Darolutamide

Indications

Darolutamide is used for: Prostate Cancer

Adult Dose

Oral Prostate Cancer Indicated for nonmetastatic castration-resistant prostate cancer (nmCRPC) 600 mg (two 300 mg tablets) BID Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had a bilateral orchidectomy

Child Dose

Renal Dose

Renal impairment Mild or moderate (eGFR 30-89 mL/min/1.73 m2): No dosage adjustment necessary Severe (eGFR 15-29 mL/min/1.73 m2) who are not receiving hemodialysis: Reduce to 300 mg PO BID End-stage renal disease (eGFR <15 mL/min/1.73 m2): Pharmacokinetics unknown

Administration

Oral Administration Take with food

Contra Indications

Hypersensitivity

Precautions

Ischemic Heart Disease: Optimize management of cardiovascular risk factors. Monitor for signs and symptoms of coronary artery disease. Discontinue Darolutamide for Grade 3-4 events. Seizure: Consider discontinuation of Darolutamide in patients who develop a seizure during treatment. Embryo-Fetal Toxicity: Darolutamide can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception

Pregnancy-Lactation

Pregnancy Safety and efficacy have not been established in females Based on its mechanism of action, fetal harm and loss of pregnancy may occur Animal embryofetal developmental toxicology studies were not conducted with darolutamide There are no human data on the use in pregnant females Contraception Males: Based on the mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose Infertility Males: Based on animal studies, fertility may be impaired in males of reproductive potential Lactation Safety and efficacy have not been established in females 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

Interactions

Combined P-gp and Strong or Moderate CYP3A Inducers: Avoid concomitant use. Combined P-gp and Strong CYP3A Inhibitors: Monitor patients more frequently for Darolutamide adverse reactions. BCRP Substrates: Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and consider dose reduction of the BCRP substrate drug. OATP1B1 and OATP1B3 Substrates: Concomitant use of Darolutamide may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. If used together, monitor patients more frequently for adverse reactions and consider dose reduction of these drugs.

Adverse Effects

Side effects of Darolutamide : All grades of severity are listed unless otherwise indicated >10% AST increased (23%) Decreased neutrophil count (20%) Fatigue (16%) Bilirubin increased (16% 1-10% Pain in extremity (6%) Ischemic heart disease (4%) Rash (3%) Heart failure (2.1%) Grade >3 Neutrophil count decreased (4%) <1% Grade >3 Fatigue (0.6%) AST increased (0.5%) Rash (0.1%) Bilirubin increased (0.1%)

Mechanism of Action

Androgen receptor (AR) inhibitor; competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription Keto-darolutamide (major metabolite) exhibited similar in vitro activity In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro Also, decreases prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer