Drug Interactions between darifenacin and givinostat

MONITOR: Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of darifenacin, which is a substrate of these isoenzymes. According to the product labeling, coadministration of darifenacin (30 mg once daily) with the mixed CYP450 inhibitor cimetidine resulted in a 42% increase in the mean darifenacin steady-state peak plasma concentration (Cmax) and a 34% increase in the systemic exposure (AUC) compared to administration of darifenacin alone. The potent CYP450 2D6 inhibitor paroxetine (20 mg) increased steady-state AUC of darifenacin (30 mg once daily) by 33%. Erythromycin, a CYP450 3A4 inhibitor, increased the mean steady-state Cmax and AUC of darifenacin (30 mg once daily) by 128% and 95%, respectively. Fluconazole, another 3A4 inhibitor, increased these values by 88% and 84%, respectively.

MANAGEMENT: Pharmacologic response to darifenacin should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the darifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of darifenacin such as severe abdominal pain or constipation for 3 or more days.