NUBEQA

Cytostatic Androgen Receptor Antagonists

Administer darolutamide with food.
Have the patient swallow the tablet whole. Do not crush or chew.
If a dose is missed, it should be taken as soon as the patient remembers prior to the next scheduled dose. Do not take 2 doses at the same time if a dose is missed.

bone fractures / Delayed / 0-8.0
hypertension / Early / 3.1-7.0
neutropenia / Delayed / 4.0-4.0
weight gain / Delayed / 0-2.1
bleeding / Early / 0-1.4
anemia / Delayed / 0.8-0.8
fatigue / Early / 0.6-0.6
elevated hepatic enzymes / Delayed / 0.5-0.5
heart failure / Delayed / 0.5-0.5
constipation / Delayed / 0-0.3
nausea / Early / 0-0.2
anorexia / Delayed / 0-0.2
seizures / Delayed / 0-0.2
rash / Early / 0.1-0.1
hyperbilirubinemia / Delayed / 0.1-0.1
exfoliative dermatitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
hemorrhagic cystitis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
stroke / Early / Incidence not known

hot flashes / Early / 0-5.2
erythema / Early / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
bullous rash / Early / Incidence not known
lymphopenia / Delayed / Incidence not known
hemoptysis / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known

diarrhea / Early / 0-6.9
musculoskeletal pain / Early / 5.8-5.8
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
lethargy / Early / Incidence not known
maculopapular rash / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
vesicular rash / Delayed / Incidence not known
epistaxis / Delayed / Incidence not known

NUBEQA

Rx

Androgen receptor inhibitor
Used as monotherapy for nonmetastatic castration-resistant prostate cancer and in combination with docetaxel for metastatic hormone-sensitive prostate cancer
Fewer side effects compared to other drugs in this class, possibly due to low penetration of blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A receptors

600 mg PO twice daily with food until disease progression or unacceptable toxicity. Ensure patient is also receiving a GnRH analog or has had a bilateral orchiectomy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind clinical trial (the ARAMIS trial; n = 1,509), treatment with darolutamide significantly improved metastasis-free survival (MFS) compared with placebo (40.4 months vs. 18.4 months); these results were consistent across subgroups for PSA doubling time (6 months or less vs. more than 6 months) or prior use of bone-targeting agents (yes vs. no). At 12 months, PSA levels were undetectable in 24.2% of patients treated with darolutamide compared to 0.4% of those who received placebo. Overall survival was not reached (NR) in either arm, although it was significantly improved in patients treated with darolutamide (range, 56.1 months to NR) compared with those who received placebo (range, 46.9 months to NR). Overall survival at 3 years was 83% versus 77%, respectively.

600 mg PO twice daily with food, in combination with docetaxel (75 mg/m2 IV every 21 days for 6 cycles). The first cycle of docetaxel should begin within 6 weeks after the start of darolutamide treatment; continue darolutamide until disease progression or unacceptable toxicity, even if a cycle of docetaxel is delayed, interrupted, or discontinued. Ensure patient is also receiving a GnRH analog or has had a bilateral orchiectomy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with metastatic hormone-sensitive prostate cancer were randomized to treatment with darolutamide or placebo with 6 cycles of docetaxel in a multicenter, randomized, phase 3 clinical trial (ARASENS). The addition of darolutamide to docetaxel significantly improved median overall survival compared with placebo plus docetaxel (not reached vs. 48.9 months) and also significantly delayed the time to pain progression. At 12 months, PSA levels were undetectable in 60.2% of patients treated with darolutamide plus docetaxel compared to 26.1% of those who received placebo and docetaxel.

Mild hepatic impairment (Child-Pugh A): No dosage adjustments are necessary.
Moderate hepatic impairment (Child-Pugh B): Reduce the dose of darolutamide to 300 mg PO twice daily with food.
Severe hepatic impairment (Child-Pugh C): The effect of severe hepatic impairment on the pharmacokinetics of darolutamide is unknown; dose recommendations are not available. Dose reduction below 300 mg twice daily is not recommended.

Mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2): No dosage adjustments are necessary.
Severe renal impairment, not receiving hemodialysis (eGFR 15 to 29 mL/min/1.73 m2): Reduce the dose of darolutamide to 300 mg PO twice daily with food.
End-stage renal disease (eGFR less than 15 mL/min/1.73 m2): The effect of end-stage renal disease on the pharmacokinetics of darolutamide is unknown; dose recommendations are not available. Dose reduction below 300 mg twice daily is not recommended.

Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Alpelisib: (Major) Avoid coadministration of alpelisib with darolutamide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and darolutamide is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Apalutamide: (Major) Avoid coadministration of darolutamide with apalutamide due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Apalutamide is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Atazanavir; Cobicistat: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with darolutamide. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and darolutamide is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor.
Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking darolutamide. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a BCRP substrate and darolutamide is a BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Brincidofovir: (Moderate) Postpone the administration of darolutamide for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and darolutamide is necessary. Brincidofovir is an OATP1B1/3 substrate and darolutamide is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Carbamazepine: (Major) Avoid coadministration of darolutamide with carbamazepine due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Carbamazepine is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Clarithromycin: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Cobicistat: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir; Cobicistat: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor. (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Dolutegravir: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Elagolix: (Contraindicated) Coadministration of elagolix with darolutamide is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and darolutamide is an OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with darolutamide is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and darolutamide is an OATP1B1 inhibitor.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and darolutamide is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; darolutamide is an inhibitor of OATP1B1/3.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with darolutamide. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and darolutamide is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor. (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor. (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; darolutamide is an inhibitor of OATP1B3.
Fosphenytoin: (Major) Avoid coadministration of darolutamide with fosphenytoin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Fosphenytoin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A; darolutamide is a CYP3A substrate. Concomitant use with another combined P-gp and strong CYP3A inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase glecaprevir exposure. Glecaprevir is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase plasma concentrations of pibrentasvir. Pibrentasvir is a BCRP substrate. Darolutamide is a BCRP inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with darolutamide is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; darolutamide is an OATP1B1/3 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with darolutamide is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; darolutamide is an OATP1B1/3 inhibitor.
Grapefruit juice: (Moderate) Inform patients that darolutamide-related adverse reactions may increase if they consume grapefruit/grapefruit juice. Grapefruit is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of darolutamide with rifampin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Rifampin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with rifampin decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of darolutamide with rifampin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Rifampin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with rifampin decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Itraconazole: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with itraconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Itraconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with itraconazole increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Ketoconazole: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ketoconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ketoconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Levoketoconazole: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ketoconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ketoconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Lopinavir; Ritonavir: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ritonavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ritonavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Lorlatinib: (Major) Avoid coadministration of darolutamide with lorlatinib due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Lorlatinib is a P-glycoprotein (P-gp) inducer and a moderate inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with combined P-gp and moderate CYP3A4 inducers is expected to decrease darolutamide exposure by 36% to 58%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of darolutamide with lumacaftor; ivacaftor due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Lumacaftor is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of darolutamide with lumacaftor; ivacaftor due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Lumacaftor is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with darolutamide is necessary. Concurrent use may increase the plasma concentrations of maraviroc. Maraviroc is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Mifepristone: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with mifepristone is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Mifepristone is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Nelfinavir: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with nelfinavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Nelfinavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Nirmatrelvir; Ritonavir: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ritonavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ritonavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Pazopanib: (Major) Avoid coadministration of pazopanib and darolutamide due to the potential for increased pazopanib exposure. Pazopanib is a BCRP substrate; darolutamide is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP.
Phenobarbital: (Major) Avoid coadministration of darolutamide with phenobarbital due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Phenobarbital is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of darolutamide with phenobarbital due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Phenobarbital is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Phenytoin: (Major) Avoid coadministration of darolutamide with phenytoin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Phenytoin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Posaconazole: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with posaconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Posaconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; darolutamide is an OATP1B1/3 inhibitor.
Primidone: (Major) Avoid coadministration of darolutamide with primidone due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Primidone is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Revefenacin: (Major) Avoid concomitant use of revefenacin and darolutamide. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; darolutamide is an inhibitor of OATP1B1 and OATP1B3.
Rifampin: (Major) Avoid coadministration of darolutamide with rifampin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Rifampin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with rifampin decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Ritonavir: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ritonavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ritonavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Rosuvastatin: (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with doralutamide. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter breast cancer resistance protein (BCRP) and OATP1B1/3; darolutamide is a BCRP and OATP1B1/3 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Rosuvastatin; Ezetimibe: (Major) Do not exceed a rosuvastatin dose of 5 mg once daily when coadministered with doralutamide. Concurrent use results in elevated rosuvastatin serum concentrations; thereby increasing the risk for myopathy, including rhabdomyolysis. Rosuvastatin is a substrate of the drug transporter breast cancer resistance protein (BCRP) and OATP1B1/3; darolutamide is a BCRP and OATP1B1/3 inhibitor. Closely monitor for statin-associated adverse reactions, such as myopathy and rhabdomyolysis.
Saquinavir: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with saquinavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Saquinavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is an OATP1B1 substrate; darolutamide is an OATP1B1 inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and darolutamide. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and darolutamide is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and darolutamide. Concomitant use may increase voxilaprevir exposure and the risk of voxilaprevir-related adverse reactions. Voxilaprevir is a substrate of OATP1B1/3; darolutamide is an OATP1B1/3 inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of darolutamide with St. John's Wort due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. St. John's Wort is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of darolutamide is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and darolutamide is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir alafenamide due to the potential for increased plasma concentrations of tenofovir alafenamide increasing the risk of adverse effects. Tenofovir alafenamide is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Topotecan: (Major) Avoid coadministration of darolutamide with oral topotecan due to increased topotecan exposure; darolutamide may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse effects. Oral topotecan is a substrate of the breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
Tucatinib: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with tucatinib is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Tucatinib is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with darolutamide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; darolutamide is a BCRP inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Zavegepant: (Major) Avoid concomitant use of zavegepant and darolutamide. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and darolutamide is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.

NUBEQA Oral Tab: 300mg

600 mg PO twice daily.

600 mg PO twice daily.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Darolutamide is an androgen receptor (AR) inhibitor that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, had similar in vitro activity to darolutamide. Darolutamide also functioned as a progesterone receptor (PR) antagonist in vitro, with approximately 1% activity compared to the AR. Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer.[64525]
The adverse reactions profile of darolutamide is thought to differ from other drugs in this class due to its distinct structure and characteristics that result in low penetration of the blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A receptors in preclinical studies.[64529] [64530] [64531]

Darolutamide is administered orally. Protein binding, mainly to serum albumin, is 92% for darolutamide and 99.8% for the active metabolite, keto-darolutamide. The apparent volume of distribution (Vd) of darolutamide after intravenous (IV) administration is 119 liters. The effective half-life of darolutamide and keto-darolutamide is approximately 20 hours in patients. The clearance following IV administration is 116 mL/min (CV%, 39.7%). After a single radiolabeled dose as an oral solution, 63.4% of darolutamide-related material is excreted in the urine (approximately 7% as unchanged drug) and 32.4% in the feces (approximately 30% as unchanged drug). More than 95% of the dose was recovered within 7 days after administration.[64525]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, BCRP, UGT1A9, UGT1A1
Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Darolutamide is a BCRP inhibitor in vivo; in vitro, it also inhibits OATP1B1 and OATP1B3. Concomitant administration decreased the mean AUC and Cmax of midazolam, a CYP3A4 substrate, by 29% and 32%, respectively.[64525]

Following administration at the recommended daily dose (600 mg PO twice daily), the mean steady-state peak plasma concentration (Cmax) of darolutamide was 4.79 mg/L (CV%, 30.9%) and the AUC from time 0 to 12 hours (AUC-12h) was 52.82 h x mcg/mL (CV%, 33.9%). The Cmax of darolutamide is reached approximately 4 hours after administration of a single dose (Tmax). Exposure (Cmax and AUC-12) of the active metabolite, keto-darolutamide, is 1.7-fold higher in plasma compared to darolutamide. Steady-state is reached 2 to 5 days after repeated dosing with food, with an approximate 2-fold accumulation ratio. Exposure of darolutamide and keto-darolutamide increase in a nearly dose-proportional manner in the dose range of 100 mg to 700 mg (0.17 to 1.17 times the FDA-approved recommended dose); no further increases in darolutamide exposure occurred at 900 mg PO twice daily (1.5 times the FDA-approved recommended dose). A PSA reduction was observed in patients with castration resistant prostate cancer receiving darolutamide at doses of 100 mg to 900 mg PO twice daily, although doses above 600 mg PO twice daily did not result in additional reductions in PSA. Absolute bioavailability is approximately 30% after oral administration of a single 300-mg tablet under fasted conditions.
Coadministration with food increases the bioavailability of darolutamide by 2 to 2.5-fold, with a similar increase of exposure for keto-darolutamide.

The safety and efficacy of darolutamide have not been established in females. The effect of darolutamide on a breast-feeding infant is unknown. There are no data on the presence of darolutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.