indication

For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

pharmacology

Darifenacin is a competitive muscarinic receptor antagonist. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.

mechanism of action

Darifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function.

toxicity

Overdosage can potentially result in severe central anticholinergic effects.

biotransformation

Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4.

absorption

The mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.

half life

The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.

drug interactions

Clarithromycin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Donepezil: Possible antagonism of action

Galantamine: Possible antagonism of action

Itraconazole: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Ketoconazole: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Nefazodone: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Nelfinavir: Nelfinavir, a strong CYP3A4 inhibitor, may decrease the metabolism of darifenacin/solifenacin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of darifenacin if nelfinavir is initiated, discontinued or dose changed.

Ritonavir: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Rivastigmine: Possible antagonism of action

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Darifenacin, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tamoxifen: Darifenacin may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Darifenacin, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Darifenacin is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Darifenacin. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Darifenacin if Telithromycin is initiated, discontinued or dose changed.

Tramadol: Darifenacin may decrease the effect of Tramadol by decreasing active metabolite production.

Triprolidine: Triprolidine and Darifenacin, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trospium: Trospium and Darifenacin, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of darifenacin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of darifenacin if voriconazole is initiated, discontinued or dose changed.