Drug Interactions between artemether / lumefantrine and Larapam SR

GENERALLY AVOID: Artemether-lumefantrine and tramadol may each cause prolongation of the QT interval. Theoretically, coadministration of multiple agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. 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. The effect of tramadol on the QT interval was evaluated in a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple-dose ECG study of 62 healthy subjects. The maximum placebo-adjusted mean change from baseline in QTcF was 5.5 msec in the 400 mg/day treatment arm (100 mg every 6 hours on days 1 through 3 with a single 100 mg dose on day 4) and 6.5 msec in the 600 mg/day treatment arm (150 mg every 6 hours on days 1 through 3 with a single 150 mg dose on day 4), both occurring at the 8-hour time point. 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).

MONITOR CLOSELY: Coadministration with lumefantrine may decrease the opioid-like effects of tramadol, a substrate of the CYP450 2D6 isoenzyme. The mechanism is decreased conversion of tramadol to its active metabolite, M1, due to inhibition of CYP450 2D6 activity by lumefantrine. In animal studies, M1 was up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in binding to mu-opioid receptors. When tramadol (50 mg orally) was given with a CYP450 2D6 inhibitor, terbinafine (250 mg once a day), the Cmax and AUC of M1 decreased by 79% and 64%, respectively, while the elimination half-life of M1 increased by 50%. In addition, terbinafine decreased the subjective drug effect of tramadol (P-value less than 0.001).

MANAGEMENT: Coadministration of artemether-lumefantrine with tramadol should generally be avoided. If concomitant use is required, careful consideration of the effects on tramadol and M1 is recommended. Patients should be monitored for opioid withdrawal, seizures, and serotonin syndrome, and care should be exercised in patients suspected to be at an increased risk of torsade de pointes. If artemether-lumefantrine is discontinued, consider reducing the tramadol dose (taking into account the elimination half-life of lumefantrine [3 to 6 days]) until stable drug effects are achieved and monitor for respiratory depression and sedation. Patients should 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.

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GENERALLY AVOID: Artemether-lumefantrine and tramadol may each cause prolongation of the QT interval. Theoretically, coadministration of multiple agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. 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. The effect of tramadol on the QT interval was evaluated in a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple-dose ECG study of 62 healthy subjects. The maximum placebo-adjusted mean change from baseline in QTcF was 5.5 msec in the 400 mg/day treatment arm (100 mg every 6 hours on days 1 through 3 with a single 100 mg dose on day 4) and 6.5 msec in the 600 mg/day treatment arm (150 mg every 6 hours on days 1 through 3 with a single 150 mg dose on day 4), both occurring at the 8-hour time point. 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).

MONITOR CLOSELY: Coadministration with lumefantrine may decrease the opioid-like effects of tramadol, a substrate of the CYP450 2D6 isoenzyme. The mechanism is decreased conversion of tramadol to its active metabolite, M1, due to inhibition of CYP450 2D6 activity by lumefantrine. In animal studies, M1 was up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in binding to mu-opioid receptors. When tramadol (50 mg orally) was given with a CYP450 2D6 inhibitor, terbinafine (250 mg once a day), the Cmax and AUC of M1 decreased by 79% and 64%, respectively, while the elimination half-life of M1 increased by 50%. In addition, terbinafine decreased the subjective drug effect of tramadol (P-value less than 0.001).

MANAGEMENT: Coadministration of artemether-lumefantrine with tramadol should generally be avoided. If concomitant use is required, careful consideration of the effects on tramadol and M1 is recommended. Patients should be monitored for opioid withdrawal, seizures, and serotonin syndrome, and care should be exercised in patients suspected to be at an increased risk of torsade de pointes. If artemether-lumefantrine is discontinued, consider reducing the tramadol dose (taking into account the elimination half-life of lumefantrine [3 to 6 days]) until stable drug effects are achieved and monitor for respiratory depression and sedation. Patients should 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.

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