Afinitor Drug Interactions

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP.
In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.
Agents that may increase everolimus blood concentrations: Everolimus blood concentrations may be increased by substances that inhibit CYP3A4 activity and thus decrease everolimus metabolism.
Everolimus blood concentrations may be increased by inhibitors of PgP that may decrease the efflux of everolimus from intestinal cells.
Concurrent treatment with strong CYP3A4/PgP inhibitors (including but not limited to ketoconazole, itraconazole, ritonavir, clarithromycin and telithromycin) should be avoided.
There was a significant increase in exposure to everolimus (C_max and AUC increased by 3.9- and 15.0-fold, respectively) in healthy subjects when everolimus was co-administered with ketoconazole (a strong CYP3A4 inhibitor and PgP inhibitor).
Concomitant treatment with moderate inhibitors of CYP3A4 (including but not limited to erythromycin, verapamil, ciclosporin, fluconazole, diltiazem, amprenavir, fosamprenavir, or aprepitant) and PgP inhibitors requires caution. Reduce the Afinitor dose if co-administered with moderate CYP3A4/PgP inhibitors (see DOSAGE & ADMINISTRATION and PRECAUTIONS).
There was an increase in exposure to everolimus in healthy subjects when everolimus was co-administered with: erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor; C_max and AUC increased by 2.0- and 4.4-fold, respectively).
Verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor; C_max and AUC increased by 2.3- and 3.5-fold, respectively).
Ciclosporin (a CYP3A4 substrate and a PgP inhibitor; C_max and AUC increased by 1.8- and 2.7-fold, respectively).
Grapefruit, grapefruit juice, star fruit, Seville oranges, and other foods that are known to affect cytochrome P450 and PgP activity should be avoided during treatment.
No difference in everolimus C_min was apparent when administered in the presence or absence of substrates of CYP3A4 and/or PgP following treatment with the 10-mg or 5-mg daily dose.
Co-administration of weak inhibitors of CYP3A4 with or without PgP inhibitors had no apparent impact on everolimus C_min following treatment with the 10-mg or 5-mg daily dose regimen.
Agents that may decrease everolimus blood concentrations: Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing the metabolism or the efflux of everolimus from intestinal cells.
Concurrent treatment with strong CYP3A4/PgP inducers should be avoided. If Afinitor must be co-administered with a strong CYP3A4/PgP inducer (e.g. rifampicin and rifabutin), it may be necessary to adjust the Afinitor dose (see DOSAGE & ADMINISTRATION and PRECAUTIONS).
Pre-treatment of healthy subjects with multiple doses of rifampicin (a strong CYP3A4 and PgP inducer) 600 mg daily for 8 days followed by a single dose of everolimus, increased everolimus oral-dose clearance nearly 3-fold and decreased C_max by 58% and AUC by 63%.
Other strong inducers of CYP3A4 and/or PgP that may increase the metabolism of everolimus and decrease everolimus blood levels include St. John's wort (Hypericum perforatum), anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin) and anti HIV agents (e.g. efavirenz, nevirapine).
Agents whose plasma concentration may be altered by everolimus: Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between Afinitor and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of Afinitor.
In vitro, everolimus competitively inhibited the metabolism of the CYP3A4 substrate ciclosporin and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady-state of everolimus C_max with an oral dose of 10 mg daily or 70 mg weekly is more than 12- to 36-fold below the Ki-values of the in vitro inhibition. An effect of everolimus on the metabolism of CYP3A4 and CYP2D6 substrates was therefore considered to be unlikely.
A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam C_max and a 30% increase in midazolam AUC_(0-inf), whereas the metabolic AUC_(0-inf) ratio (1-hydroxymidazolam/midazolam) and the terminal t_1/2 of midazolam were not affected. This suggests that increased exposure to midazolam is due to effects of everolimus in the gastrointestinal system when both drugs are taken at the same time. Therefore, everolimus may affect the bioavailability of orally co-administered drugs which are CYP3A4 substrates. Everolimus is unlikely to affect the exposure of other CYP3A4 substrate drugs which are administered by non-oral routes such as intravenous, subcutaneous, and transdermal administration (see PRECAUTIONS).
Everolimus increased pre-dose concentrations of the antiepileptic drugs (AEDs) carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by approximately 10%. The increase in the pre-dose concentrations of these AEDs may not be clinically significant and dose adjustments for AEDs with a narrow therapeutic index, e.g. carbamazepine, may be considered. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide). Everolimus had no impact on the pre-dose concentration of other AEDs, including valproic acid, topiramate, oxcarbazepine, phenobarbital, phenytoin and primidone.
Co-administration of everolimus and depot octreotide increased octreotide C_min with a geometric mean ratio (everolimus/placebo) of 1.47 (90% CI: 1.32 to 1.64) which was unlikely to have clinically significant effects on the efficacy response to everolimus in patients with advanced neuroendocrine tumors.
Co-administration of everolimus and exemestane increased exemestane C_min and C2h by 45% and 71%, respectively. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety.
Vaccinations: Immunosuppressants may affect the response to vaccination and vaccination during treatment with Afinitor may therefore be less effective. The use of live vaccines should be avoided during treatment with Afinitor (see PRECAUTIONS). Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.