Drug Interactions between Kisqali Femara Co-Pack and trabectedin

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 inhibitors of CYP450 3A4 may increase the plasma concentrations of trabectedin, which is primarily metabolized by the isoenzyme. In eight study patients with advanced malignancies, administration of a single 0.58 mg/m2 infusion of trabectedin following the second dose of ketoconazole (200 mg twice daily for 15 doses), a potent CYP450 3A4 inhibitor, increased the dose-normalized mean trabectedin peak plasma concentration (Cmax) and systemic exposure (AUC) by 22% and 66%, respectively, compared to infusion of a single 1.3 mg/m2 dose of trabectedin alone.

MONITOR: Coadministration of trabectedin with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Reversible, acute increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have occurred frequently in patients treated with trabectedin alone or with pegylated liposomal doxorubicin in clinical trials. In one U.S. trial with 378 patients, grade 3 or 4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) were reported in 35% of patients receiving trabectedin. ALT or AST elevations greater than eight times the upper limit of normal (ULN) occurred in 18% of patients, and drug-induced liver injury (defined as concurrent elevations in ALT or AST more than three times ULN, alkaline phosphatase less than two times ULN, and total bilirubin at least two times ULN) occurred in 1.3% of patients.

MANAGEMENT: Caution is advised when trabectedin is prescribed with CYP450 3A4 inhibitors that are also potentially hepatotoxic (e.g., azole antifungal agents; bicalutamide; cyclosporine (high dosages); dronedarone; macrolide antibiotics; protein kinase inhibitors; zafirlukast). Patients should be monitored for toxicities such as myelosuppression, rhabdomyolysis, hepatotoxicity, and cardiomyopathy, and the trabectedin dosage adjusted accordingly or treatment discontinued as necessary. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of alkaline phosphatase, bilirubin, AST, and ALT should occur regularly during trabectedin treatment in accordance with the product labeling, or as often as necessary when clinical symptoms develop. Trabectedin must not be used in patients with elevated bilirubin at the time of initiation of cycle. Elevated liver function tests should be managed with treatment interruption, dosage reduction, or permanent discontinuation depending on the severity and duration of abnormality.