Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 and/or P-glycoprotein (P-gp) may significantly 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.

MANAGEMENT: Concomitant use of everolimus with potent CYP450 3A4 and/or P-gp inducers should generally be avoided. Alternative therapeutic agents with less enzyme induction potential should be considered. Some manufacturers recommend that, if concomitant use is unavoidable, the daily everolimus dose should be doubled to achieve the recommended therapeutic range for the condition being treated. Please refer to the manufacturer's labeling for specific dosing information. If the potent CYP450 3A4 and/or P-gp inducer is discontinued, the everolimus dosage should be returned to the dosage used before the potent inducer was commenced after a washout period of approximately 3 to 5 days. 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 potent inducers.

ADJUST DOSING INTERVAL: Fat-rich food enhances the absorption of mitotane. One study evaluated blood levels of mitotane (o,p'-DDD) after subjects ingested a single dose of 2 g administered using various delivery vehicles (e.g., tablets, granules, milk, chocolate or oil emulsion). Mitotane plasma levels were significantly higher for milk, chocolate, and oil emulsion when compared to those who received tablets or granules alone. In the same study, mitotane levels were evaluated in subjects following long-term treatment (total dose of 200 g over 30 to 60 days) in tablet, oil emulsion, or milk formulations. Significantly higher mean plasma levels were recorded in subjects who received mitotane as an oil emulsion or mixed in milk, when compared to tablets alone. Additionally, the recovery of o,p'-DDD from the feces was about 5 times higher in subjects who received tablets alone, suggesting absorption was reduced when compared to subjects who received mitotane mixed with a fat-rich vehicle (e.g., oil emulsion or milk).

GENERALLY AVOID: Concomitant use of mitotane with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence and sedation.

MANAGEMENT: According to product labeling, mitotane tablets should be taken during meals containing fat-rich food (e.g., milk, chocolate, or oil) and with a full glass of water. Patients should be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as 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.