Darolutamide is an androgen receptor inhibitor. It works by competitively inhibiting androgen binding to androgen receptors, thus inhibiting nuclear translocation of androgen receptors and their interaction with DNA. It is indicated as monotherapy for the treatment of nonmetastatic castration-resistant prostate cancer and in combination with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer. Darolutamide differs from other FDA-approved androgen receptor inhibitors (e.g., apalutamide, enzalutamide) in that it has a distinct structure with fewer side effects, thought to be due to low penetration of the blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A receptors.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-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.
Fatigue, including asthenia, lethargy, and malaise, was reported in 15.8% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 11.4% of those who received placebo in a randomized, double-blind clinical trial (grade 3 or 4, 0.6% vs. 1.1%). Fatigue was among the most frequent adverse reactions requiring dose reduction in patients treated with darolutamide (0.7%).
Rash, including dermatitis, erythema, maculopapular rash, and pustular rash, was reported in 2.9% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 0.9% of those who received placebo in a randomized, double-blind clinical trial (grade 3 or 4, 0.1% vs. 0%). Rash occurred in 20% of patients treated with darolutamide plus docetaxel compared with 15% of those who received placebo with docetaxel in another randomized clinical trial (grade 3 or 4, 1.8% vs. 0.2%); in this trial, rash included the terms previously mentioned as well as palmar-plantar erythrodysesthesia (hand and foot syndrome), eczema, acneiform rash, erythema multiforme, exfoliative dermatitis, penile rash, dyshidrotic eczema, bullous rash, follicular rash, vesicular rash, and toxic skin eruption.
Ischemic heart disease occurred in 3.2% of prostate cancer patients treated with darolutamide in clinical trials (grade 3 or 4, 2.1% to 2.4%); ischemic events led to death in 0.1% to 0.3% of patients. Optimize management of cardiovascular risk factors such as hypertension, diabetes, or dyslipidemia. Monitor patients for signs and symptoms of ischemic heart disease; discontinue darolutamide for grade 3 or 4 ischemic heart disease. Hypertension was reported in 6.6% to 14% of darolutamide-treated prostate cancer patients in 2 randomized clinical trials (grade 3 or 4, 5.2% to 7%) including hypertensive emergency and hypertensive crisis.
Musculoskeletal pain (i.e., pain in extremities) was reported in 5.8% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 3.2% of those who received placebo in a randomized, double-blind clinical trial (grade 3 or 4, 0% vs. 0.2%). Bone fractures occurred in 8% of patients with metastatic castration-sensitive prostate cancer treated with darolutamide plus docetaxel in another randomized clinical trial.
Diarrhea was reported in 6.9% of patients with advanced prostate cancer treated with darolutamide monotherapy compared with 5.6% of those who received placebo in a randomized, double-blind clinical trial (grade 3 or 4, 0% vs. 0.2%). Constipation occurred with a similar incidence in prostate cancer patients treated with docetaxel plus darolutamide compared with docetaxel plus placebo (23% vs. 20%; grade 3 or 4, 0.3% vs. 0.3%).
Nausea was reported less often in patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with those who received placebo in a randomized, double-blind clinical trial (5% vs. 5.8%; grade 3 or 4, 0.2% vs. 0%). However, it was among the most frequent adverse reactions requiring a dose reduction in patients treated with darolutamide in this trial (0.3%).
Hot flashes were reported in 5.2% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 4.2% of those who received placebo in a randomized, double-blind clinical trial.
Anorexia (decreased appetite) occurred in 19% of advanced prostate cancer patients treated with docetaxel plus darolutamide compared with 13% of those who received docetaxel plus placebo in a randomized clinical trial (grade 3 or 4, 0.2% vs. 0.6%). Weight gain occurred in 18% of patients who received darolutamide plus docetaxel compared with 16% or patients who received placebo and docetaxel (grade 3 or 4, 2.1% vs. 1.2%).
Neutropenia was reported in 20% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 9% of those who received placebo in a randomized, double-blind clinical trial (grade 3 or 4, 4% vs. 0.6%). Anemia was also reported more often in the darolutamide arm compared with placebo (5.6% vs. 4.5%; grade 3 or 4, 0.8% vs. 0.4%). In another randomized clinical trial, the incidence of anemia (72% vs. 71%; grade 3 or 4, 6% vs. 7%), lymphopenia (52% vs. 49%; grade 3 or 4, 12% vs. 13%), and neutropenia (49% vs. 44%; grade 3 or 4, 33% vs. 31%) were similar in patients with metastatic castration-sensitive prostate cancer treated with darolutamide plus docetaxel compared with those who received docetaxel plus placebo.
Elevated hepatic enzymes and hyperbilirubinemia have been reported with darolutamide treatment. In a randomized, double-blind clinical trial, increased AST was reported in 23% of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 14% of those who received placebo (grade 3 or 4, 0.5% vs. 0.2%). Transaminitis occurred in 37% to 40% (grade 3 or 4, 3.6% to 3.7%) of patients with metastatic castration-sensitive prostate cancer treated with darolutamide plus docetaxel in another randomized clinical trial, including 5.3% with ALT/AST increases of at least 5 times the upper limit of normal (ULN) and 0.3% with increases of 20 times ULN or more; transaminitis occurred in 31% to 35% (grade 3 or 4, 2.9%) of those who received placebo and docetaxel. The median time to onset of transaminitis in patients treated with darolutamide and docetaxel was 2.8 months. Increased bilirubin occurred in 16% of prostate cancer patients treated with darolutamide compared with 7% of those who received placebo (grade 3 or 4, 0.1% vs. 0%); the addition of darolutamide to docetaxel also increased the incidence of increased bilirubin compared with placebo plus docetaxel (20% vs. 10%; grade 3 or 4, 0.5% vs. 0.3%); drug-induced liver injury was reported in 0.3% of patients who received darolutamide with docetaxel.
Heart failure including cardiogenic shock was reported in 1.9% to 2.1% (grade 3 or 4, 0.5%) of patients with nonmetastatic castration-resistant prostate cancer treated with darolutamide compared with 0.9% of those who received placebo in a randomized, double-blind clinical trial. Additionally, ischemic heart disease (4% vs. 3.4%) and coronary artery disorder (e.g., arteriosclerosis, coronary artery disease, coronary artery occlusion, and coronary artery stenosis) (3.2% vs. 2.5%; grade 3 or 4, 1.7% vs. 0.4%) occurred more often in the darolutamide arm.
Seizures occurred in 0.2% to 0.6% of patients treated with darolutamide in clinical trials (grade 3, 0.2%) in a time frame ranging from 38 to 456 days after initiation of therapy. It is unknown whether antiepileptic medications will prevent seizures with darolutamide. Advise patients of the risk of developing a seizure while receiving darolutamide and engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of darolutamide in patients who develop a seizure during treatment.
Bleeding occurred in 18% of patients treated with darolutamide plus docetaxel compared with 13% of those who received placebo with docetaxel in another randomized clinical trial (grade 3 or 4, 1.4% vs. 1.4%), including hematuria, epistaxis, anal hemorrhage, hemorrhoidal bleeding, GI bleeding, hemoptysis, hematuria, hemorrhagic stroke, hemorrhagic cystitis, subcutaneous hemorrhage, and nail bed bleeding.
Hyperglycemia occurred in 57% of patients with metastatic castration-sensitive prostate cancer treated with darolutamide plus docetaxel compared with 53% of those who received placebo and docetaxel in a randomized clinical trial (grade 3 or 4, 7% vs. 10%).
Hypocalcemia occurred in 31% of patients with metastatic castration-sensitive prostate cancer treated with darolutamide plus docetaxel compared with 28% of those who received placebo and docetaxel in a randomized clinical trial (grade 3 or 4, 2.8% vs. 1.9%).
Use darolutamide with caution in patients with renal disease; it has not been evaluated in patients with end-stage renal disease (eGFR less than 15 mL/min/1.73 m2) or in patients with renal failure receiving dialysis. A dosage adjustment is necessary for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2); no dose adjustment is necessary for patients with mild to moderate renal impairment.
Use darolutamide with caution in patients with hepatic disease; it has not been evaluated in patients with severe hepatic disease (Child-Pugh C). A dosage adjustment is necessary for patients with moderate hepatic impairment (Child-Pugh B); no dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh A).
Use darolutamide with caution in patients with a history of cardiac disease. Optimize management of cardiovascular risk factors such as hypertension, diabetes mellitus, or hyperlipidemia. Monitor patients for signs and symptoms of ischemic heart disease; discontinue darolutamide for grade 3 or 4 ischemic heart disease.
Use darolutamide with caution in patients with a seizure disorder. Seizures have occurred in patients treated with darolutamide including some with a history of seizure disorder, and it is unknown whether antiepileptic medications will prevent seizures with darolutamide. Advise patients of the risk of developing a seizure while receiving darolutamide and engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of darolutamide in patients who develop a seizure during treatment.
The safety and efficacy of darolutamide have not been established in females. Based on its mechanism of action, darolutamide can cause fetal harm and death if administered during pregnancy. Animal embryo-fetal developmental toxicology studies were not conducted with darolutamide. There are no human data on the use of darolutamide in pregnant females.
Counsel patients about the reproductive risk and contraception requirements during darolutamide treatment. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with darolutamide. Although there are no data regarding the effect of darolutamide on human fertility, male infertility has been observed in animal studies.
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.
For the treatment of prostate cancer:
-for the treatment of nonmetastatic castration-resistant prostate cancer:
Oral dosage:
Adults: 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.
-for the treatment of metastatic hormone-sensitive prostate cancer, in combination with docetaxel:
Oral dosage:
Adults: 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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Ischemic Heart Disease
-Grade 3 or 4: Discontinue darolutamide therapy.
Seizure
-Consider discontinuation of darolutamide therapy in any patient who develops a seizure during treatment.
Other Adverse Reactions
-Grade 3 or higher, or intolerable adverse reaction: Hold darolutamide or reduce the dose to 300 mg PO twice daily. When the adverse reaction resolves to baseline, treatment may be resumed at a dose of 600 mg PO twice daily. Dose reduction below 300 mg PO twice daily is not recommended.
Maximum Dosage Limits:
-Adults
600 mg PO twice daily.
-Geriatric
600 mg PO twice daily.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-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.
Patients with Renal Impairment Dosing
-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.
*non-FDA-approved indication
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.
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.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; darolutamide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
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.
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.
Resmetirom: (Major) Avoid concomitant use of resmetirom and darolutamide due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and darolutamide is an OATP1B1/3 inhibitor.
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.
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.
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.
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.
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.
-Route-Specific Pharmacokinetics
Oral Route
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.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (Child-Pugh A) does not cause a clinically significant change in the pharmacokinetics of darolutamide. In noncancer subjects with moderate hepatic impairment (Child-Pugh B), darolutamide exposure increased by about 1.9-fold compared to healthy subjects. The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of darolutamide has not been studied.
Renal Impairment
Mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) does not cause a clinically significant change in the pharmacokinetics of darolutamide. In noncancer subjects with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2) not receiving dialysis, darolutamide exposure increased by about 2.5-fold compared to healthy subjects. The effect of end-stage renal disease (eGFR less than 15 mL/min/1.73 m2) on the pharmacokinetics of darolutamide has not been studied.
Geriatric
Age (41 to 95 years) does not cause a clinically significant change in the pharmacokinetics of darolutamide.
Ethnic Differences
Race (i.e., White, Asian, Black or African American) does not cause a clinically significant change in the pharmacokinetics of darolutamide.