Drug Interactions between Kisqali Femara Co-Pack and lonafarnib

CONTRAINDICATED: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of lonafarnib. In vitro, lonafarnib has been shown to be primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. When a single 50 mg oral dose of lonafarnib was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone. Increased exposure to lonafarnib may increase the risk and/or severity of adverse effects such as nausea, vomiting, diarrhea, anorexia, electrolyte disturbances, liver enzyme elevations, myelosuppression, infection, and hypertension.

MANAGEMENT: Concomitant use of lonafarnib with potent or moderate CYP450 3A4 inhibitors is considered contraindicated.

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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 lonafarnib may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Lonafarnib is a potent CYP450 3A time-dependent and mechanism-based inhibitor in vitro. When a single 3 mg oral dose of midazolam, a sensitive CYP450 3A4 substrate, was administered with lonafarnib (100 mg orally twice daily for 5 days) in healthy subjects, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 180% and 639%, respectively.

MANAGEMENT: Caution is advised when lonafarnib is used concomitantly with drugs that are substrates of 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 lonafarnib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. The prescribing information recommends avoiding concomitant use of lonafarnib and sensitive CYP450 3A4 substrates or substrates with narrow therapeutic ranges when possible. These drugs include, but are not limited to: alfentanil, cisapride, colchicine, cyclosporine, fentanyl, ivacaftor, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, quinidine, sildenafil, ergot derivatives, macrolide immunosuppressants, and vinca alkaloids.