Drug Interactions between Kisqali Femara Co-Pack and lefamulin

CONTRAINDICATED: When administered orally, lefamulin may significantly increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. Increased exposure to sensitive CYP450 3A4 substrates that can prolong the QT interval may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death. Based on interaction with midazolam, a sensitive CYP450 3A4 substrate, lefamulin may be a moderate CYP450 3A4 inhibitor. When oral midazolam was administered concomitantly with and at 2 or 4 hours after administration of lefamulin tablets, mean midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 100% and 200%, respectively. No clinically significant differences in the pharmacokinetics of midazolam were observed when administered concomitantly with lefamulin injection.

Because lefamulin itself may cause prolongation of the QT interval, the potential for a pharmacodynamic interaction with other agents that can prolong the QT interval should also be considered. In two randomized, double-blind, double-dummy, active-controlled (moxifloxacin 400 mg once daily) studies, a concentration-dependent QTc prolongation effect of lefamulin was observed. The mean change from baseline QTcF around Tmax on day 3 or 4 was 13.6 msec for lefamulin 150 mg administered twice daily by infusion and 9.3 msec for lefamulin 600 mg administered twice daily orally, compared to 16.4 msec for moxifloxacin 400 mg administered once daily by infusion and 11.6 msec for moxifloxacin 400 mg administered once daily orally. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of oral (but not intravenous) lefamulin with sensitive CYP450 3A4 substrates that can prolong the QT interval is considered contraindicated. However, because lefamulin itself can also cause QT prolongation regardless of the route of administration, concomitant use with other drugs that can prolong the QT interval should generally be avoided even when lefamulin is administered intravenously.

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: When administered orally, lefamulin may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. Based on interaction with midazolam, a sensitive CYP450 3A4 substrate, lefamulin may be a moderate CYP450 3A4 inhibitor. When oral midazolam was administered concomitantly with and at 2 or 4 hours after administration of lefamulin tablets, mean midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 100% and 200%, respectively. No clinically significant differences in the pharmacokinetics of midazolam were observed when administered concomitantly with lefamulin injection.

MANAGEMENT: Caution is advised when oral lefamulin is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever oral lefamulin is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a moderate CYP450 3A4 inhibitor like lefamulin and for any dosage adjustments that may be required.