Table 6.

Examples of potential drug–drug interactions between enzalutamide, apalutamide, or darolutamide and concomitant medications

A. Effects of enzalutamide, apalutamide, or darolutamide on the exposure of CYP enzyme or transporter substrates
Enzyme/transporter	Apalutamide [13, 14]	Enzalutamide [11, 12]	Darolutamide [23]	Examples of drugs [4, 29, 30, 32, 33]
	Effect on substrate exposure
CYP3A4				Analgesics: fentanyl, oxycodone Anticoagulants: rivaroxaban Antihypertensives / CV agents: amlodipine, amiodarone, dronedarone, felodipine, nisoldipine, ranolazine Antiplatelet agents: ticagrelor CNS drugs: alprazolam, buspirone, donepezil, midazolam, quetiapine, triazolam Lipid-modifying agents: lovastatin, simvastatin Urological agents: avanafil, darifenacin, dutasteride, oxybutynin, solifenacin, tamsulosin, tolterodine, vardenafil
CYP2C9				Anticoagulants: warfarin Antidiabetics: glimepiride Antihypertensives: losartan Anti-inflammatories: celecoxib Lipid-modifying agents: fluvastatin
CYP2C19				Beta-blockers: propanolol CNS drugs: diazepam PPIs: lansoprazole, omeprazole, rabeprazole
UGT				Analgesics: buprenorphine Antiretrovirals: zidovudine CNS drugs: morphine Anti-epileptics: valproic acid
P-gp				Analgesics: fentanyl, oxycodone Anticoagulants: dabigatran etexilate CV agents: digoxin, ranolazine
BCRP				CV agents: furosemide Lipid-modifying agents: atorvastatin, rosuvastatin, fluvastatin DMARDs: sulfasalazine
OATP1B1				Hypertension/CV agents: atenolol Lipid-modifying agents: atorvastatin, pitavastatin, rosuvastatin, pravastatin Antidiabetics: glyburide, nateglinide, repaglinide

B. Effects of CYP enzyme or drug transporter inhibitors and inducers on the exposure of enzalutamide, apalutamide, or darolutamide
Enzyme/transporter	Apalutamide [13, 14]	Enzalutamide [11, 12]	Darolutamide [23]	Examples of drugs [4, 29, 30, 32, 33]
	Effect on exposure of apalutamide, enzalutamide or darolutamide
Inhibitors
CYP3A4				Antibiotics: clarithromycin, erythromycin Antifungals: itraconazole, ketoconazole Antihypertensives: diltiazem, verapamil Antiretrovirals: indinavir, nelfinavir, ritonavir
CYP2C8				Antibiotics (systemic): trimethoprim Antiplatelet agents: clopidogrel, gemfibrozil
Inducers
CYP3A4				Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin
P-gp				Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin Systemic corticosteroids: dexamethasone

Blue symbols are supported by clinical data, orange symbols are supported by in vitro data only

AR androgen receptor, BCRP breast cancer resistance protein, CNS central nervous system, CV cardiovascular, CYP cytochrome P450, DDI drug–drug interaction, DMARD disease-modifying antirheumatic drug, EMA European Medicines Agency, FDA Food and Drug Administration, mCRPC metastatic castration-resistant prostate cancer, OATP organic anion-transporting peptide, P-gp P-glycoprotein, PPI proton pump inhibitor, SPC summary of product characteristics, UGT uridine 5′-diphospho-glucuronosyltransferase

Indicates risk of increased exposure; strong effect, with avoidance or substitution of coadministered drug recommended

Indicates risk of decreased exposure and loss of efficacy; strong effect, with avoidance or substitution of coadministered drug recommended

↑ Indicates risk of increased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended

↓ Indicates risk of decreased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended

‘–’ Indicates data indicate no clinically significant effect

^†Based on the EMA SPC for XTANDI (UGT substrates are not mentioned in the US PI) [11, 12]

^‡Avoid concomitant use with drugs that are BCRP substrates where possible; if used together, monitor patients more frequently for adverse reactions and consider dose reduction of BCRP substrate drug [23]

^§If combined P-gp and strong CYP3A4 inhibitors are used together, monitor patients more frequently for darolutamide adverse reactions [23]

^‖Note that the information for XTANDI differs between the US PI and the EMA SPC [11, 12]

^¶Avoid concomitant use of combined P-gp and strong or moderate CPY3A4 inducers [23]