MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of artemether and lumefantrine, both of which are primarily metabolized by the isoenzyme. In 13 healthy subjects, concurrent oral administration of the potent inhibitor ketoconazole (400 mg on day 1, followed by 200 mg for 4 days) and a single dose of artemether-lumefantrine (80 mg-480 mg) with food resulted in modest increases in systemic exposure (AUC) to artemether (2.3-fold), its active metabolite dihydroartemisinin (1.5-fold), and lumefantrine (1.6-fold). High plasma levels of artemether and lumefantrine may theoretically increase the risk of QT interval prolongation and ventricular arrhythmias including torsade de pointes. 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: Coadministration with artemether may decrease the plasma concentrations of CYP450 3A4 substrates such as protease inhibitors, macrolide antibiotics, and azole antifungal agents. In vitro and human studies have demonstrated that artemisinins including artemether have some capacity to induce CYP450 3A4. The clinical significance is unknown.
MANAGEMENT: No dose adjustment of artemether-lumefantrine is necessary when administered in combination with potent CYP450 3A4 inhibitors such as azole antifungal agents, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics. However, caution is advised due to increased risk of QT interval prolongation. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Patients should also be monitored for reduced effects or potential loss of efficacy of the concomitant drug(s), especially antiretroviral agents.
clarithromycin and artemether (Major Drug-Drug)
