Table 4 Drug interactions of note with everolimus [19]

Potent CYP3A4 and/or P-gp inhibitors

Ketoconazole, itraconazole, posaconazole, voriconazole telithromycin, clarithromycin, nefazodone, ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir

Concomitant treatment of everolimus and potent inhibitors is not recommended.

Moderate CYP3A4 and/or P-gp inhibitors

Erythromycin, imatinib, verapamil, ciclosporin oral, fluconazole diltiazem, dronedarone, amprenavir, fosamprenavir

Use caution when co-administration of moderate CYP3A4 inhibitors or P-gp inhibitors cannot be avoided.

For patients with AML:

If patients require co-administration of a moderate CYP3A4 or P-gp inhibitor, dose reduction to 5 mg or 2.5 mg daily may be considered. However, there are no clinical data to guide this dose adjustment. Due to between-subject variability, the recommended dose adjustments may not be optimal in all individuals; therefore, close monitoring of adverse events is recommended. If the moderate inhibitor is discontinued, consider a washout period of at least 2–3 days before the everolimus dose is returned to the dose used prior to initiation of the co-administration.

For patients with SEGA:

If patients require co-administration of a moderate CYP3A4 or P-pg inhibitor, dose reduction by approximately 50% may be considered. Further dose reduction may be required to manage adverse reactions. Trough concentrations should be assessed approximately 2 weeks after the addition of the CYP3A4/P-gp inhibitor; if this inhibitor is discontinued a 2–3 washout period should be considered before everolimus reinitiation. Everolimus trough concentrations should be assessed approximately 2 weeks after any change in dose.

Potent and moderate CYP3A4 inducers

Rifampicin, dexamethasone, antiepileptic agents (e.g. carbamazepine, phenobarbital, phenytoin), efavirenz, nevirapine

Avoid the use of concomitant potent CYP3A4 inducers.

For patients with AML:

If patients require co-administration of a potent CYP3A4 inducer, an everolimus dose increase from 10 mg/day up to 20 mg/day should be considered, using 5 mg increments or less applied on Days 4 and 8 following start of the inducer. This dose of everolimus is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data to support this dose adjustment. If treatment with the inducer is discontinued, consider a washout period of at least 3–5 days (reasonable time for significant enzyme de-induction) before the everolimus dose is returned to the dose used prior to initiation of the co-administration

For patients with SEGA:

Patients receiving concomitant potent CYP3A4 inducers may require an increased everolimus dose to achieve the same exposure as patients not taking inducers. Dosing should be titrated to attain trough concentrations of 5–15 ng/mL; daily dose may be increased by 2.5 every 2 weeks if values are below this, checking the tolerability and trough levels before increasing. If the inhibitor is discontinued a 2–3 washout period should be considered before everolimus reinitiation. Everolimus trough concentrations should be assessed approximately 2 weeks after any change in dose.

CYP3A4 inducer

St John’s Wort (Hypericum perforatum)

Preparations containing St John’s Wort should not be used during treatment with everolimus