patients treated with darifenacin discontinued due to all adverse events vs 2.6% in placebo. Dry mouth and constipation were the leading causes of study discontinuation.

Adverse events were reported by 54% and 66% of patients receiving darifenacin 7.5 and 15 mg once daily, respectively. The majority of adverse events in darifenacin-treated subjects were mild or moderate in severity, and most occurred during the first 2 weeks of treatment.

Pharmacokinetics: After oral administration of darifenacin, peak plasma concentrations are reached approximately 7 hours after multiple dosing, and steady state plasma concentrations are achieved by the sixth day of dosing. The mean oral bioavailability of darifenacin at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.

Darifenacin is approximately 98% bound to plasma proteins. The steady-state volume of distribution is estimated to be 163 L.

Darifenacin is extensively metabolized by the liver following oral dosing. Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. Inducers of CYP3A4 or inhibitors of either of these enzymes may alter darifenacin pharmacokinetics. The daily dose of darifenacin should not exceed 7.5 mg when coadministered with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, and nefazodone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, and verapamil).

Enablex (darifenacin) Extended-Release Tablets Labeling

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