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Darolutamide

Class: Antineoplastic Agents
- Antiandrogens
Chemical Name: N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-[(1R)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide
Molecular Formula: C19H19ClN6O2
CAS Number: 1297538-32-9
Brands: Nubeqa

Medically reviewed by Drugs.com on May 11, 2020. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Darolutamide

Prostate Cancer

Treatment of nonmetastatic castration-resistant prostate cancer.

Darolutamide Dosage and Administration

General

  • Use concurrently with a gonadotropin-releasing hormone (GnRH) analog unless patient has undergone bilateral orchiectomy.

Restricted Distribution

  • Obtain darolutamide only through a limited network of specialty pharmacies. Consult Bayer at 833-337-3833 or at [Web] for specific availability information.

Administration

Oral Administration

Administer orally twice daily with food. Swallow tablets whole.

Dosage

Adults

Prostate Cancer
Oral

600 mg twice daily. In principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.

Dosage Modification for Toxicity
Oral

If an intolerable or grade 3 or greater adverse effect occurs, interrupt therapy or reduce dosage to 300 mg twice daily until symptoms improve; then may resume recommended dosage of 600 mg twice daily.

Dosage <300 mg twice daily not recommended.

Prescribing Limits

Adults

Prostate Cancer
Oral

Dosages <300 mg twice daily not recommended.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No initial dosage adjustment required.

Moderate hepatic impairment (Child-Pugh class B): 300 mg twice daily.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m2): No initial dosage adjustment required.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m2) not receiving hemodialysis: 300 mg twice daily.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m2): Not studied.

Geriatric Patients

No special dosage recommendations; most patients in principal efficacy study were geriatric.

Cautions for Darolutamide

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm and potential loss of pregnancy. Safety and efficacy not established in females.

Men with female partners of reproductive potential should use effective methods of contraception during therapy and for 1 week after the last dose of the drug.

Impairment of Fertility

Based on animal studies, darolutamide may impair male fertility.

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether darolutamide or its metabolites are distributed into milk, affect milk production, or affect nursing infants.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in safety or efficacy relative to younger adults. In principal efficacy study in men with nonmetastatic castration-resistant prostate cancer, 88% of patients were ≥65 years of age, 49% were ≥75 years of age, and 9% were ≥85 years of age.

Hepatic Impairment

Exposure to darolutamide increased in individuals with moderate hepatic impairment. Pharmacokinetics not established in patients with severe hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Exposure to darolutamide increased in individuals with severe renal impairment not receiving dialysis. Pharmacokinetics not established in patients with end-stage renal disease. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Fatigue, pain in extremity, rash, neutropenia, elevated AST concentrations, elevated bilirubin concentrations.

Interactions for Darolutamide

Metabolized principally by CYP3A4; also metabolized by UGT1A9 and UGT1A1.

Induces CYP3A4 and inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro; also inhibits organic anion transport protein (OATP) 1B1 and OATP1B3 in vitro.

Did not inhibit the major CYP enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or transporters, including multidrug resistance protein 2 (MRP2), bile salt export pump (BSEP), organic anion transporters (OATs), organic cation transporters (OCTs), multidrug and toxin extrusion transporters (MATEs), OATP2B1, and sodium taurocholate co-transporting polypeptide (NTCP), at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes and Efflux Transport Systems

Combined P-gp and potent CYP3A4 inhibitors: Increased darolutamide exposure and possible increased risk of darolutamide adverse effects. Monitor patients more frequently for darolutamide toxicity, and modify darolutamide dosage as needed. (See Dosage Modification for Toxicity under Dosage and Administration.)

Combined P-gp and moderate or potent CYP3A4 inducers: Decreased darolutamide exposure and possible decreased darolutamide activity. Avoid concomitant use.

Moderate CYP3A4 inducers: Decrease of 36–58% in darolutamide exposure expected.

Drugs Affected by Breast Cancer Resistance Protein

BCRP substrates: Increased exposure of BCRP substrate and possible increased risk of BCRP substrate-related toxicity. Avoid concomitant use when possible. If concomitant use cannot be avoided, monitor patients more frequently for adverse effects; consult manufacturer's prescribing information for BCRP substrate and consider dosage reduction of BCRP substrate.

Specific Drugs

Drug

Interaction

Comments

Dabigatran

No clinically important effects on dabigatran pharmacokinetics

Itraconazole

Darolutamide AUC and peak plasma concentration increased by 1.7- and 1.4-fold, respectively

Monitor more frequently for darolutamide toxicity; modify darolutamide dosage as needed (see Dosage Modification for Toxicity under Dosage and Administration)

Midazolam

Midazolam AUC and peak plasma concentration decreased by 29 and 32%, respectively

Not considered clinically important

Rifampin

Darolutamide AUC and peak plasma concentration decreased by 72 and 52%, respectively

Avoid concomitant use

Rosuvastatin

Rosuvastatin AUC and peak plasma concentration increased approximately fivefold; no clinically important effects on darolutamide pharmacokinetics

In efficacy study, increased Scr, AST/ALT, and bilirubin concentrations more common in those receiving darolutamide (rather than placebo) with a BCRP substrate statin (e.g., rosuvastatin)

Avoid concomitant use; if concomitant use cannot be avoided, monitor more frequently for adverse effects; consult rosuvastatin prescribing information and consider rosuvastatin dosage reduction

Darolutamide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability of a 300-mg dose administered orally under fasted conditions is approximately 30%.

Following oral administration of a single 600-mg dose, peak plasma concentration is attained in approximately 4 hours.

Steady-state concentrations are achieved after 2–5 days of repeated dosing with food, with approximately twofold accumulation.

Exposure is nearly dose proportional over a dose range of 100–700 mg.

Food

Bioavailability increases 2 to 2.5-fold when administered with food.

Special Populations

Mild hepatic impairment (Child-Pugh class A): No clinically important effect on pharmacokinetics in patients with nonmetastatic castration-resistant prostate cancer.

Moderate hepatic impairment (Child-Pugh class B): Darolutamide exposure increased 1.9-fold compared with individuals with normal hepatic function.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not established.

Mild to moderate renal impairment (eGFR 30–80 mL/minute per 1.73 m2): No clinically important effect on pharmacokinetics in prostate cancer patients.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m2) not receiving dialysis: Darolutamide exposure in individuals without cancer increased 2.5-fold compared with those with normal renal function.

End-stage renal disease (eGFR <15 mL/minute per 1.73 m2): Effect on pharmacokinetics not established.

Age (range: 48–95 years): No clinically important effects on pharmacokinetics of darolutamide in prostate cancer patients.

Race: No clinically important effects on pharmacokinetics of darolutamide in prostate cancer patients.

Distribution

Extent

Not known whether darolutamide or its metabolites are distributed into milk.

Crosses blood-brain barrier to negligible or lesser extent compared with enzalutamide and apalutamide.

Plasma Protein Binding

Darolutamide: 92% (mainly albumin).

Keto-darolutamide: 99.8% (mainly albumin).

Elimination

Metabolism

Metabolized principally by CYP3A4 to form keto-darolutamide, as well as by UGT1A9 and 1A1. Keto-darolutamide has similar activity as the parent drug in vitro, but is expected to be of minor pharmacologic importance in vivo because of its small unbound fraction.

Elimination Route

Excreted in urine (63.4%; 7% as unchanged drug) and feces (32.4%; 30% as unchanged drug).

Half-life

Darolutamide: Approximately 20 hours.

Keto-darolutamide: Approximately 20 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C). Keep bottle tightly closed.

Actions

  • Competitively inhibits androgen binding to androgen receptors; mechanisms of action are similar to those of enzalutamide and apalutamide.

  • Inhibits nuclear translocation of the androgen receptor, interaction of the androgen receptor with DNA, and androgen receptor-mediated gene transcription.

  • Inhibits tumor growth in vitro and decreases tumor volume in xenograft models of castration-resistant prostate cancer in mice.

  • Structurally unrelated to enzalutamide and apalutamide; darolutamide appears to cross blood-brain barrier to negligible or lesser extent and to have less affinity for GABA type A (GABAA) receptors, with the potential for an improved CNS adverse effect profile (e.g., decreased seizure risk).

  • Unlike conventional antiandrogens but similar to other second generation antiandrogens (e.g., enzalutamide, apalutamide), darolutamide does not exhibit agonistic activity in cells that overexpress the androgen receptor.

  • In addition to inhibiting wild-type androgen receptors, darolutamide also inhibits mutant androgen receptors known to trigger bicalutamide, enzalutamide, and apalutamide antagonist-to-agonist switch.

Advice to Patients

  • For patients currently receiving GnRH analog therapy, importance of continuing this therapy during darolutamide therapy.

  • Importance of advising patients to take darolutamide as instructed with food and of swallowing tablets whole. If a dose is missed, importance of taking the missed dose as soon as it is remembered prior to the next scheduled dose. Do not double the dose to make up for a missed dose.

  • Risk of fetal harm. Necessity of advising patients with female partners of reproductive potential to use effective methods of contraception during darolutamide therapy and for 1 week after the last dose of the drug.

  • Potential for darolutamide to impair male fertility.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of darolutamide is restricted. (See Restricted Distribution under Dosage and Administration.)

Darolutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

300 mg

Nubeqa

Bayer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 11, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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