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The elimination of apalutamide and formation of its active metabolite, N-desmethyl apalutamide, is mediated by both CYP2C8 and CYP3A4 to a similar extent at steady-state. No clinically meaningful changes in their overall exposure is expected as a result of drug interaction with inhibitors or inducers of CYP2C8 or CYP3A4. Apalutamide is an inducer of enzymes and transporters and may lead to an increase in elimination of many commonly used medicinal products.
Potential for other medicinal products to affect apalutamide exposures: Medicinal products that inhibit CYP2C8: CYP2C8 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 21% while AUC increased by 68% following co-administration of apalutamide 240 mg single dose with gemfibrozil (strong CYP2C8 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 21% while AUC increased by 45%. No initial dose adjustment is necessary when ERLEADA is co-administered with a strong inhibitor of CYP2C8 (e.g., gemfibrozil, clopidogrel) however, a reduction of the ERLEADA dose based on tolerability should be considered (see Dosage & Administration). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide.
Medicinal products that inhibit CYP3A4: CYP3A4 plays a role in the elimination of apalutamide and in the formation of its active metabolite. In a drug-drug interaction study, the Cmax of apalutamide decreased by 22% while AUC was similar following co-administration of ERLEADA as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). For the active moieties (sum of apalutamide plus the potency adjusted active metabolite), Cmax decreased by 22% while AUC was again similar. No initial dose adjustment is necessary when ERLEADA is co-administered with a strong inhibitor of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) however, a reduction of the ERLEADA dose based on tolerability should be considered (see Dosage & Administration). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide.
Medicinal products that induce CYP3A4 or CYP2C8: The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Based on the drug-drug interaction study results with strong CYP3A4 inhibitor or strong CYP2C8 inhibitor, CYP3A4 or CYP2C8 inducers are not expected to have clinically relevant effects on the pharmacokinetics of apalutamide and the active moieties therefore no dose adjustment is necessary when ERLEADA is co-administered with inducers of CYP3A4 or CYP2C8.
Potential for apalutamide to affect exposures to other medicinal products: Apalutamide 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.
Drug metabolising enzymes: In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations. The effect of apalutamide on CYP2B6 substrates has not been evaluated in vivo and the net effect is presently unknown. When substrates of CYP2B6 (e.g., efavirenz) are administered with ERLEADA, monitoring for an adverse reaction and evaluation for loss of efficacy of the substrate should be performed and dose adjustment of the substrate may be required to maintain optimal plasma concentrations.
In humans, apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. In a drug-drug interaction study using a cocktail approach, co-administration of apalutamide with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (CYP3A4 substrate), 85% decrease in the AUC of omeprazole (CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (CYP2C9 substrate). Apalutamide did not cause clinically meaningful changes in exposure to the CYP2C8 substrate. Concomitant use of ERLEADA with medicinal products that are primarily metabolised by CYP3A4 (e.g., darunavir, felodipine, midazolam, simvastatin), CYP2C19 (e.g., diazepam, omeprazole), or CYP2C9 (e.g., warfarin, phenytoin) can result in lower exposure to these medicinal products. Substitution for these medicinal products is recommended when possible or evaluation for loss of efficacy should be performed if the medicinal product is continued. If given with warfarin, INR should be monitored during ERLEADA treatment.
Induction of CYP3A4 by apalutamide suggests that UDP-glucuronosyl transferase (UGT) may also be induced via activation of the nuclear pregnane X receptor (PXR). Concomitant administration of ERLEADA with medicinal products that are substrates of UGT (e.g., levothyroxine, valproic acid) can result in lower exposure to these medicinal products. When substrates of UGT are co-administered with ERLEADA, evaluation for loss of efficacy of the substrate should be performed and dose adjustment of the substrate may be required to maintain optimal plasma concentrations.
Drug transporters: Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. A drug-drug interaction study using a cocktail approach showed that co-administration of apalutamide with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (P-gp substrate) and 41% decrease in the AUC of rosuvastatin (BCRP/OATP1B1 substrate) but had no impact on Cmax. Concomitant use of ERLEADA with medicinal products that are substrates of P-gp (e.g., colchicine, dabigatran etexilate, digoxin), BCRP or OATP1B1 (e.g., lapatinib, methotrexate, rosuvastatin, repaglinide) can result in lower exposure of these medicinal products. When substrates of P-gp, BCRP or OATP1B1 are co-administered with ERLEADA, evaluation for loss of efficacy of the substrate should be performed and dose adjustment of the substrate may be required to maintain optimal plasma concentrations.
Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl metabolite cannot be excluded. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed.
GnRH Analog: In mHSPC subjects receiving leuprolide acetate (a GnRH analog), co-administration with apalutamide had no apparent effect on the steady-state exposure of leuprolide.
Medicinal products which prolong the QT interval: Since androgen deprivation treatment may prolong the QT interval, the concomitant use of ERLEADA 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 (e.g. haloperidol), etc. should be carefully evaluated (see Precautions).
Paediatric population: Interaction studies have only been performed in adults.
