Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.3 · PDF-Seite 7

HOS-214248 · Präparat HOS-155312

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Gegenanzeigen · Votubia

Votubia 1 mg dispersible tablets Votubia 2 mg dispersible tablets Votubia 3 mg dispersible tablets Votubia 5 mg dispersible tablets · Abschnitt 4.3 · PDF-Seite 34

HOS-214298 · Präparat HOS-155312

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214249 · Präparat HOS-155312

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214250 · Präparat HOS-155312

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 2 below.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214251 · Präparat HOS-155312

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214252 · Präparat HOS-155312

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214253 · Präparat HOS-155312

CYP3A4 and PgP inducers decreasing everolimus concentrations

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10

HOS-214254 · Präparat HOS-155312

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 10–11

HOS-214255 · Präparat HOS-155312

10 Table 2 Effects of other active substances on everolimus

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 11

HOS-214256 · Präparat HOS-155312

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, posaconazole, Not studied. Large increase in voriconazole everolimus concentration is Telithromycin, expected. 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 For patients with renal Cmax ↑ 2.2-fold angiomyolipoma associated with Verapamil AUC ↑3.5-fold TSC: (range 2.2-6.3) If patients require co-administration Cmax ↑2.3-fold of a moderate CYP3A4 or PgP (range1.3-3.8) inhibitor, dose reduction to 5 mg or Ciclosporin oral AUC ↑2.7-fold 2.5 mg 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 inhibitor) AUC ↑2.5-fold recommended dose adjustments may Cmax ↑2.5-fold not be optimal in all individuals, Fluconazole Not studied. Increased exposure therefore close monitoring of side Diltiazem expected. effects is recommended. If the Dronedarone Not studied. Increased exposure moderate inhibitor is discontinued, expected. consider a washout period of at least Amprenavir, fosamprenavir Not studied. Increased exposure 2 to 3 days (average elimination time expected. for most commonly used moderate inhibitors) before the Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): indinavir (HOS-084518) diltiazem (HOS-086288) nefazodone (HOS-084519) atazanavir (HOS-086180) nelfinavir (HOS-084520) dronedarone (HOS-086144) ketoconazole (HOS-084513) cannabidiol (HOS-090609) imatinib (HOS-110212) voriconazole (HOS-084524) telithromycin (HOS-084523) itraconazole (HOS-084516) saquinavir (HOS-084522) fluconazole (HOS-087945) clarithromycin (HOS-084517) erythromycin (HOS-084514) amprenavir (HOS-086183) darunavir (HOS-086181) fosamprenavir (HOS-086182) ritonavir (HOS-084521) posaconazole (HOS-085622) verapamil (HOS-090602)

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 11

HOS-214257 · Präparat HOS-155312

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 11–12

HOS-214258 · Präparat HOS-155312

11  concentrations should be assessed at least 1 week 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 Votubia dose is returned to the dose used prior to initiation of the co-administration. The everolimus trough concentration should be assessed at least 1 week later (see sections 4.2 and 4.4). Grapefruit juice or other Not studied. Increased exposure Combination should be avoided. food affecting CYP3A4/PgP expected (the effect 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 patients with renal Dexamethasone Not studied. Decreased angiomyolipoma associated with exposure expected. TSC: Antiepileptics (e.g. Not studied. Decreased If patients require co-administration carbamazepine, exposure expected. of a potent CYP3A4 inducer, a phenobarbital, phenytoin) Votubia dose increase from 10 mg Efavirenz, nevirapine Not studied. Decreased daily up to 20 mg daily should be exposure expected. considered using 5 mg increments or less applied on Day 4 and 8 following start of the inducer. This dose of Votubia 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 Votubia dose is returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): phenobarbital (HOS-085617) carbamazepine (HOS-085618) grapefruit juice (HOS-088787) dexamethasone (HOS-084535) efavirenz (HOS-087947) nevirapine (HOS-088064) phenytoin (HOS-084531)

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 12

HOS-214259 · Präparat HOS-155312

For patients with SEGA associated with TSC: Patients receiving concomitant potent CYP3A4 inducers may require an increased Votubia 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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 12–13

HOS-214260 · Präparat HOS-155312

12  be increased by 2.5 mg every 2 weeks, checking the trough level and assessing tolerability before increasing the dose.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13

HOS-214261 · Präparat HOS-155312

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13

HOS-214262 · Präparat HOS-155312

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. 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 2 to 4 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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13

HOS-214263 · Präparat HOS-155312

Agents whose plasma concentration may be altered by everolimus

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13

HOS-214264 · Präparat HOS-155312

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): midazolam (HOS-086167)

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13

HOS-214265 · Präparat HOS-155312

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): felbamate (HOS-110308) zonisamide (HOS-113349) carbamazepine (HOS-085618) diazepam (HOS-085904) clonazepam (HOS-116372) clobazam (HOS-115305)

Wechselwirkungen · Votubia

Votubia 2.5 mg tablets Votubia 5 mg tablets Votubia 10 mg tablets · Abschnitt 4.5 · PDF-Seite 13–14

HOS-214270 · Präparat HOS-155312

13 Concomitant use of ACE inhibitors

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.