Drug Interactions between Cinvanti and Kisqali Femara Co-Pack

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and laboratory monitoring may be appropriate for some drugs whenever aprepitant or fosaprepitant is added to or withdrawn from therapy.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.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib 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 ribociclib is added to or withdrawn from therapy.

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of aprepitant, which is primarily metabolized by the isoenzyme. According to the manufacturer, administration of a single 125 mg dose of aprepitant on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 10 days) resulted in a 5-fold increase in mean aprepitant systemic exposure (AUC) and a 3-fold increase in mean terminal half-life. In patients with mild to moderate hypertension, coadministration of aprepitant (approximately 230 mg once a day) and the moderate inhibitor diltiazem (120 mg three times a day for 5 days) resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in that of diltiazem. No clinically significant changes in ECG, heart rate, or blood pressure were observed beyond those induced by diltiazem alone.

MANAGEMENT: The manufacturer of aprepitant recommends avoiding its concomitant use with potent or moderate inhibitors of CYP450 3A4.