Drug Interactions between solifenacin and telaprevir

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of solifenacin, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of solifenacin (10 mg) in combination with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) increased solifenacin mean peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.5- and 2.7-fold, respectively, compared to administration alone. Solifenacin is associated with dose-related prolongation of the QT interval. A nearly threefold increase in AUC would be approximately equivalent to administration of a 30 mg dose, whose effect on the QT interval has been studied in a multidose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) study of 76 female volunteers aged 19 to 79 years. For the 10 mg and 30 mg doses, mean changes in Fridericia-corrected QT interval (QTcF) from baseline at the time of peak plasma concentration (Tmax) were 2 and 8 msec, respectively, relative to placebo. These changes are less than those observed with moxifloxacin 400 mg, whose placebo-subtracted mean changes in QTcF from baseline ranged from 11 to 16 msec in three sessions. However, the confidence intervals overlapped, and the study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

MANAGEMENT: The dosage of solifenacin should not exceed 5 mg/day when used with potent CYP450 3A4 inhibitors. Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to contact their physician if they experience undue adverse effects of solifenacin such as severe abdominal pain or constipation for 3 or more days. Patients should seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. Concomitant use of solifenacin with potent CYP450 3A4 inhibitors, such as itraconazole, is considered contraindicated by some authorities in patients with severe renal impairment or moderate to severe hepatic impairment during and for 2 weeks after treatment with these drugs.