darifenacin er 15 mg tablet generic enablex

Uses

Overactive Bladder

Darifenacin hydrobromide is used in the management of overactive bladder for the relief of symptoms associated with voiding such as urge urinary incontinence, urgency, and frequency.

Safety and efficacy of darifenacin for this indication were established in four 12-week randomized, double-blind, placebo-controlled studies in more than 1400 patients with symptoms of urinary frequency, urgency, and/or urge or mixed incontinence that had persisted for at least 6 months. In these studies, darifenacin 7.5-15 mg daily was more effective than placebo in reducing the number of urge incontinence episodes per week, reducing the number of micturitions per 24 hours, and increasing the volume of urine voided per micturition. In the 3 fixed-dose studies, patients received darifenacin 7.5 or 15 mg once daily or placebo; in these studies, urge incontinence episodes were decreased from baseline by 8.1-11.4 or 5.9-9 occurrences per week, urinary frequency was decreased from baseline by 1.6-1.9 or 0.8-1.2 micturitions per 24 hours, and urine volume voided per micturition was increased by 14.9-30.9 or 4.6-7.6 mL per micturition in patients receiving darifenacin or placebo, respectively. In the flexible-dose study, patients received darifenacin 7.5 mg once daily (with the option to increase dosage to 15 mg once daily) or placebo; in this study, urge incontinence episodes were decreased from baseline by 8.2 or 6 occurrences per week, urinary frequency was decreased from baseline by 1.9 or 1 micturition per 24 hours, and urine volume voided per micturition was increased by 18.8 or 6.6 mL per micturition in patients receiving darifenacin or placebo, respectively. Among patients who required dosage escalation to 15 mg daily, clinical outcome achieved at 12 weeks was comparable to that achieved in patients who initially responded to the 7. 5-mg daily dosage. Reduction in the number of urge incontinence episodes was observed within the first 2 weeks of therapy, and this effect was sustained throughout the 12-week treatment period.

In addition to objective improvements, a beneficial effect on quality-of-life scores has been demonstrated with darifenacin. Data from a pooled analysis indicate that treatment with darifenacin 7.5 or 15 mg daily was associated with improvements in quality-of-life aspects related to incontinence impact, severity measures, emotions and role, and social and physical limitations. However, treatment did not improve aspects related to personal relationships, sleep and energy, or general health.

Limited data from a short-term (2-week) efficacy study in patients with overactive bladder indicate that extended-release darifenacin (15 mg once daily) may be as effective as immediate-release oxybutynin (5 mg 3 times daily) in reducing the frequency of urinary incontinence and the frequency and severity of urgency. However, the efficacy of extended-release oxybutynin and extended-release darifenacin has not been compared.

Dosage and Administration

Administration

Darifenacin hydrobromide is administered orally once daily without regard to meals. Darifenacin hydrobromide extended-release tablets should be administered with liquids and swallowed whole; the tablets should not be chewed, divided, or crushed.

Dosage

Dosage of darifenacin hydrobromide is expressed in terms of darifenacin.

For the management of overactive bladder, the recommended initial dosage of darifenacin in adults is 7.5 mg once daily. Depending on individual response, dosage may be increased (as early as 2 weeks after initiating therapy) to 15 mg once daily.

Special Populations

No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). However, in patients with moderate hepatic impairment (Child-Pugh class B), dosage of darifenacin should not exceed 7.5 mg daily. Use of darifenacin is not recommended in patients with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is required in patients with renal impairment.

Dosage of darifenacin should not exceed 7.5 mg daily in patients receiving the drug concomitantly with potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme (e.g., clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir). (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Cautions

Contraindications

Urinary retention, gastric retention, or uncontrolled angle-closure glaucoma or risk of these conditions.

Known hypersensitivity to darifenacin hydrobromide or any ingredient in the formulation.

Warnings/Precautions

Major Toxicities

Genitourinary Effects

Severe acute urinary retention requiring treatment has been reported in certain patients (e.g., patients with detrusor hyperreflexia secondary to a stroke, patients with benign prostatic hypertrophy, patients with irritable bowel syndrome, patients receiving a dosage of 30 mg daily). Acute urinary retention requiring bladder catheterization for 1-2 days also has been reported in at least 2 patients receiving therapeutic dosages of darifenacin.

Because of the risk of urinary retention, use with caution in patients with clinically important bladder outflow obstruction.

General Precautions

Decreased GI Motility

May decrease GI motility; use with caution in patients with severe constipation, ulcerative colitis, or myasthenia gravis. Because of the risk of gastric retention, darifenacin should be used with caution in patients with obstructive GI disorders.

Severe constipation has been reported with darifenacin. Chronic constipation persisting for up to 9 months and requiring hospitalization was reported in at least 1 patient receiving darifenacin.

Controlled Angle-closure Glaucoma

In patients being treated for angle-closure glaucoma, darifenacin should be used only if the potential benefits outweigh the risks. (See Cautions: Contraindications.)

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; not known whether darifenacin is distributed into human milk. Exercise caution before administering the drug in nursing women.

Pediatric Use

Safety and efficacy of darifenacin have not been established in pediatric patients.

Geriatric Use

Possible decreased clearance. (See Description.) However, no substantial differences in safety and efficacy relative to younger adults have been observed. Therefore, no dosage adjustment is required in geriatric patients.

Hepatic Impairment

Decreased protein binding and, thus, increased darifenacin exposure has been observed in patients with moderate hepatic impairment (Child-Pugh class B). (See Dosage and Administration: Special Populations.) Use of darifenacin has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and, therefore, is not recommended in such patients.

Renal Impairment

No clear relationship between the extent of renal impairment and darifenacin clearance was found in patients with varying degrees of renal impairment (creatinine clearance 10-136 mL/minute).

Common Adverse Effects

Adverse effects reported in 10% or more of patients receiving darifenacin and with an incidence at least twice that reported with placebo included dry mouth and constipation.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of cytochrome P-450 (CYP) 3A4 isoenzyme: Pharmacokinetic interaction observed during concomitant use with erythromycin, fluconazole, or ketoconazole (increased plasma darifenacin concentrations). Dosage of darifenacin should not exceed 7.5 mg daily in patients receiving the drug concomitantly with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir). No dosage adjustment is required in patients receiving darifenacin concomitantly with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, fluconazole, verapamil).

Inhibitors of CYP2D6: Pharmacokinetic interaction observed during concomitant use with paroxetine (increased plasma darifenacin concentrations). However, no dosage adjustment is required in patients receiving darifenacin concomitantly with CYP2D6 inhibitors.

Mixed inhibitors of CYP isoenzymes: Pharmacokinetic interaction observed during concomitant use with cimetidine (increased plasma darifenacin concentrations). However, no dosage adjustment is required.

Inducers of CYP3A4: Potential pharmacokinetic interaction (altered plasma darifenacin concentrations).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Potential pharmacokinetic interaction observed during concomitant use with midazolam (increased midazolam concentrations).

Substrates of CYP2D6: Potential pharmacokinetic interaction observed during concomitant use with imipramine (increased plasma concentrations of imipramine and desipramine). Caution advised when used concomitantly with drugs metabolized principally by CYP2D6 that have a narrow therapeutic index (e.g., flecainide, thioridazine, tricyclic antidepressants).

Substrates of CYP1A2 or CYP2C9: Pharmacokinetic interaction not expected at therapeutic dosages.

Drugs Affected by GI Motility

Potential pharmacokinetic interaction (altered absorption because of decreased GI motility). (See Decreased GI Motility under Warnings/Precautions: General Precautions, in Cautions.)

Anticholinergic Agents

Potential pharmacologic interaction (additive anticholinergic effects). Potential for additive effects on GI motility, further altering absorption of other drugs. (See Drugs Affected by GI Motility.)

Digoxin

Potential pharmacokinetic interaction (increased digoxin exposure). Routine monitoring of digoxin therapy should be continued.

Oral Contraceptives

Pharmacokinetic interaction unlikely with oral contraceptives containing ethinyl estradiol and levonorgestrel.

Warfarin

Pharmacologic interaction unlikely. No substantial effect on prothrombin time (PT) observed during concomitant use. Routine monitoring of PT should be continued.