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Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever givosiran is added to or withdrawn from therapy with these drugs.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: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.