Drug Interaction Report

MONITOR: Coadministration with givosiran may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of CYP450 1A2 and/or CYP450 2D6. The proposed mechanism is decreased clearance due to givosiran-mediated inhibition of CYP450 1A2 and 2D6 isoenzymes. Concomitant administration of a single subcutaneous dose of givosiran (2.5 mg/kg) increased the systemic exposure (AUC) and peak plasma concentration (Cmax) of caffeine (sensitive CYP450 1A2 substrate) by 3.1-fold and 1.3-fold, respectively, and dextromethorphan (sensitive CYP450 2D6 substrate) by 2.4-fold and 2.0-fold, respectively.

MANAGEMENT: Caution and monitoring are recommended when givosiran is given with drugs that are substrates of CYP450 1A2 and/or 2D6. Concomitant use should generally be avoided with CYP450 1A2 or 2D6 substrates that have a narrow therapeutic range where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, the dosage of the CYP450 1A2 or 2D6 substrate should be reduced according to approved product labeling or clinical response and tolerance. Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever givosiran is added to or withdrawn from therapy with these drugs.

GENERALLY AVOID: Alcohol may have additive CNS- and/or respiratory-depressant effects with propoxyphene. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse.

MANAGEMENT: The use of alcohol during propoxyphene therapy should be avoided. Patients should be warned not to exceed the recommended dosage of propoxyphene and to avoid activities requiring mental alertness until they know how these agents affect them.