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Medication News & Update

The Food & Drug Administration recently approved darifenacin (Enablex, Novartis Pharmaceuticals) extended-release tablets for the treatment of OAB with symptoms of urge urinary incontinence, urgency, and frequency. Darifenacin is supplied in 7.5- and 15-mg tablets, and is now available.

Darifenacin is a potent M3 receptor antagonist. Its mechanism of action is similar to that of the recently approved solifenacin (Vesicare, GlaxoSmithKline/Yamanouchi Pharma America) although experimental evidence suggests that it may be more selective for the M3 receptor with a shorter serum half-life compared with solifenacin.

The clinical trials were the first to evaluate the effect of darifenacin on the OAB "triad" of urgency, frequency, and urge incontinence. No data exist to suggest that other nonselective antimuscurinic drugs simultaneously help with all the components of this triad.

Darifenacin may have some theoretical value in treating patients with neurogenic causes of OAB, particularly those with cognitive dysfunction and in whom one worries about the cognitive effects of anticholinergics. However, no direct comparator studies with other M3 antagonists have been done. Also since the drug has typical anticholinergic side effects (see second to last paragraph) it likewise poses same risk as older agents used for treating this problem in geriatric patients and especially those with dementia.

The recommended starting dose of darifenacin is 7.5 mg taken once daily. The manufacturer said that based on individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy. In those with moderate hepatic impairment, or when coadministered with potent cytochrome p450 3A4 inhibitors, the daily dose of darifenacin should not exceed 7.5 mg.

The manufacturer advises that caution be taken when darifenacin is given concomitantly with medications that are metabolized predominantly by the cytochrome p450 2D6 pathway and which have a narrow therapeutic window, such as flecainide, thioridazine, and tricyclic antidepressants.

Darifenacin has the same contraindications as other antimuscarinic agents. Darifenacin should not be used by those with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. It is also contraindicated in persons with known hypersensitivity to the drug or its ingredients.

The most frequently reported adverse effects associated with darifenacin were dry mouth and constipation. Pharmacists should recommend regular dental care and sugar-free candies to counteract dry mouth, and stool softeners and laxatives to help with constipation.

OAB is such a prevalent yet embarrassing problem, and treatments are so inadequate considering the magnitude of the issue, that it is nice to have another therapeutic option in this drug class .

My final thoughts about this product, Enablex: Enablex is somewhat M3 specific, but it’s a very potent anticholinergic and still has ~1/5th the affinity for M1 receptors as well as for M3. I’d probably still have to call it a level 3on the clinician rated scale. I haven’t reviewed the studies, but I suspect that they weren’t really looking for cognitive changes with any systematic tests, i.e. a patient would have to complain of it for it to be reported. They also probably excluded anyone with pre-existing cognitive impairment, thus removing those at the highest risk. I don’t believe oxybutynin or tolterodine were associated with too many CNS adverse effects in their trials, at least few were reported beyond sedation in a minority of patients. However, we’ve seen what they can do to those at risk.

When I addressed this issue specifically to the drug rep and asked that he have someone in the clinical department contact me all they sent were the monograph and one study which didn’t address or answer the questions I raised in my comments above. Hope this helps all of you.