Certican Drug Interactions

Everolimus is mainly metabolised 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 3A4-inhibitors and inducers is not recommended. Inhibitors of P-glycoprotein 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 3A4- and 2D6 substrates with a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant ciclosporin.
Ciclosporin (CYP3A4/PgP inhibitor): The bioavailability of everolimus was significantly increased by co-administration of ciclosporin. In a single-dose study in healthy subjects, ciclosporin for microemulsion (Neoral) increased everolimus AUC by 168 % (range, 46 % to 365 %) and Cmax by 82 % (range, 25 % to 158 %) compared with administration of everolimus alone. Dose adjustment of everolimus might be needed if the ciclosporin dose is altered (see Dosage & Administration). Certican had a clinically minor influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.
Rifampicin (CYP3A4 inducer): Pre-treatment of healthy subjects with multiple-dose rifampicin followed by a single dose of Certican increased everolimus clearance nearly 3-fold, and decreased Cmax by 58 % and AUC by 63 %. Combination with rifampicin is not recommended (see Precautions).
Atorvastatin (CYP3A4-substrate) and pravastatin (PgP-substrate): Single-dose administration of Certican 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 Summary of Product Characteristics of HMG-CoA reductase inhibitors.
Oral CYP3A4A substrates: An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A4 substrate probe, with everolimus resulted in a 25 % increase in midazolam Cmax and a 30 % increase in midazolam AUC. The effect is likely due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected. If everolimus is taken with orally administered CYP3A4 substrates with narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate.
Other possible interactions: Moderate inhibitors of CYP3A4 and PgP may increase everolimus blood levels (e.g. antifungal substances: fluconazole; macrolide antibiotics: erythromycin; calcium channel blockers: verapamil, nicardipin, diltiazem; protease inhibitors: nelfinavir, indinavir, amprenavir. Inducers of CYP3A4 may increase the metabolism of everolimus and decrease everolimus blood levels (e.g. St. John's wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin; anti HIV drugs: efavirenz, nevirapine).
Grapefruit and grapefruit juice affect cytochrome P450 and PgP activity and should therefore be avoided.
Vaccination: Immunosuppressants may affect response to vaccination and vaccination during treatment with Certican may be less effective. The use of live vaccines should be avoided.