Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
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 (PgP). 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 a mixed inhibitor of CYP2D6. All in vivo interaction studies were conducted without concomitant ciclosporin.

Table 3      Effects of other active substances on everolimus

Active substance by            Interaction – Change in               Recommendations concerning co- interaction                    Everolimus AUC/Cmax                   administration Geometric mean ratio
(observed range)
Strong CYP3A4/PgP inhibitors
Ketoconazole             AUC ↑15.3-fold                              Co-administration with strong (range 11.2-22.5)                           CYP3A4/PgP-inhibitors is not Cmax ↑4.1-fold                              recommended unless the benefit (range 2.6-7.0)                             outweighs the risk.
Itraconazole,            Not studied. Large increase in posaconazole,            everolimus concentration is voriconazole             expected.
Telithromycin,
clarithromycin
Nefazodone
Ritonavir, atazanavir,
saquinavir, darunavir,
indinavir, nelfinavir
Moderate CYP3A4/PgP inhibitors
Erythromycin            AUC ↑4.4-fold                                Everolimus whole blood trough (range 2.0-12.6)                             concentrations should be monitored Cmax ↑2.0-fold                               whenever inhibitors of CYP3A4/PgP (range 0.9-3.5)                              are concurrently administered and Imatinib                AUC ↑3.7-fold                                after their discontinuation.
Cmax ↑2.2-fold
Use caution when co-
Verapamil                      AUC ↑3.5-fold
(range 2.2-6.3)                       administration of moderate
Cmax ↑2.3-fold                        CYP3A4 inhibitors or PgP inhibitors (range1.3-3.8)                        cannot be avoided.
Closely monitor for side effects and
Ciclosporin oral               AUC ↑2.7-fold
(range 1.5-4.7)                       adjust the everolimus dose as needed Cmax ↑1.8-fold                        (see sections 4.2 and 4.4).
(range 1.3-2.6)


Cannabidiol (P-gp             AUC ↑ 2.5-fold inhibitor)                    Cmax ↑ 2.5-fold


Fluconazole                   Not studied. Increased exposure
Diltiazem,                    expected.
Nicardipine
Dronedarone                   Not studied. Increased exposure expected.


Amprenavir,                   Not studied. Increased exposure
Fosamprenavir                 expected.


Grapefruit juice or other     Not studied. Increased exposure      Combination should be avoided.
food affecting                expected (the effect varies
CYP3A4/PgP                    widely).
Strong and moderate CYP3A4 inducers
Rifampicin                    AUC ↓63%                             Co-administration with strong (range 0-80%)                        CYP3A4-inducers is not
Cmax ↓58%                            recommended unless the benefit (range 10-70%)                       outweighs the risk.
Rifabutin                     Not studied. Decreased exposure expected.
Carbamazepine                 Not studied. Decreased exposure expected.
Phenytoin                     Not studied. Decreased exposure expected.
Phenobarbital                 Not studied. Decreased exposure      Everolimus whole blood trough expected.                            concentrations should be monitored whenever inducers of
CYP3A4 are concurrently
Efavirenz, nevirapine         Not studied. Decreased exposure administered and after their expected.
discontinuation.

St John’s Wort                Not studied. Large decrease in       Preparations containing St John’s (Hypericum perforatum)        exposure expected.                   Wort should not be used during treatment with everolimus

Agents whose plasma concentrations may be altered by everolimus:

Octreotide
Co-administration of everolimus (10 mg daily) with depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47-fold.

Ciclosporin
Certican had a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.


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.

Oral CYP3A4A substrates
Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. 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 to be 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 a 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.

Vaccinations
Immunosuppressants may affect the response to vaccination and vaccination during treatment with Certican may be less effective. The use of live vaccines should be avoided.

Paediatric population
Interaction studies have only been performed in adults.