Drug Interaction Report

GENERALLY AVOID: Coadministration of fenfluramine with potent 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%. Reduced efficacy of fenfluramine may occur.

MANAGEMENT: Concomitant use of fenfluramine with potent inducers of CYP450 1A2, 2B6, or 3A4/5 should be avoided when possible. If coadministration is required, monitor the patient for reduced efficacy and consider increasing the dosage of fenfluramine as needed in accordance with the product labeling, but not to exceed the recommended maximum daily dosage. If a potent inducer of CYP450 1A2, 2B6, or 3A4/5 is discontinued during maintenance treatment with fenfluramine, consider a gradual reduction to the fenfluramine dosage that was administered prior to initiating the inducer.

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.