Drug Interaction Report

Coadministration of fenfluramine with inducers of CYP450 1A2, 2B6, or 3A4/5 may decrease exposure to fenfluramine and its major active metabolite, norfenfluramine. Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP450 1A2, 2B6 and 2D6, but also to a minor extent by CYP450 2C9, 2C19 and 3A4/5. When a single 0.35 mg/kg dose of fenfluramine oral solution was coadministered with 600 mg once daily rifampin (a weak CYP450 1A2, moderate CYP450 2B6, and potent CYP450 3A4/5 inducer) at steady state in healthy volunteers, fenfluramine peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 40% and 58%, respectively, compared to fenfluramine administered alone. The AUC of norfenfluramine also decreased by 50%, while the Cmax increased by 13%. The interaction has not been studied with other, less potent CYP450 inducers; however, a clinically significant interaction is not expected.

GENERALLY AVOID: Alcohol may potentiate the central nervous system and cardiovascular effects of centrally-acting appetite suppressants. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state.

MANAGEMENT: Concomitant use of centrally-acting appetite suppressants and alcohol should be avoided if possible, especially in patients with a history of cardiovascular disease. Patients should be counselled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

ADJUST DOSING INTERVAL: Coadministration with food increases the oral bioavailability of etravirine. The mechanism is unknown. Compared to administration following a meal, the systemic exposure (AUC) to etravirine was decreased by about 50% when the drug was administered under fasting conditions. The types of meal studied (ranging from 345 kilocalories containing 17 grams fat to 1160 kilocalories containing 70 grams fat) did not appear to make a difference with respect to impact on etravirine bioavailability.

MANAGEMENT: Etravirine should always be administered following a meal.