DRUG INTERACTIONS
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. Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with strong inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (e.g., rifampin, rifabutin) of CYP3A4 is not recommended. Inhibitors of P-glycoprotein (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 co-administering everolimus with CYP3A4 and CYP2D6 substrates with a narrow therapeutic index. [ See
Therapeutic Drug Monitoring
(
2.2
) ]
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.
Cyclosporine (CYP3A4/P-gp inhibitor and CYP3A4 substrate)
The steady-state Cmax and AUC estimates of everolimus were significantly increased by co-administration of single dose cyclosporine. [ S
ee
Clinical
Pharmaco
logy
(12.3) ] Dose adjustment of everolimus might be needed if the cyclosporine dose is altered. [ See
Dosage and Administration (
2.
3) ] Everolimus had a clinically minor influence on cyclosporine pharmacokinetics in transplant patients receiving cyclosporine (Neoral).
Ketoconazole (Strong CYP3A4 Inhibitor)
Multiple-dose ketoconazole administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) not be co-administered with everolimus. [ See
Warnings and Precautions (
5.11
), and
Clinical
Pharmaco
logy (12.3) ]
Erythromycin (Moderate CYP3A4 Inhibitor)
Multiple-dose erythromycin administration to healthy volunteers significantly increased single dose estimates of everolimus Cmax, AUC, and half-life. If erythromycin is co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [ See Clinical Pharmaco
logy (12.3) ]
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 co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [ See Clinical Pharmaco
logy (12.3
) ]
Atorvastatin (CYP3A4 substrate) and P ravastatin (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 events as described in the respective labeling for these products.
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. [ See Warnings and Precautions (5.7) ]
Rifampin (Strong CYP3A4) Inducers
Pre-treatment of healthy subjects with multiple-dose rifampin followed by a single dose of everolimus increased everolimus clearance and decreased the everolimus Cmax and AUC estimates. Combination with rifampin is not recommended. [ See Warnings and Precautions (
5.1
) and Clinical Pharmacology (12.3) ]
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).
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