Darifenacin Extended-Release Tablets (Enablex)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD
The FDA has approved another muscarinic receptor antagonist, after trospium, for overactive bladder. Darifenacin is a potent, tertiary amine, selective, antagonist for the M3 receptor subtype. It is marketed as extended-release tablets by Novartis as Enablex®.
Darifenacin is indicated for the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency. It may be taken without regard to meals but should not be chewed, divided, or crushed.1
The recommended starting dose is 7.5 mg daily. The dose may be increased to 15 mg daily after a minimum of a 2-week trial period. The dose should not exceed 7.5 mg for patients with moderate hepatic impairment. No dosage adjustment is recommended for renal impairment or mild hepatic impairment.1
Darifenacin is available as 7.5 mg and 15 mg tablets.
Darifenacin can be taken once daily and possesses high selectivity for the M3 receptor subtype for the bladder over the salivary gland.2
The dose of darifenacin should not exceed 7.5 mg if used concomitantly with a potent CYP3A4 inhibitor (ie, itraconazole, nelfinavir, clarithromycin). The concomitant use with drugs with a narrow therapeutic range that are metabolized by CYP2D6 (ie, tricyclic antidepressants) should be undertaken with caution.1 Oxybutynin and tolterodine also have potential drug-drug interactions with these isoenzymes. Similar to other antimuscarinic agents, dry mouth (19-35% vs 8% for placebo) and constipation (14-21% vs 7%) are the most common side effects1,3
The efficacy of darifenacin was evaluated in 3 fixed-dosed, placebo-controlled, double-blind, 12-week studies and 1 dose-titration, 12-week, placebo-controlled study1,3 In these studies, a total of 1254 patients were treated with placebo, darifenacin 7.5 mg or 15 mg. While the vast majority of differences between darifenacin and placebo for the various end points were statistically significant, the absolute differences were modest. The median reduction, compared to placebo, in incontinence episodes per week ranged from 1.4 to 4.3, reduction in micturitions per day (0.5-0.9), and volume of urine passed per void (9.1 mL-20.1 mL).
Typically these studies show a large placebo response. Most common side effects were dry mouth and constipation. Darifenacin did not appear to have an effect on cognitive function in elderly volunteers treated for 2 weeks.4 Comparative studies between darifenacin and other agents are lacking. The wholesale cost of darifenacin is about $2.70 daily and priced similarly to other available agents.
Overactive bladder is defined as detrusor overactivity. This condition is characterized by urgency with or without incontinence, usually with frequency and nocturia.5 Overactive bladder has significant impact on one’s quality of life. Treatment includes lifestyle intervention, bladder training and pelvic floor exercises, pharmacotherapy, and surgery. Pharmacotherapy primarily involves the use of an antimuscarinic agent directed at the M3 receptor subtype. This receptor subtype mediates cholinergic contraction of the detrusor muscle found in the bladder and salivary gland. Dry mouth is the most common side effect. Current choices include oxybutynin, tolterodine, trospium, and now, darifenacin. Different drug delivery systems (ie, transdermal, controlled-release) have been used to reduce anticholinergic side effects and improve dosing convenience. Darifenacin may have more selectivity for the bladder over the salivary gland. Unfortunately the magnitude of the benefit of this class of drugs in general is modest.6,7
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.
1. Enablex Product Information. Novartis Pharmaceutical, Inc. December, 2004.
2. Chapple CR et al. Urology. 2002;60(5 suppl 1):82-88.
3. Haab F, et al. Eur Urol. 2004;45(4):420-429.
4. Lipton, RB et al. J Urol. 2005;173(2):493-498.
5. Hashim H, Abrams P. Drugs. 2004;64(15): 1643-1656.
6. Hay-Smith J, et al. Cochran Database Syst Rev. 2004(4).
7. Herbison P, et al BMJ. 2003;326:841.