Damid

Approved Indications:

• Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC):
• Indicated in adult men with nmCRPC to delay metastasis in combination with ongoing androgen deprivation therapy (ADT).
• Metastatic Hormone-Sensitive Prostate Cancer (mHSPC):
• Indicated in combination with docetaxel and ADT for adult patients with mHSPC.

Clinically Accepted Off-label Uses:

• No established or widely accepted off-label indications at this time.

Adults (≥18 years):

• Recommended Dose:
• 600 mg orally twice daily (total 1200 mg/day) with food.
• Co-administration with ADT:
• Continue GnRH analog or bilateral orchiectomy for medical or surgical castration.
• With Docetaxel (for mHSPC):
• Docetaxel initiated within 6 weeks of starting Darolutamide, per protocol. Administer 75 mg/m² IV every 3 weeks for 6 cycles.

Missed Dose:

• Take the missed dose as soon as possible with food on the same day. Do not double the dose.

Pediatrics:

• Not indicated; safety and efficacy not established in pediatric populations.

Elderly:

• No dose adjustment required based on age alone.

Renal Impairment:

• Mild/Moderate (eGFR ≥30 mL/min): No adjustment.
• Severe (eGFR <30 mL/min, not on dialysis): Reduce dose to 300 mg twice daily.
• End-Stage Renal Disease (on dialysis): Not recommended due to lack of data.

Hepatic Impairment:

• Mild/Moderate (Child-Pugh A/B): No adjustment.
• Severe (Child-Pugh C): Not recommended.

Darolutamide is a nonsteroidal androgen receptor (AR) antagonist that competitively inhibits androgen binding to the AR and blocks AR nuclear translocation and DNA binding. Unlike older AR inhibitors, darolutamide has a unique structure that minimizes blood-brain barrier penetration, reducing CNS-related side effects. By inhibiting androgen-mediated signaling, darolutamide suppresses prostate cancer cell proliferation and survival even in the castration-resistant state.

Absorption:

• Rapid absorption with peak plasma concentrations (Tmax) at ~4 hours when taken with food.
• Food increases absorption; must be administered with meals.

Bioavailability:

• Absolute oral bioavailability is ~30% when taken with food.

Distribution:

• Volume of distribution: ~119 L
• Plasma protein binding: ~92%

Metabolism:

• Metabolized primarily by CYP3A4 and UGT1A9 into the active metabolite (ketodarolutamide), which contributes to pharmacologic activity.

Elimination:

• Half-life: ~20 hours (darolutamide and metabolite).
• Excreted via urine (63.4%) and feces (32.4%).

• Pregnancy:
• Contraindicated in women who are or may become pregnant due to teratogenicity and potential embryo-fetal toxicity. Animal studies show fetal harm.
• Lactation:
• Not for use in women; unknown if excreted in human milk. Men with female partners of reproductive potential should use effective contraception during treatment and for 1 week after final dose.

• Primary Class: Antiandrogen
• Subclass: Androgen receptor inhibitor (nonsteroidal, second-generation)

• Hypersensitivity to darolutamide or any excipient
• Use in women who are or may become pregnant

• Seizures: Although rare, there is a potential risk due to AR inhibition in the CNS; avoid in patients with predisposing conditions.
• Embryo-Fetal Toxicity: May cause fetal harm when administered to pregnant women.
• Fractures and Falls: Increased incidence reported; monitor elderly patients.
• Hypertension: Monitor blood pressure during treatment.
• CNS Effects: Darolutamide shows reduced blood-brain barrier penetration, but caution is advised in patients with seizure history.

Common:

• Fatigue
• Pain in extremities
• Rash
• Decreased neutrophil count
• Increased liver enzymes
• Diarrhea

Less Common:

• Falls
• Fractures
• Nausea
• Hypertension
• Arthralgia

Serious/Rare:

• Seizures
• Hepatotoxicity (elevated ALT/AST)
• Hypersensitivity reactions
• Cardiovascular events (rare)

• CYP3A4 Inducers (e.g., rifampin): May decrease darolutamide levels. Avoid use.
• CYP3A4 Inhibitors: No significant effect; no dose adjustment required.
• P-gp and BCRP Substrates (e.g., digoxin, rosuvastatin): Darolutamide inhibits these transporters; monitor for toxicity.
• No QT prolongation: Unlike some older AR inhibitors, darolutamide does not prolong QT interval.

• 2023–2024: Darolutamide approved in several countries for mHSPC based on ARASENS trial showing survival benefit when combined with ADT and docetaxel.
• NCCN and EAU Guidelines: Recommend darolutamide as a first-line treatment option in nmCRPC and as part of combination therapy in mHSPC.
• Ongoing evaluation for use in earlier prostate cancer settings.

• Storage Temperature:
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F).
• Humidity and Light:
• Protect from excessive moisture; store in original container.
• Handling Precautions:
• Keep out of reach of children.
• Do not crush or chew tablets.