Drug Interaction Report

MONITOR: Coadministration with osilodrostat may increase the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2C19, 2D6, and/or 3A4. Osilodrostat has been shown to be a moderate inhibitor of CYP450 1A2, a mild to borderline moderate inhibitor of CYP450 2C19, and a weak inhibitor of CYP450 2D6 and 3A4. In a pharmacokinetic study with 20 healthy volunteers using a single 50 mg dose of osilodrostat and a probe drug cocktail, osilodrostat increased the exposures to caffeine (CYP450 1A2 substrate), omeprazole (CYP450 2C19 substrate), dextromethorphan (CYP450 2D6 substrate), and midazolam (CYP450 3A4/5 substrate) by 2.5-, 1.9-, 1.5- and 1.5-fold, respectively.

MANAGEMENT: Caution is advised when osilodrostat is used concurrently with drugs that are substrates of CYP450 1A2, 2C19, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osilodrostat is added to or withdrawn from therapy.

GENERALLY AVOID: The concurrent use of ethanol and alpha-1 adrenergic blockers may cause increased hypotensive effects. Patients with aldehyde dehydrogenase deficiencies (primarily Asians) may be at a higher risk of this interaction. The mechanism has not been determined. Data exist for prazosin and other alpha adrenergic blockers are expected to interact also. In addition, any patients taking alpha adrenergic blockers may experience excessive orthostatic hypotension with ethanol ingestion, due to ethanol's unopposed vasodilatory effects in the presence of alpha adrenergic blockade.

MANAGEMENT: Patients who develop a flushing reaction after ethanol ingestion (indicates a possible aldehyde dehydrogenase deficiency) should be advised to avoid ethanol or limit their intake. All patients should be warned about the possibility of orthostatic hypotension with concurrent ethanol use.