Certican Drug Interactions

Everolimus is mainly metabolized 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 C_max 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 C_max 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 increased the AUC of everolimus by 168% (range 46% to 365%), and C_max 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 C_max 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 C_max 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 C_min 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 C_max of midazolam increased 1.25-fold (90% CI, 1.14 to 1.37) and the AUC_inf increased 1.30-fold (1.22 to 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 (e.g. carbamazepine, phenobarbital, phenytoin), anti HIV drugs (e.g. efavirenz, nevirapine)).
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 concentration.
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 exercized 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.