Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 3 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.

Table 2     Effects of other active substances on everolimus

Active substance by       Interaction – Change in                  Recommendations concerning interaction               Everolimus AUC/Cmax                      co-administration Geometric mean ratio
(observed range)
Potent CYP3A4/PgP inhibitors
Ketoconazole              AUC ↑15.3-fold                           Concomitant treatment of Votubia (range 11.2-22.5)                        and potent inhibitors is not Cmax ↑4.1-fold                           recommended.
(range 2.6-7.0)
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                            Use caution when co-administration (range 2.0-12.6)                         of moderate CYP3A4 inhibitors or Cmax ↑2.0-fold                           PgP inhibitors cannot be avoided.
(range 0.9-3.5)
Imatinib                  AUC ↑ 3.7-fold                           If patients require co-administration Cmax ↑ 2.2-fold                          of a moderate CYP3A4 or PgP Verapamil                 AUC ↑3.5-fold                            inhibitor, reduce the daily dose by (range 2.2-6.3)                          approximately 50%. Further dose Cmax ↑2.3-fold                           reduction may be required to manage (range1.3-3.8)                           adverse reactions (see sections 4.2 Ciclosporin oral          AUC ↑2.7-fold                            and 4.4). Everolimus trough (range 1.5-4.7)                          concentrations should be assessed Cmax ↑1.8-fold                           approximately 1 to 2 weeks after the (range 1.3-2.6)                          addition of a moderate CYP3A4 or Cannabidiol (PgP          AUC ↑2.5-fold                            PgP inhibitor.
inhibitor)                Cmax ↑2.5-fold                           If the moderate inhibitor is Fluconazole               Not studied. Increased exposure          discontinued, the Votubia dose should Diltiazem                 expected.                                be returned to the dose used prior to Dronedarone               Not studied. Increased exposure          initiation of the co-administration.
expected.                                The everolimus trough concentration Amprenavir,               Not studied. Increased exposure          should be assessed approximately 2 fosamprenavir             expected.                                weeks later (see sections 4.2 and 4.4).
Grapefruit juice or other Not studied. Increased exposure          Combination should be avoided.
food affecting            expected (the effect varies
CYP3A4/PgP                widely).
Potent and moderate CYP3A4 inducers
Rifampicin                  AUC ↓63%                               Avoid the use of concomitant potent (range 0-80%)                          CYP3A4 inducers.
Cmax ↓58%
(range 10-70%)
Dexamethasone               Not studied. Decreased           Patients with seizures receiving exposure expected.               concomitant strong CYP3A4 inducers
Antiepileptics (e.g.        Not studied. Decreased           (e.g., enzyme inducing antiepileptics carbamazepine,              exposure expected.               carbamazepine, phenobarbital, and phenobarbital, phenytoin)                                    phenytoin) at the start of treatment Efavirenz, nevirapine       Not studied. Decreased           with everolimus require an increased exposure expected.               starting dose to attain trough concentrations of 5 to 15 ng/ml (see
Table 1).

For patients not receiving concomitant strong inducers at the start of everolimus treatment, the co-administration may require an increased Votubia dose. The daily dose should be doubled, and tolerability assessed. The everolimus trough concentration should be assessed approximately two weeks after doubling the dose, and the dose further adjusted by increments of 2 to
4 mg as necessary to maintain the target trough concentration

The addition of another concomitant strong CYP3A4 inducer may not require additional dose adjustment.
Assess the everolimus trough level approximately 2 weeks after initiating the additional inducer. Adjust the dose by increments of 2 to 4 mg as necessary to maintain the target trough concentration.
Discontinuation of one of multiple strong CYP3A4 inducers may not require additional dose adjustment.
Assess the everolimus trough level approximately 2 weeks after discontinuation of one of multiple strong CYP3A4 inducers. If all potent inducers are discontinued, consider a washout period of at least 3 to 5 days
(reasonable time for significant enzyme de-induction) before the
Votubia dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentrations should be assessed approximately 2 weeks later since the natural degradation time of the induced enzymes has to be taken into account (see sections 4.2 and
4.4).
St John’s Wort (Hypericum   Not studied. Large decrease in   Preparations containing St John’s perforatum)                     exposure expected.                 Wort should not be used during treatment with everolimus

Agents whose plasma concentration may be altered by everolimus

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 CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). 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 (see section 4.4).

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide).

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4).

Concomitant ketogenic diet

The effect of a ketogenic diet may be mediated through mTOR inhibition. In the absence of clinical data, the possibility of an additive effect on adverse events cannot be excluded when everolimus is given in conjunction with a ketogenic diet.

Vaccinations

The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Votubia. The use of live vaccines should be avoided during treatment with Votubia. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.

Radiation treatment

Potentiation of radiation treatment toxicity has been reported in patients receiving everolimus (see sections 4.4 and 4.8).