Drug Interaction Report

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of tolterodine, which is primarily metabolized by this isoenzyme in most patients (referred to as "extensive metabolizers") to an active metabolite that is equipotent to tolterodine. A subset of the population (about 7%) is devoid of CYP450 2D6 (referred to as "poor metabolizers" or PMs) and uses CYP450 3A4 to metabolize tolterodine to an inactive metabolite instead. In a study to assess this interaction, fluoxetine (a potent CYP450 2D6 inhibitor) was administered concurrently with immediate release tolterodine. It was observed that fluoxetine significantly inhibited the metabolism of tolterodine immediate release in extensive metabolizers, resulting in a 4.8-fold increase in tolterodine systemic exposure (AUC). There was a 52% decrease in the peak plasma concentration (Cmax) and a 20% decrease in the AUC of tolterodine's active metabolite. During this interaction the sums of unbound serum concentrations of tolterodine and its active metabolite are about 25% higher, meaning little alteration in the overall pharmacological activity of tolterodine is expected. However, increased plasma concentrations may increase the risk of adverse effects associated with tolterodine, including QT prolongation and anticholinergic effects.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Increased monitoring may be particularly important when the CYP450 2D6 inhibitor has a similar adverse effect profile to that of tolterodine or when its inhibitory effects are long lasting (e.g., rolapitant can increase the plasma concentrations and risk of adverse effects of CYP450 2D6 substrates for at least 28 days). Patients should be counseled to report any increases in side effects or changes in condition.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentration of halofantrine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. After administration of 500 mg with 250 mL regular-strength grapefruit juice daily for 3 days, average halofantrine AUC increased 2.8-fold and peak plasma concentrations increased 3.2-fold, compared to water, in healthy subjects (n=12). QT interval prolongation increased from an average of 17 ms with water to 31 ms with grapefruit juice. Halofantrine, even at recommended doses, can cause dose-related prolongation of the QT interval, resulting in an elevated risk of potentially fatal ventricular arrhythmias including ventricular tachycardia and torsade de pointes.

ADJUST DOSING INTERVAL: The presence of food may increase the absorption and toxicity of halofantrine. Peak plasma concentrations increased seven-fold and AUC increased three-fold in healthy subjects when halofantrine was administered with high-fat food.

MANAGEMENT: The authors of the study recommend that grapefruit juice be avoided during halofantrine therapy. The manufacturer recommends performing an ECG before initiating halofantrine therapy and cardiac monitoring during and for 8 to 12 hours after completion of therapy. Halofantrine should be taken on an empty stomach at least 1 hour before or 2 hours after food.