Drug Interactions between Amabelz and fosaprepitant

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, administration of the CYP450 3A4 substrate dexamethasone (20 mg orally on day 1 and 8 mg on days 2 through 5) in combination with aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) resulted in a 2.2-fold increase in dexamethasone systemic exposure (AUC) on days 1 and 5. Similarly, aprepitant increased the AUC of methylprednisolone (125 mg intravenously on day 1 and 40 mg orally on days 2 and 3) by 1.34-fold on day 1 and 2.5-fold on day 3. 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.

MANAGEMENT: Caution is advised when aprepitant or fosaprepitant is used concomitantly with drugs that undergo metabolism by CYP450 3A4, 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and laboratory monitoring may be appropriate for some drugs whenever aprepitant or fosaprepitant is added to or withdrawn from therapy. 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.

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ADDITIONAL CONTRACEPTION RECOMMENDED: Aprepitant and its prodrug, fosaprepitant, may reduce the efficacy of low-dose hormonal contraceptives during and for up to 28 days after treatment. The proposed mechanism is aprepitant induction of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of contraceptive hormones. According to the product labeling, coadministration of aprepitant (100 mg once a day for 14 days) and an oral contraceptive containing ethinyl estradiol-norethindrone (35 mcg-1 mg) resulted in a 43% decrease in the area under the plasma concentration-time curve (AUC) of ethinyl estradiol and an 8% decrease in the AUC of norethindrone. In another study, coadministration of an oral contraceptive containing ethinyl estradiol-norethindrone on days 1 through 21 and aprepitant on days 8 through 10 (125 mg on day 8 and 80 mg/day on days 9 and 10, with ondansetron 32 mg IV on day 8 and oral dexamethasone 12 mg on day 8 and 8 mg/day on days 9, 10, and 11) resulted in a 19% decrease in the ethinyl estradiol AUC on day 10 and up to a 64% decrease in ethinyl estradiol trough concentrations during days 9 through 21. While there was no effect of aprepitant on the AUC of norethindrone on day 10, up to a 60% decrease in norethindrone trough concentrations was observed during days 9 through 21.

MANAGEMENT: Women using low-dose hormonal contraceptives should be advised of the risk of breakthrough bleeding and unintended pregnancy during concomitant therapy with aprepitant or fosaprepitant. Alternative or additional methods of birth control is recommended during treatment with aprepitant and for one month following the last dose of aprepitant. Data are not available for single-dosing of aprepitant 40 mg. However, since the timing of aprepitant administration relative to ovulation could cause contraceptive failure, the same precaution as for the 125 mg/80 mg regimen should be observed. Intrauterine systems are unlikely to be significantly affected because of their local action. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed.

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