Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of lesinurad, which is primarily metabolized by the isoenzyme. According to the manufacturer, administration of lesinurad with the moderate CYP450 2C9 inhibitor fluconazole (200 mg daily) increased lesinurad peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 35% and 55%, respectively, compared to administration of lesinurad alone. In a cross-study pharmacogenomic analysis conducted in patients receiving single or multiple doses of lesinurad, patients who were deficient in CYP450 2C9 activity (i.e., CYP450 2C9 poor metabolizers) had an approximately 1.8-fold higher exposure to lesinurad at the 400 mg dose than extensive metabolizers.

MANAGEMENT: Caution is advised when lesinurad is prescribed with CYP450 2C9 inhibitors. Patients should be closely monitored for adverse renal effects such as serum creatinine elevations, renal function impairment, and nephrolithiasis. It may be advisable to avoid concomitant use with a potent CYP450 2C9 inhibitor such as gemfibrozil.

ADJUST DOSING INTERVAL: Administration with food increases the plasma concentrations of efavirenz and may increase the frequency of adverse reactions. According to the product labeling, administration of efavirenz capsules (600 mg single dose) with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with mean increases of 39% and 51% in efavirenz peak plasma concentration (Cmax) and 22% and 17% in systemic exposure (AUC), respectively, compared to administration under fasted conditions. For efavirenz tablets, administration of a single 600 mg dose with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) resulted in a 79% increase in mean Cmax and a 28% increase in mean AUC of efavirenz relative to administration under fasted conditions.

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of efavirenz. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Efavirenz should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams and hallucinations, although they often resolve on their own after the first 2 to 4 weeks of therapy . Patients should be advised of the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs, and to avoid driving or operating hazardous machinery until they know how the medication affects them.