Wirkstoffe & Arzneimittelsicherheit

Wechselwirkungen · Xtandi

Xtandi - 40 mg soft capsules · Abschnitt 4.5 · PDF-Seite 7

HOS-127897 · Präparat HOS-096479

Effect of food on enzalutamide exposures Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi was administered without regard to food.

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 35

HOS-127916 · Präparat HOS-096479

Potential for other medicinal products to affect enzalutamide exposures

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 35

HOS-127917 · Präparat HOS-096479

CYP2C8 inhibitors CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil (600 mg twice daily) to healthy male subjects, the AUC of enzalutamide increased by 326% while Cmax of enzalutamide decreased by 18%. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 77% while Cmax decreased by 19%. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see 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): gemfibrozil (HOS-088403)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 35

HOS-127918 · Präparat HOS-096479

CYP3A4 inhibitors CYP3A4 plays a minor role in the metabolism of enzalutamide. Following oral administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily) to healthy male subjects, the AUC of enzalutamide increased by 41% while Cmax was unchanged. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC increased by 27% while Cmax was again unchanged. No dose adjustment is necessary when Xtandi is co-administered with inhibitors of CYP3A4.

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): itraconazole (HOS-084516)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 35

HOS-127919 · Präparat HOS-096479

CYP2C8 and CYP3A4 inducers Following oral administration of the moderate CYP2C8 and strong CYP3A4 inducer rifampin (600 mg once daily) to healthy male subjects, the AUC of enzalutamide plus the active metabolite decreased by 37% while Cmax remained unchanged. No dose adjustment is necessary when Xtandi is co- administered with inducers of CYP2C8 or CYP3A4.

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): rifampin (HOS-088791)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 35–36

HOS-127920 · Präparat HOS-096479

35 Potential for enzalutamide to affect exposures to other medicinal products

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127921 · Präparat HOS-096479

Enzyme induction Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Some transporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and the organic anion transporting polypeptide 1B1 (OATP1B1).

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): lead (HOS-085592) uridine (HOS-085192)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127922 · Präparat HOS-096479

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In a clinical study in patients with metastatic CRPC, Xtandi (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m2 by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (GMR) = 0.882 (90% CI: 0.767, 1.02)] while Cmax decreased by 4% [GMR = 0.963 (90% CI: 0.834, 1.11)].

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): docetaxel (HOS-084505) warfarin (HOS-085950) midazolam (HOS-086167) omeprazole (HOS-085912)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127923 · Präparat HOS-096479

Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127924 · Präparat HOS-096479

Groups of medicinal products that can be affected include, but are not limited to:

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127925 · Präparat HOS-096479

• Analgesics (e.g. fentanyl, tramadol) • Antibiotics (e.g. clarithromycin, doxycycline) • Anticancer agents (e.g. cabazitaxel) • Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid) • Antipsychotics (e.g. haloperidol) • Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel) • Betablockers (e.g. bisoprolol, propranolol) • Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil) • Cardiac glycosides (e.g. digoxin) • Corticosteroids (e.g. dexamethasone, prednisolone) • HIV antivirals (e.g. indinavir, ritonavir) • Hypnotics (e.g. diazepam, midazolam, zolpidem) • Immunosuppressant (e.g. tacrolimus) • Proton pump inhibitor (e.g. omeprazole) • Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin) • Thyroid agents (e.g. levothyroxine)

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): doxycycline (HOS-127860) indinavir (HOS-084518) diltiazem (HOS-086288) prednisolone (HOS-086337) nifedipine (HOS-086289) nicardipine (HOS-090619) valproic acid (HOS-088515) atorvastatin (HOS-086304) felodipine (HOS-108908) carbamazepine (HOS-085618) simvastatin (HOS-086158) digoxin (HOS-086172) diazepam (HOS-085904) calcium (HOS-085615) clonazepam (HOS-116372) zolpidem (HOS-086327) dexamethasone (HOS-084535) bisoprolol (HOS-127867) clopidogrel (HOS-087927) clarithromycin (HOS-084517) tacrolimus (HOS-085202) cabazitaxel (HOS-124028) fentanyl (HOS-086196) haloperidol (HOS-085602) ritonavir (HOS-084521) propranolol (HOS-084529) acenocoumarol (HOS-109456) phenytoin (HOS-084531) warfarin (HOS-085950) midazolam (HOS-086167) primidone (HOS-090551) omeprazole (HOS-085912) tramadol (HOS-112871) verapamil (HOS-090602) levothyroxine (HOS-086339)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36

HOS-127926 · Präparat HOS-096479

The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days, see section 5.2), effects on enzymes may

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 36–37

HOS-127927 · Präparat HOS-096479

36 persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127928 · Präparat HOS-096479

CYP1A2 and CYP2C8 substrates Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or Cmax of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while Cmax decreased by 18%. The AUC and Cmax of caffeine decreased by 11% and 4%, respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with Xtandi.

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): caffeine (HOS-085902) pioglitazone (HOS-089663)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127929 · Präparat HOS-096479

P-gp substrates In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mild inhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients with prostate cancer that received a single oral dose of the probe P-gp substrate digoxin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The plasma levels of digoxin were measured using a validated liquid chromatography-tandem mass spectrometry assay. The AUC and Cmax of digoxin increased by 33% and 17%, respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Xtandi and may require dose adjustment to maintain optimal plasma concentrations.

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): digoxin (HOS-086172) colchicine (HOS-086147) dabigatran etexilate (HOS-086233)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127930 · Präparat HOS-096479

Laboratory Test Interference Falsely elevated digoxin plasma level results with the chemiluminescent microparticle immunoassay (CMIA) have been identified in patients treated with enzalutamide, independently of being treated with digoxin. Therefore, results of digoxin plasma levels obtained by CMIA should be interpreted with caution and confirmed by another type of assay before taking any action with digoxin doses.

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): digoxin (HOS-086172)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127931 · Präparat HOS-096479

BCRP substrates At steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probe breast cancer resistance protein (BCRP) substrate rosuvastatin in patients with prostate cancer that received a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC of rosuvastatin decreased by 14% while Cmax increased by 6%. No dose adjustment is necessary when a BCRP substrate is co-administered with Xtandi.

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): rosuvastatin (HOS-086307)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127932 · Präparat HOS-096479

MRP2, OAT3 and OCT1 substrates Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.

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

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127933 · Präparat HOS-096479

Medicinal products which prolong the QT interval Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (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): sotalol (HOS-085597) methadone (HOS-086198) dofetilide (HOS-085598) ibutilide (HOS-085599) quinidine (HOS-085593) disopyramide (HOS-085595) moxifloxacin (HOS-085604) amiodarone (HOS-085596)

Wechselwirkungen · Xtandi

Xtandi - 40 mg film-coated tablets Xtandi - 80 mg film-coated tablets · Abschnitt 4.5 · PDF-Seite 37

HOS-127934 · Präparat HOS-096479

Effect of food on enzalutamide exposures Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi was administered without regard to food.

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