Drug Interaction Report

MONITOR: Coadministration with rolapitant may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. Rolapitant is a moderate CYP450 2D6 inhibitor, with inhibitory effect lasting at least 7 days after a single dose. When a 30 mg dose of dextromethorphan, a CYP450 2D6 probe substrate, was administered with a 180 mg dose of rolapitant on day 1 of a pharmacokinetic study, dextromethorphan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 120% and 160%, respectively. When dextromethorphan was administered on day 8 without rolapitant, Cmax and AUC increased by 180% and 230%, respectively. The duration of CYP450 2D6 inhibition was not studied beyond 7 days and may last longer.

MANAGEMENT: Caution is advised when rolapitant is prescribed with drugs that are significantly metabolized by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever rolapitant is added to or withdrawn from therapy. Due to the prolonged duration of CYP450 2D6 inhibition by rolapitant, prolonged monitoring for adverse effects of drugs that are substrates of CYP450 2D6 may be required for at least 28 days after administration of rolapitant.

ADJUST DOSING INTERVAL: The bioavailability of metoprolol may be enhanced by food.

MANAGEMENT: Patients may be instructed to take metoprolol at the same time each day, preferably with or immediately following meals.

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.