Enzalutamide

🔴 Red Flag (Important) Information

• Seizure risk: Avoid in patients with seizure history, brain metastases, or significant neurological disorders.

• Strong CYP inducer: Enzalutamide reduces plasma levels of many drugs (e.g. warfarin, opioids, antiepileptics, statins) — review co-medications.

• Falls and fractures: Increased risk; ensure bone protection and fall prevention strategies.

• Cardiac caution: Monitor BP and cardiac status — risk of hypertension, QT prolongation, and ischaemic events.

• Posterior Reversible Encephalopathy Syndrome (PRES): Rare but serious; discontinue if headache, confusion, visual changes, or seizures occur.

• Continue ADT: Maintain castrate testosterone levels during treatment.

• Not for women or children: Contraindicated in pregnancy, lactation, and paediatric patients.

🔹 1. Basic Information

Generic name: Enzalutamide
Brand name: Xtandi
Drug class: Androgen receptor inhibitor (anti-androgen)
Formulation: Soft gelatine capsules
Strength: 40 mg
Mechanism of Action:
Inhibits androgen receptor signalling at multiple steps:
→ Blocks androgen binding
→ Prevents nuclear translocation of activated receptor
→ Inhibits receptor binding to DNA
Result: Inhibits androgen-dependent tumour growth and promotes regression of prostate cancer cells.

🔹 2. Indications

Prostate Cancer (Adult men):

• Metastatic hormone-sensitive prostate cancer (mHSPC): With androgen deprivation therapy (ADT).

• High-risk non-metastatic castration-resistant prostate cancer (nmCRPC).

• Metastatic castration-resistant prostate cancer (mCRPC):

  • Asymptomatic or mildly symptomatic after ADT failure (pre-chemotherapy).

  • Post-docetaxel disease progression.

🔹 3. Dosing & Administration

• Dose: 160 mg (4 × 40 mg capsules) once daily.

• Route: Oral (swallow whole with water; do not chew or open).

• With or without food: Both acceptable.

• Missed dose: Take as soon as remembered; if missed for a whole day, resume next day.

• Continue ADT in non-surgically castrated men.

Dose Modifications:

• For ≥Grade 3 toxicity or intolerable side effects → withhold for 1 week or until ≤Grade 2 → resume at 120 mg or 80 mg daily if needed.

• If co-administered with strong CYP2C8 inhibitors (e.g. gemfibrozil) → reduce dose to 80 mg daily.

• No adjustment required for mild–moderate hepatic or renal impairment.

🔹 4. Contraindications

• Hypersensitivity to enzalutamide or excipients.

• Uncontrolled seizures.

• Women (contraindicated in pregnancy and lactation).

🔹 5. Warnings & Precautions

• Seizure risk: Avoid in patients with history of seizures, brain injury, metastases, or alcoholism.

• Posterior Reversible Encephalopathy Syndrome (PRES): Rare; discontinue if diagnosed.

• QT prolongation: Use caution in cardiac disease or QT-prolonging drugs.

• Bone health: Risk of fractures and falls.

• Hepatic impairment: Prolonged half-life in severe impairment.

• Renal impairment: Use caution in severe impairment.

• Concomitant drugs: Potent CYP enzyme inducer — can reduce effect of many drugs (see interactions).

• Cardiac disease: Use cautiously in recent MI, unstable angina, or heart failure (NYHA III–IV).

• Sorbitol content: Contraindicated in hereditary sorbitol intolerance.

🔹 6. Drug Interactions

Avoid or monitor:

• Strong CYP2C8 inhibitors (e.g. gemfibrozil): ↑ enzalutamide exposure.

• Warfarin / CYP2C9 substrates: Monitor INR closely.

• CYP3A4, CYP2C9, CYP2C19 substrates: Enzalutamide decreases levels (enzyme induction).

• QT-prolonging drugs: Amiodarone, sotalol, methadone, antipsychotics, moxifloxacin.

• Drugs affected by enzyme induction:

  • Analgesics (fentanyl, tramadol).

  • Antiepileptics (carbamazepine, phenytoin).

  • Anticoagulants (warfarin).

  • Beta-blockers, calcium channel blockers, statins.

  • Corticosteroids, immunosuppressants, antibiotics.

Key point: Enzalutamide is a strong inducer of CYP3A4 and moderate inducer of CYP2C9/CYP2C19 → may reduce efficacy of many co-administered drugs for up to 1 month after discontinuation.

🔹 7. Side Effects & Management

Very common (>10%)
Fatigue, asthenia, hot flushes, hypertension, fractures, falls
→ Supportive care; fracture prevention measures

Common (1–10%)
Headache, memory impairment, anxiety, rash, dry skin, gynaecomastia, arthralgia
→ Symptomatic treatment

Uncommon (<1%)
Cognitive disorder, seizure, visual hallucination, neutropenia, ischaemic heart disease
→ Monitor closely; discontinue if severe

Rare / Post-marketing
Posterior Reversible Encephalopathy Syndrome (PRES), thrombocytopenia, QT prolongation, hypersensitivity (facial/tongue/lip oedema), myalgia, muscle weakness
→ Discontinue and manage supportively

🔹 8. Use in Special Populations

• Elderly: No dose adjustment.

• Hepatic impairment: No change for mild–moderate; caution in severe impairment.

• Renal impairment: Caution in severe or end-stage disease.

• Paediatric use: Not indicated.

• Pregnancy/Lactation: Contraindicated.

• Fertility: May impair male fertility; contraception required during and for 3 months after treatment.

🔹 9. Overdose

• No specific antidote.

• Discontinue drug and provide supportive care.

• Seizure risk increases with overdose.

🔹 10. Duration of Use / When to Stop

Continue until:

• Disease progression (clinical or radiological).

• Unacceptable toxicity (e.g. seizure, severe hepatic or cardiac event).

Permanently discontinue if:

• Seizure, PRES (Posterior Reversible Encephalopathy Syndrome), life-threatening hypersensitivity, or severe cardiac event.

REFERENCE: 

https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2024/03/ZA_Xtandi_en_-29Feb2024_PI.pdf