Drug Interactions between aprepitant and clorazepate

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may increase the plasma concentrations of benzodiazepines that are metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) and midazolam (2 mg orally on days 1 and 5) resulted in an increase in the area under the plasma concentration-time curve (AUC) of midazolam by 2.3-fold on day 1 and 3.3-fold on day 5. The same regimen of aprepitant given for 3 days with intravenous midazolam (2 mg prior to initiation of aprepitant and on days 4, 8 and 15) increased midazolam AUC by 25% on day 4 but decreased it by 19% on day 8. Midazolam AUC on day 15 was similar to that observed at baseline. Thus, the effect of aprepitant on the pharmacokinetics of CYP450 3A4 substrates is expected to be greater when the substrates are administered orally as opposed to intravenously and may be altered following prolonged administration. Benzodiazepines known to be metabolized by CYP450 3A4 include alprazolam, diazepam, midazolam, and triazolam.

MANAGEMENT: Caution is advised if aprepitant or fosaprepitant is administered with benzodiazepines that are metabolized by CYP450 3A4. The potential for increased pharmacologic effects of the benzodiazepine, including central nervous system and respiratory depression, should be considered. The interaction is not expected to occur with lorazepam, oxazepam or temazepam, which are primarily metabolized via glucuronidation. Chronic, continuous use of aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during long-term use.