Enablex^®

Patients should be informed that anticholinergic agents, such as ENABLEX, may produce clinically significant adverse effects related to anticholinergic pharmacological activity including constipation, urinary retention and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as ENABLEX are used in a hot environment. Because anticholinergics, such as ENABLEX, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effects have been determined. Patients should read the patient information leaflet before starting therapy with ENABLEX.

      ENABLEX extended-release tablets should be taken once daily with liquid. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

The daily dose of ENABLEX should not exceed 7.5 mg when coadministered with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone) (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). 

      Caution should be taken when ENABLEX is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants (see CLINICAL PHARMACOLOGY).

      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.

Interactions between darifenacin and laboratory tests have not been studied.

Carcinogenicity studies with darifenacin were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated human-free AUC_0-24h reached with 15 mg, the maximum recommended human dose (AUC at MRHD) and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at MRHD in female rats and approximately eight times the AUC at MRHD in male rats.

      Darifenacin was not mutagenic in the bacterial mutation assays (Ames test) and the Chinese hamster ovary assay, and not clastogenic in the human lymphocyte assay, and the in vivo mouse bone marrow cytogenetics assay. 

      There was no evidence for effects on fertility in male or female rats treated at oral doses up to 50 mg/kg/day. Exposures in this study correspond to approximately 78 times the AUC at MRHD.

Darifenacin was not teratogenic in rats and rabbits at doses up to 50 and 30 mg/kg/day, respectively. At the dose of 50 mg/kg in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at 10 mg/kg (approximately 13 times the AUC of free plasma concentration at MRHD). Exposure in this study at 50 mg/kg corresponds to approximately 59 times the AUC of free plasma concentration at MRHD. Dystocia was observed in dams at 10 mg/kg/day (17 times the AUC of free plasma concentration at MRHD). Slight developmental delays were observed in pups at this dose. At 3 mg/kg/day (five times the AUC of free plasma concentration at MRHD) there were no effects on dams or pups. At the dose of 30 mg/kg in rabbits, darifenacin was shown to increase post-implantation loss but not at 10 mg/kg (nine times the AUC of free plasma concentration at MRHD). Exposure to unbound drug at 30 mg/kg in this study corresponds to approximately 28 times the AUC at MRHD. In rabbits, dilated ureter and/or kidney pelvis was observed in offspring at 30 mg/kg/day and one case was observed at 10 mg/kg/day along with urinary bladder dilation consistent with pharmacological action of darifenacin. No effect was observed at 3 mg/kg/day (2.8 times the AUC of free plasma concentration at MRHD). There are no studies of darifenacin in pregnant women. 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.

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.

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

In the Phase III fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with ENABLEX were over 65 years of age. No overall differences in safety or efficacy were observed between these patients (n=207) and younger patients <65 years (n= 464). No dose adjustment is recommended for elderly patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and CLINICAL STUDIES).

During the clinical development of ENABLEX^® (darifenacin) extended-release tablets, a total of 7,363 patients and volunteers were treated with doses of darifenacin from 3.75 mg to 75 mg once daily.

      The safety of ENABLEX was evaluated in Phase II and III controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with ENABLEX. Of this total, 1,069 patients participated in three, 12-week, Phase III, fixed-dose efficacy and safety studies. Of this total, 337 and 334 patients received ENABLEX 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with ENABLEX for at least 24 and 52 weeks, respectively.

      In all placebo-controlled trials combined, the incidence of serious adverse events for 7.5 mg, 15 mg and placebo was similar.

      In all fixed-dose Phase III studies combined, 3.3% of patients treated with ENABLEX discontinued due to all adverse events versus 2.6% in placebo. Dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with ENABLEX 7.5 mg daily, ENABLEX 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with ENABLEX 7.5 mg daily, ENABLEX 15 mg daily and placebo, respectively.

      Table 4 uls the adverse events reported (regardless of causality) in 2% or more of patients treated with 7.5-mg or 15-mg ENABLEX extended-release tablets and greater than placebo in the three, fixed-dose, placebo-controlled Phase III studies (Studies 1, 2 and 3). Adverse events were reported by 54% and 66% of patients receiving 7.5 mg and 15 mg once-daily ENABLEX extended-release tablets, respectively, and by 49% of patients receiving placebo. In these studies, the most frequently reported adverse events were dry mouth and constipation. The majority of adverse events in ENABLEX-treated subjects were mild or moderate in severity and most occurred during the first two weeks of treatment.

      Other adverse events reported, regardless of causality, by ≥1% of ENABLEX patients in either the 7.5 mg or 15 mg once-daily darifenacin-dose groups in these fixed-dose, placebo-controlled Phase III studies include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, pain, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis.

      Study 4 was a 12-week, placebo-controlled, dose-titration regimen study in which ENABLEX was administered in accordance with dosing recommendations (see DOSAGE and ADMINISTRATION). All patients initially received placebo or ENABLEX 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to ENABLEX 15 mg if needed. In this study, the most commonly reported adverse events were also constipation and dry mouth. The incidence of discontinuation due to all adverse events was 3.1% and 6.7% for placebo and for ENABLEX, respectively. Table 5 uls the adverse events (regardless of causality) reported in >3% of patients treated with ENABLEX extended-release tablets and greater than placebo.

      Acute urinary retention (AUR) requiring treatment was reported in a total of 16 patients in the ENABLEX Phase I-III clinical trials. Of these 16 cases, seven were reported as serious adverse events, including one patient with detrusor hyperreflexia secondary to a stroke, one patient with benign prostatic hypertrophy (BPH), one patient with irritable bowel syndrome (IBS) and four overactive bladder (OAB) patients taking darifenacin 30 mg daily. Of the remaining nine cases, none were reported as serious adverse events. Three occurred in OAB patients taking the recommended doses, and two of these required bladder catheterization for 1-2 days.

      Constipation was reported as a serious adverse event in six patients in the ENABLEX Phase I-III clinical trials, including one patient with benign prostatic hypertrophy (BPH), one OAB patient taking darifenacin 30 mg daily, and only one OAB patient taking the recommended doses. The latter patient was hospitalized for investigation with colonoscopy after reporting nine months of chronic constipation that was reported as being moderate in severity.

Overdosage with antimuscarinic agents, including ENABLEX^® (darifenacin) extended-release tablets, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. ENABLEX has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision.

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