Drug Interactions between Coartem and hydromorphone / ropivacaine

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including hydromorphone. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of alcohol while taking sustained-release formulations of hydromorphone may cause rapid release of the drug, resulting in high systemic levels of hydromorphone that may be potentially lethal even in opioid-tolerant patients. Alcohol appears to disrupt the extended release mechanism, causing 'dose-dumping' into the bloodstream. In 48 healthy volunteers, coadministration of a 12 mg dose of sustained-release hydromorphone with 240 mL of 40% (80 proof) alcohol resulted in a mean peak hydromorphone concentration (Cmax) approximately six times greater than when taken with water. One subject had a 16-fold increase in hydromorphone Cmax with 40% alcohol compared to water. In some subjects, coadministration with 8 ounces of 4% alcohol (equivalent to 2/3 of a typical serving of beer) resulted in almost twice the hydromorphone Cmax than when coadministered with water. The effect of alcohol was more pronounced in a fasted state.

MANAGEMENT: Patients taking sustained-release formulations of hydromorphone should not consume alcohol or use medications that contain alcohol on days of hydromorphone dosing. In general, potent narcotics such as hydromorphone should not be combined with alcohol.

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GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of artemether and lumefantrine. The mechanism is decreased clearance due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. High plasma levels of artemether and lumefantrine may 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.

ADJUST DOSING INTERVAL: Food enhances the oral absorption of artemether and lumefantrine. In healthy volunteers, the relative bioavailability of artemether increased by two- to threefold and that of lumefantrine by sixteenfold when administered after a high-fat meal as opposed to under fasted conditions.

MANAGEMENT: Patients receiving artemether-lumefantrine therapy should avoid the consumption of grapefruits and grapefruit juice. To ensure maximal oral absorption, artemether-lumefantrine should be taken with food. Inadequate food intake can increase the risk for recrudescence of malaria. Patients who are averse to food during treatment should be closely monitored and encouraged to resume normal eating as soon as food can be tolerated.

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