Certican Drug Interactions

Everolimus is mainly metabolised in the liver and, to some extent, in the intestinal wall by CYP3A4. It is also a substrate for the multidrug efflux pump, P-glycoprotein (PgP). Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or PgP.
Observed interactions resulting in concomitant use not being recommended: Rifampicin (CYP3A4 inducer): Pre-treatment of healthy subjects with multiple-doses of rifampicin followed by a single dose of Certican increased everolimus clearance nearly 3-fold, decreasing Cmax by 58% and AUC by 63%. Combination with rifampicin is not recommended (see Precautions).
Ketoconazole (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose ketoconazole followed by a single dose of Certican increased everolimus Cmax by 3.9-fold and AUC by 15.0-fold (see Precautions).
Anticipated interactions resulting in concomitant use not being recommended: Strong inhibitors, inducers of CYP3A4: Concurrent treatment with strong CYP3A4-inhibitors and/or inducers is not recommended (e.g itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, and/or rifampicin, rifabutin) (see Precautions).
Observed interactions to be considered: Interactions affecting use of Certican: 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 the AUC of everolimus by 168% (range 46% to 365%) and Cmax by 82% (range 25% to 158%), as compared with everolimus alone. Dose adjustment of everolimus may be needed if the ciclosporin dose is altered (see Dosage & Administration).
Erythromycin (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose erythromycin followed by a single dose of Certican increased everolimus Cmax by 2.0-fold and AUC by 4.4-fold.
Verapamil (CYP3A4 inhibitor): Pre-treatment of healthy subjects with multiple-dose verapamil followed by a single dose of Certican increased everolimus Cmax by 2.3-fold and AUC by 3.5-fold.
Interactions resulting in effects on other drugs: Ciclosporin (CYP3A4/PgP inhibitor): Certican had only a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.
Octreotide: Coadministration of everolimus with depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47-fold.
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 Prescribing Information of HMG-CoA reductase inhibitors.
Midazolam (CYP3A4A substrate): In a two-period, fixed-sequence, crossover drug interaction study, 25 healthy subjects received a single oral 4 mg dose of midazolam in period 1. In period 2, they received everolimus 10 mg once-daily for 5 days and a single 4 mg dose of midazolam with the last dose of everolimus. The Cmax of midazolam increased 1.25-fold (90% CI, 1.14 - 1.37) and the AUCinf increased 1.30-fold (1.22 - 1.39). The half-life of midazolam was unaltered. This study indicated that everolimus is a weak inhibitor of CYP3A4.
Anticipated interactions to be considered: Interactions affecting the use of Certican: Moderate inducers of CYP3A4: 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).
ACE inhibitors: Concomitant administration of Certican and ACE inhibitors may increase the risk of angioedema.
Moderate inhibitors of CYP3A4: Moderate inhibitors of CYP3A4 and PgP may increase everolimus blood levels (e.g. antifungal substances: fluconazole, calcium channel blockers: nicardipine, diltiazem, protease inhibitors: nelfinavir, indinavir, amprenavir).
Inhibitors of PgP: Inhibitors of PgP may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
CYP3A4 and CYP2D6 substrates: 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 having a narrow therapeutic index. All in vivo interaction studies were conducted without concomitant use of ciclosporin.
Vaccination: Immunosuppressants may affect the response to vaccination and vaccination during treatment with Certican may therefore be less effective. The use of live vaccines should be avoided.
Drug-food/drink interactions: Grapefruit: Grapefruit and grapefruit juice affect cytochrome P450 and PgP activity and should therefore be avoided.