Everolimusinteractions

Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole, erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect everolimus concentrations. Consider everolimus dose adjustment Therapeutic drug monitoring and dose reduction for everolimus should be considered when everolimus is coadministered with cannabidiol

7.1 Interactions

With Strong Inhibitors or Inducers of CYP3A4 and P-glycoprotein Everolimus is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein (P-gp). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-gp. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-gp (e.g., digoxin, cyclosporine) may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and of CYP2D6, potentially increasing the concentrations of medicinal products eliminated by these enzymes. Thus, caution should be exercised when coadministering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant cyclosporine. Pharmacokinetic interactions between everolimus and concomitantly administered drugs are discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

7.2 Cyclosporine (CYP3A4/P-gp

Inhibitor and CYP3A4 Substrate) The steady-state C max and area under the curve (AUC) estimates of everolimus were significantly increased by coadministration of single dose cyclosporine. Dose adjustment of everolimus might be needed if the cyclosporine dose is altered. Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral).

7.3 Ketoconazole and

Other Strong CYP3A4 Inhibitors Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus C max, AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be coadministered with everolimus.

7.4 Erythromycin (Moderate CYP3A4

Inhibitor) Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus C max, AUC, and half-life. If erythromycin is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary.

7.5 Verapamil (CYP3A4 and P-gp

Substrate) Multiple-dose verapamil administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax and AUC. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary.

7.6 Atorvastatin (CYP3A4

Substrate) and Pravastatin (P-gp Substrate) Single-dose administration of everolimus with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However, these results cannot be extrapolated to other HMG-CoA reductase inhibitors. Patients should be monitored for the development of rhabdomyolysis and other adverse reactions as described in the respective labeling for these products.

7.7 Simvastatin and

Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin.

7.8 Rifampin (Strong CYP3A4/P-gp

Inducers) Pretreatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus C max and AUC estimates. Combination with rifampin is not recommended.

7.9 Midazolam (CYP3A4/5

Substrate) Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates.

7.10 Other Possible

Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir). Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood concentrations (e.g., St. John’s Wort [Hypericum perforatum]; anticonvulsants: carbamazepine, phenobarbital, phenytoin; efavirenz, nevirapine).

7.11 Octreotide

Coadministration of everolimus and depot octreotide increased octreotide C min by approximately 50%.

7.12 Tacrolimus

There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and consequently, dose adjustment of everolimus is not necessary when everolimus is coadministered with tacrolimus.

7.13 Cannabidiol

The blood levels of everolimus may increase upon concomitant use with cannabidiol. When cannabidiol and Zortress are coadministered, closely monitor for an increase in everolimus blood levels and for adverse reactions suggestive of everolimus toxicity. A dose reduction of Zortress should be considered as needed when Zortress is coadministered with cannabidiol.