Drug Interactions between ketoconazole and tolterodine

ADJUST DOSE: Coadministration with drugs that are potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tolterodine, which is partially metabolized by the isoenzyme. Tolterodine is primarily metabolized by CYP450 2D6 in most patients (referred to as "extensive metabolizers" or "EMs") to an equipotent, active metabolite, 5-hydroxymethyl tolterodine (5-HMT). However, in patients who are CYP450 2D6-deficient, or so-called "poor metabolizers" or "PMs" of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent), tolterodine is metabolized primarily by CYP450 3A4 to N-dealkylated tolterodine. Coadministration of tolterodine with ketoconazole 200 mg daily, a potent CYP450 3A4 inhibitor, increased the tolterodine mean peak plasma concentration (Cmax) by 2-fold and the mean systemic concentrations (AUC) by 2.5-fold in PMs. Data are not available for coadministration of tolterodine with CYP450 3A4 inhibitors in EMs or less potent CYP450 3A4 inhibitors.

Tolterodine may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a QTc study conducted in 48 healthy subjects, the mean change in QTc interval from baseline to peak tolterodine concentration was 5 msec for immediate release tolterodine 2 mg twice daily. At twice the therapeutic dosage of tolterodine, 4 mg twice daily, the mean change in QTc interval from baseline to peak tolterodine concentration was 11.8 msec. The QTc interval increases in PMs administered tolterodine 2 mg twice daily were comparable to those observed in EMs administered 4 mg twice daily in a pharmacokinetic/pharmacodynamic model. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The manufacturer recommends a maximum tolterodine dosage of 2 mg once daily (extended-release capsule) and 1 mg twice daily (immediate-release and extended-release tablet) in patients receiving potent CYP450 3A4 inhibitors. Some authorities recommend avoiding concomitant use of tolterodine and potent CYP450 3A4 inhibitors. Clinical and laboratory monitoring, including QTc interval and serum electrolytes, is advised. Patients should have regular ECGs and be monitored for arrhythmias when the QTc interval is prolonged. If the QTc interval becomes markedly prolonged or symptoms of arrhythmia occur, drug discontinuation should be considered. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Patients should be advised to notify their physician if they experience new or worsening side effects of tolterodine including severe blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, or GI upset.