Drug Interactions between aprepitant and famotidine / ibuprofen

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 2C9. The mechanism is accelerated clearance due to induction of CYP450 2C9 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 and 3) and the CYP450 2C9 substrate tolbutamide (500 mg orally prior to initiation of aprepitant and on days 4, 8 and 15) resulted in a decrease in tolbutamide systemic exposure (AUC) by 23% on day 4, 28% on day 8, and 15% on day 15. Similarly, healthy subjects stabilized on chronic warfarin therapy given the same regimen of aprepitant had a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the INR five days after completion of aprepitant dosing. However, there was no effect on the AUC of R(+) and S(-) warfarin determined on day 3.

MANAGEMENT: Caution is advised if aprepitant or fosaprepitant must be used concomitantly with medications that undergo metabolism by CYP450 2C9, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever aprepitant or fosaprepitant is added to or withdrawn from therapy.

H2 antagonists may alter the pharmacokinetic disposition of some nonsteroidal anti-inflammatory drugs (NSAIDs), resulting in increased or decreased plasma concentrations. Data have been varied, even for the same NSAID. The mechanism may involve inhibition of metabolism, changes in gastric pH resulting in altered absorption, and/or reduced urinary elimination of the affected NSAIDs. Statistically significant changes have been small and of limited clinical significance when interactions have been observed.