Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and P-glycoprotein may significantly increase the plasma concentrations of everolimus following oral administration. Everolimus is a substrate of both the CYP450 3A4 isoenzyme and P-glycoprotein drug efflux transporter, thus their inhibition in the intestine can enhance the absorption of everolimus. The risk of side effects such as pneumonitis, stomatitis, infection, dyspnea, diarrhea, anemia, leucopenia, thrombocytopenia, hyperglycemia, and hyperlipidemia may be increased.

MANAGEMENT: Concomitant use of everolimus with potent inhibitors of CYP450 3A4 and P-glycoprotein should generally be avoided. Some authorities recommend avoiding concomitant use of everolimus during and for 2 weeks after treatment with itraconazole.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or P-glycoprotein may increase the blood concentrations of everolimus following oral administration. Everolimus is a substrate of both the CYP450 3A4 isoenzyme and P-glycoprotein drug efflux transporter, thus their inhibition in the intestine can enhance the absorption of everolimus.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of everolimus therapy should be considered during coadministration with CYP450 3A4 and/or P-glycoprotein inhibitors, including adverse effects such as pneumonitis, stomatitis, infection, dyspnea, diarrhea, anemia, leucopenia, thrombocytopenia, hyperglycemia, and hyperlipidemia. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.