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.

ADJUST DOSING INTERVAL: According to the manufacturer, coadministration with a meal high in calories, fat, and protein reduces the absorption of indinavir. In ten patients given indinavir in this manner, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of indinavir decreased by an average of 84% and 77%, respectively. In contrast, grapefruit juice may have only minor effects on the oral bioavailability of indinavir. The manufacturer's package labeling states that administration of a single 400 mg dose of indinavir with 8 oz. of grapefruit juice decreased indinavir AUC by an average of 26%. Likewise, a study consisting of 14 HIV-infected subjects found no uniform nor significant changes in steady-state indinavir AUC during administration with double-strength grapefruit juice compared to water. There was, however, a delay in absorption (Tmax) due to grapefruit juice that is unlikely to be of clinical significance.

MANAGEMENT: To ensure maximal oral absorption, indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal (e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; corn flakes, skim milk and sugar).