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 2 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 Afinitor (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



AFI API SEP22 V11                                               REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Erythromycin       AUC ↑4.4-fold                       Use caution when co-administration of (range 2.0-12.6)                    moderate CYP3A4 inhibitors or PgP Cmax ↑2.0-fold                      inhibitors cannot be avoided.
(range 0.9-3.5)
Imatinib           AUC ↑ 3.7-fold                      Oncology patient and patients with Cmax ↑ 2.2-fold                     renal angiomyolipoma associated with Verapamil          AUC ↑3.5-fold                       TSC:
(range 2.2-6.3)                     If patients require co-administration of Cmax ↑2.3-fold                      a moderate CYP3A4 or PgP inhibitor, (range1.3-3.8)                      dose reduction to 5 mg daily or 2.5 mg Ciclosporin oral   AUC ↑2.7-fold                       daily may be considered.
(range 1.5-4.7)                     However, there are no clinical data Cmax ↑1.8-fold                      with this dose adjustment. Due to (range 1.3-2.6)                     between subject variability the
Cannabidiol (PgP   AUC ↑2.5-fold                       recommended dose adjustments may inhibitor)         Cmax ↑2.5-fold                      not be optimal in all individuals, Fluconazole        Not studied. Increased              therefore close monitoring of side Diltiazem          exposure expected.                  effects is recommended (see Dronedarone        Not studied. Increased              sections 4.2 and 4.4). If the moderate exposure expected.                  inhibitor is discontinued, consider a 


AFI API SEP22 V11                                  REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Amprenavir,               Not studied. Increased              washout period of at least 2 to 3 days fosamprenavir             exposure expected.                  (average elimination time for most commonly used moderate inhibitors) before the Afinitor dose is returned to the dose used prior to initiation of the co-administration.
(see also Therapeutic drug monitoring in section 4.2).

For patients with SEGA associated with TSC:
If patients require co-administration of a moderate CYP3A4 or PgP inhibitor,
reduce the daily dose by approximately
50%. Further dose reduction may be required to manage adverse reactions
(see sections 4.2 and 4.4). Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 or
PgP inhibitor. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the
Afinitor dose is returned to the dose used prior to initiation of the co- administration. The everolimus trough concentration should be assessed approximately 2 weeks after any change in dose (see sections 4.2 and
4.4)
Grapefruit juice or     Not studied. Increased                Combination should be avoided.
other food affecting    exposure expected (the effect
CYP3A4/PgP              varies 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%)                          For oncology patients and patients Dexamethasone           Not studied. Decreased                  with renal angiomyolipoma exposure expected.                      associated with TSC:
Antiepileptics (e.g.    Not studied. Decreased                  If patients require co-administration carbamazepine,          exposure expected.                      of a potent CYP3A4 inducer, an phenobarbital,                                                  Afinitor dose increase from 10 mg phenytoin)                                                      daily up to 20 mg daily should be Efavirenz, nevirapine   Not studied. Decreased                  considered using 5 mg increments or exposure expected.                      less applied on Day 4 and 8 following start of the inducer. This
AFI API SEP22 V11                                         REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 dose of Afinitor is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment. If treatment with the inducer is discontinued, consider a washout period of at least 3 to 5 days
(reasonable time for significant enzyme de-induction) before the
Afinitor dose is returned to the dose used prior to initiation of the co-administration (see also
Therapeutic drug monitoring in section 4.2).

For patients with SEGA associated with TSC:
Patients receiving concomitant potent CYP3A4 inducers may require an increased Afinitor dose to achieve the same exposure as patients not taking potent inducers.
Dosing should be titrated to attain trough concentrations of 5 to
15 ng/ml. If concentrations are below
5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks,
checking the trough level and assessing tolerability before increasing the dose.

The addition of another concomitant strong CYP3A4 inducer may not require additional dose adjustment.
Assess the everolimus trough level
2 weeks after initiating the additional inducer. Adjust the dose by increments of 2.5 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
2 weeks after discontinuation of one of multiple strong CYP3A4 inducers.

AFI API SEP22 V11                   REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 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
Afinitor dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentrations should be assessed approximately 2 weeks after any change in dose (see sections 4.2 and 4.4).
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 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).

Co-administration of everolimus and depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumours could not be established.

Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse reactions related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety.

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).


AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022 Vaccinations
The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Afinitor. The use of live vaccines should be avoided during treatment with Afinitor (see section 4.4). 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).