Drug Interaction Report

MONITOR: Coadministration with ropeginterferon alfa-2b may increase the plasma concentrations of drugs that are metabolized by CYP450 pathways. The formation of hepatic CYP450 enzymes is down-regulated by increased levels of certain proinflammatory cytokines including interferons, thus treatment with ropeginterferon alfa-2b can effectively suppress CYP450 enzymes resulting in increased exposures of some CYP450 substrates. Clinical data demonstrating the interaction are currently lacking. Ropeginterferon alfa-2b did not inhibit CYP450 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes. However, since interferons may influence CYP450 enzymes via mechanisms that require an extended duration to exert effect (e.g., by modulating transcription factors and altering protein expression and/or structure), enzyme inhibition cannot be evaluated by in vitro assays.

MANAGEMENT: Caution is advised when ropeginterferon alfa-2b is coadministered with drugs that are CYP450 substrates, particularly those with narrow therapeutic ranges (e.g., antiarrhythmics, anticonvulsants, immunosuppressants, theophylline) or sensitive substrates where increases in plasma levels may be significant or undesirable (e.g., statins, benzodiazepines, opioids). Clinical and/or laboratory monitoring should be considered following the initiation or withdrawal of ropeginterferon alfa-2b, and the dosage(s) of the CYP450 substrate(s) adjusted accordingly. Clinicians should note that the effects of interferons on CYP450 activities may persist for several weeks after stopping therapy.

GENERALLY AVOID: Grapefruit juice may significantly increase the systemic exposure to eliglustat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because eliglustat is predicted to cause prolongation of the PR, QTc, and QRS cardiac intervals at substantially elevated plasma concentrations, consumption of grapefruit juice during treatment may increase the risk of bradycardia, atrioventricular block, cardiac arrest, and serious ventricular arrhythmias such as torsade de pointes.

MANAGEMENT: Patients treated with eliglustat should avoid consumption of grapefruit and grapefruit juice.