Drug Interactions between Kisqali Femara Co-Pack and lazertinib

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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.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: Lazertinib may increase the concentration and adverse effects of drugs which rely on CYP450 3A4 and/or breast cancer resistance protein (BCRP) for clearance via inhibition of the isoenzyme and/or the efflux transporter. However, for drugs whose therapeutic effects are dependent on the formation of active metabolites via CYP450 3A4 (e.g., amiodarone, cyclophosphamide, ifosfamide), inhibition of this isoenzyme may result in a reduction in efficacy. In one pharmacokinetic study, healthy participants (n=20) received the sensitive CYP450 3A4 substrate midazolam and BCRP substrate rosuvastatin at baseline and again with steady-state lazertinib. Coadministration increased midazolam's peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.4- and 1.5-fold, respectively. Likewise, rosuvastatin's Cmax and AUC increased by 2.2- and 2-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if lazertinib is used concurrently with agents that are substrates of CYP450 3A4 and/or the efflux transporter BCRP. This may be particularly important in cases where minimal changes in the substrate's concentration could result in serious adverse reactions (if the agent is cleared via CYP450 3A4 and/or BCRP) or a significant reduction in efficacy (if the medication has active metabolites formed via CYP450 3A4). Dose adjustments and/or increased monitoring may be required. Consultation with the labeling of the substrate in question is advised.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and risk of adverse effects of ribociclib, which is a substrate of the isoenzyme. Administration of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase ribociclib Cmax and AUC by 1.3- and 1.9-fold, respectively. Data with other, less potent inhibitors, are limited.

MANAGEMENT: Caution is advised when ribociclib is used with CYP450 3A4 inhibitors. Dosage adjustment for ribociclib is not generally considered necessary for suspected interactions with mild to moderate inhibitors. However, some manufacturers of ribociclib recommend that concomitant use with verapamil should be avoided (AU, UK). Patients should be monitored for the development of ribociclib-related adverse effects such as infections, neutropenia, leucopenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, stomatitis, anorexia, alopecia, fatigue, headache, and abnormal liver function.