Drug Interactions between Coartem and mefloquine

GENERALLY AVOID: Artemether-lumefantrine and mefloquine may have additive prolonging effects on the QT interval. Theoretically, coadministration may increase the risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes, which can lead to cardiac arrest and sudden death in some cases. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.

MONITOR CLOSELY: Pretreatment with mefloquine may decrease the plasma concentrations of lumefantrine. The proposed mechanism is reduced lumefantrine absorption secondary to a mefloquine-induced decrease in bile production. In 14 healthy volunteers, administration of three doses of mefloquine (500 mg, 250 mg, 250 mg) followed 12 hours later by a six-dose regimen of artemether-lumefantrine (80 mg-480 mg/dose) resulted in a 30% reduction in lumefantrine peak plasma concentration (Cmax) and a 40% reduction in systemic exposure (AUC) compared to administration of lumefantrine alone. Mefloquine pretreatment had no effect on the plasma concentrations of artemether or the ratio of artemether to its active metabolite, dihydroartemisinin (DHA). Artemether-lumefantrine also had no effect on plasma mefloquine concentrations compared to placebo.

MANAGEMENT: Coadministration of artemether-lumefantrine with other drugs that can prolong the QT interval should be avoided. Moreover, artemether-lumefantrine should generally not be used in combination with other antimalarial agents due to limited safety data. Caution and close monitoring of the ECG are advised when QT-prolonging antimalarial agents are used following treatment with artemether-lumefantrine because of the long elimination half-life of lumefantrine (3 to 6 days). Patients should be monitored for reduced antimalarial efficacy if artemether-lumefantrine is prescribed immediately after mefloquine treatment, and food consumption should be encouraged at dosing times to compensate for the decrease in lumefantrine bioavailability. Patients should also be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

GENERALLY AVOID: Artemether-lumefantrine and mefloquine may have additive prolonging effects on the QT interval. Theoretically, coadministration may increase the risk of ventricular arrhythmias including ventricular tachycardia and torsade de pointes, which can lead to cardiac arrest and sudden death in some cases. In clinical trials, asymptomatic prolongation of the Fridericia-corrected QT interval (QTcF) by more than 30 msec from baseline was reported in approximately one-third of patients treated with artemether-lumefantrine, and prolongation by more than 60 msec was reported in more than 5% of patients. A few patients (0.4%) in the adult/adolescent population and no patient in the infant/children population experienced a QTcF greater than 500 msec. However, the possibility that these increases were disease-related cannot be ruled out. In a study of healthy adult volunteers, administration of the six-dose regimen of artemether-lumefantrine was associated with mean changes in QTcF from baseline of 7.45, 7.29, 6.12 and 6.84 msec at 68, 72, 96, and 108 hours after the first dose, respectively. There was a concentration-dependent increase in QTcF for lumefantrine. No subject had a greater than 30 msec increase from baseline nor an absolute increase to more than 500 msec.

MONITOR CLOSELY: Pretreatment with mefloquine may decrease the plasma concentrations of lumefantrine. The proposed mechanism is reduced lumefantrine absorption secondary to a mefloquine-induced decrease in bile production. In 14 healthy volunteers, administration of three doses of mefloquine (500 mg, 250 mg, 250 mg) followed 12 hours later by a six-dose regimen of artemether-lumefantrine (80 mg-480 mg/dose) resulted in a 30% reduction in lumefantrine peak plasma concentration (Cmax) and a 40% reduction in systemic exposure (AUC) compared to administration of lumefantrine alone. Mefloquine pretreatment had no effect on the plasma concentrations of artemether or the ratio of artemether to its active metabolite, dihydroartemisinin (DHA). Artemether-lumefantrine also had no effect on plasma mefloquine concentrations compared to placebo.

MANAGEMENT: Coadministration of artemether-lumefantrine with other drugs that can prolong the QT interval should be avoided. Moreover, artemether-lumefantrine should generally not be used in combination with other antimalarial agents due to limited safety data. Caution and close monitoring of the ECG are advised when QT-prolonging antimalarial agents are used following treatment with artemether-lumefantrine because of the long elimination half-life of lumefantrine (3 to 6 days). Patients should be monitored for reduced antimalarial efficacy if artemether-lumefantrine is prescribed immediately after mefloquine treatment, and food consumption should be encouraged at dosing times to compensate for the decrease in lumefantrine bioavailability. Patients should also be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.