Drug Interactions between atazanavir / cobicistat and fenfluramine

MONITOR: Coadministration with fenfluramine may decrease the plasma concentrations and therapeutic efficacy of drugs that are substrates of the CYP450 2B6 and/or CPY3A4 isoenzymes. The proposed mechanism, based on in vitro data, might be increased clearance due to induction of CYP450 2B6 and intestinal CYP450 3A4.

MANAGEMENT: Caution and monitoring are recommended if fenfluramine is used concomitantly with drugs that are substrates of CYP450 2B6 and/or CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. Monitoring for potential loss of therapeutic efficacy is recommended. The prescribing information for concomitant medications may be consulted to assess the benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of a CYP450 2B6 and/or CYP450 3A4 inducer.

MONITOR: Coadministration with inhibitors of CYP450 1A2 or 2D6 may increase the plasma concentrations of fenfluramine. 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 50 mg once daily fluvoxamine (a potent CYP450 1A2 inhibitor) at steady state in healthy volunteers, fenfluramine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 22% and 102%, respectively, while the Cmax and AUC of norfenfluramine decreased by 44% and 22%, respectively. Coadministration with 30 mg once daily paroxetine (a potent CYP450 2D6 inhibitor) at steady state in healthy volunteers increased the Cmax and AUC of fenfluramine by 13% and 81%, respectively, and decreased Cmax and AUC of norfenfluramine by 29% and 13%, respectively. Coadministration with repeated doses of cannabidiol (a weak CYP450 1A2 inhibitor with the potential to also inhibit CYP450 2B6, 2C8, 2C9, and 2C19 at clinically relevant concentrations) increased the Cmax and AUC of fenfluramine by 10% and 59%, respectively, and decreased Cmax and AUC of norfenfluramine by 33% and 22%, respectively. Elevated plasma levels of fenfluramine may increase the risk of serious adverse effects such as valvular heart disease, pulmonary arterial hypertension, blood pressure increases, and serotonin syndrome.

MANAGEMENT: Caution is advised when fenfluramine is used with CYP450 1A2 or 2D6 inhibitors. Patients should be monitored for increased adverse effects, and the dosage of fenfluramine adjusted as necessary.