Drug Interaction Report

ADJUST DOSE: Coadministration with moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of capivasertib, which is a substrate of the isoenzyme. Based on clinical studies and model-informed approaches, concomitant use with the moderate CYP450 3A4 inhibitors erythromycin and verapamil is predicted to increase capivasertib systemic exposure (AUC) by up to 1.5-fold and peak plasma concentration (Cmax) by up to 1.3-fold. Increased exposure to capivasertib may increase the risk of adverse effects such as diarrhea, cutaneous adverse reactions, decreased lymphocytes, decreased hemoglobin, hyperglycemia, nausea, and fatigue.

MANAGEMENT: When concomitant use with a moderate CYP450 3A4 inhibitor is required, the prescribing information recommends reducing the dosage of capivasertib to 320 mg orally twice daily for 4 days followed by 3 days off. Following discontinuation of the moderate CYP450 3A4 inhibitor, the capivasertib dosage should be returned (after 3 to 5 half-lives of the inhibitor) to the dosage that was used before starting the inhibitor. Monitoring patients for adverse reactions is also advised.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

MONITOR: Coadministration with capivasertib may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 via inhibition of the isoenzyme. Based on clinical studies and model-informed approaches, concomitant use of capivasertib and midazolam, a sensitive CYP450 3A4 substrate, increased midazolam systemic exposure (AUC) by 1.8-fold on day 4 and by 1.2-fold on day 7 of capivasertib treatment.

MANAGEMENT: Caution is advised if capivasertib is coadministered with CYP450 3A4 substrates, particularly sensitive substrates, or those with a narrow therapeutic range. Clinical and laboratory monitoring may be appropriate whenever capivasertib is added to or withdrawn from therapy. The prescribing information for concomitant medications may be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of capivasertib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been studied with other CYP450 3A4 inhibitors. Based on clinical studies and model-informed approaches, concomitant use with the potent CYP450 3A4 inhibitor itraconazole is predicted to increase capivasertib systemic exposure (AUC) by up to 1.7-fold and peak plasma concentration (Cmax) by up to 1.4-fold. Coadministration with the moderate CYP450 3A4 inhibitors erythromycin and verapamil is predicted to increase the AUC and Cmax of capivasertib by up to 1.5-fold 1.3-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to capivasertib may increase the risk of adverse effects such as diarrhea, cutaneous adverse reactions, decreased lymphocytes, decreased hemoglobin, hyperglycemia, nausea, and fatigue.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with capivasertib.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.