Risk of Urinary Retention
ENABLEX® (darifenacin) extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
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.
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.
Patients with Hepatic Impairment
There are no dosing adjustments for patients with mild hepatic impairment. The daily dose of ENABLEX should not exceed 7.5 mg for patients with moderate hepatic impairment. ENABLEX has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and DOSAGE AND ADMINISTRATION).
Information for Patients
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.
Drug Laboratory Test Interactions
Interactions between darifenacin and laboratory tests have not been studied.
Carcinogenesis/Mutagenesis/Impairment of Fertility
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 AUC0-24h 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.
Pregnancy Category C
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 postimplantation 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).