Drug Interactions between Coartem 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.

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.