Drug Interaction Report

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 primarily metabolized 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.

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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.