Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may decrease the blood concentrations and pharmacologic effects of everolimus. In a study of healthy volunteers, multiple doses of the potent inducer rifampin increased the oral clearance of everolimus by threefold, representing mean decreases in peak blood concentration (Cmax) and systemic exposure (AUC) of 58% and 63%, respectively. The extent to which other inducers of CYP450 3A4 interact with everolimus is unknown.

MANAGEMENT: Some manufacturers recommend avoiding concomitant use of everolimus with moderate CYP450 3A4 and/or P-gp inducers such as bosentan, efavirenz, and nevirapine. If concomitant use is required, a dose adjustment of everolimus should be considered to achieve the recommended therapeutic range for the condition being treated. Please refer to the manufacturer's labeling for specific dosing information. Everolimus whole blood trough levels should be closely monitored during treatment, particularly 2 weeks after a dose increase and 2 weeks after discontinuation of the inducer.

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.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered everolimus. The mechanism is inhibition of CYP450 3A4 and P-glycoprotein activity in the gut wall by certain compounds present in grapefruit.

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