Enzalutamide

Approved Indications:

• Metastatic Castration-Resistant Prostate Cancer (mCRPC):
• As monotherapy in patients previously treated with androgen deprivation therapy.
• For patients who have received prior docetaxel chemotherapy or are chemotherapy-naïve.
• Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC):
• For men at high risk of developing metastases, evidenced by rapidly rising PSA levels despite castrate testosterone levels.

Off-Label / Clinically Accepted Uses:

• Occasionally used in combination with androgen deprivation therapy in advanced prostate cancer.
• Investigational use in certain androgen receptor-positive tumors in clinical trials.

Adults:

• Standard dose: 160 mg orally once daily, taken as four 40 mg capsules simultaneously.
• Administer at the same time each day, with or without food.

Special Populations:

• Renal Impairment: No dose adjustment for mild or moderate renal impairment; use caution in severe cases.
• Hepatic Impairment:
• Mild to moderate impairment: no dose adjustment required.
• Severe impairment: use not recommended due to limited data.
• Elderly: No dosage adjustment required solely based on age.

Pediatrics: Not indicated for use in pediatric patients.

Duration: Continuous daily administration until disease progression or unacceptable toxicity occurs.

Enzalutamide is a second-generation non-steroidal antiandrogen that competitively inhibits androgen receptor signaling at multiple levels:

1.        Androgen receptor binding inhibition – prevents androgens (testosterone, dihydrotestosterone) from binding to their receptor.

2.        Nuclear translocation blockade – prevents androgen receptor from entering the nucleus and activating gene transcription.

3.        DNA binding inhibition – blocks androgen receptor binding to DNA, preventing transcription of androgen-dependent genes.

These actions suppress androgen-driven tumor growth and proliferation in prostate cancer cells.

• Absorption: Rapidly absorbed orally; peak plasma concentration in 1–2 hours.
• Bioavailability: High, unaffected by food.
• Distribution: Highly protein-bound (~97–98%), volume of distribution ~110 L.
• Metabolism: Primarily hepatic via CYP2C8 and CYP3A4; produces active metabolite N-desmethyl enzalutamide.
• Elimination: Mainly excreted in urine (71%) and feces (14%).
• Half-Life: Parent compound ~5.8 days; active metabolite ~8 days.
• Onset of Action: Clinical response observed within weeks; PSA decline typically within 4–12 weeks.

• Pregnancy: Category D (contraindicated in pregnant women; can cause fetal harm). Not applicable in men except potential reproductive toxicity.
• Lactation: Not applicable; men’s drug use.
• Caution: Fertility may be affected; men should use contraception during therapy and for at least 3 months after discontinuation.

• Primary Class: Antineoplastic agent
• Subclass: Androgen receptor inhibitor, Non-steroidal antiandrogen, Second-generation

• Known hypersensitivity to Enzalutamide or any formulation excipients.
• Severe hepatic impairment (use not recommended).
• Concomitant use with drugs that strongly induce CYP3A4 without monitoring.

• Seizure Risk: Can lower seizure threshold; avoid in patients with history of seizures or conditions predisposing to seizures.
• Falls and Fractures: Increased risk; monitor bone health.
• Cardiovascular: Rare cases of hypertension and ischemic heart disease; monitor blood pressure.
• Hepatic: Monitor liver function periodically.
• Drug Interactions: Strong CYP2C8 inhibitors or CYP3A4 inducers may alter drug levels; adjust therapy as needed.

Common Adverse Effects:

• Fatigue
• Hot flashes
• Hypertension
• Nausea
• Diarrhea
• Edema

Serious or Rare Adverse Effects:

• Seizures (<1%)
• Posterior reversible encephalopathy syndrome (rare)
• Severe hepatotoxicity
• Ischemic heart disease events

Timing and Severity:

• Fatigue and hot flashes typically occur early in therapy.
• Seizure risk may appear at any time. Most common side effects are mild to moderate.

• CYP2C8 inhibitors (e.g., gemfibrozil): Can increase enzalutamide exposure; may increase toxicity.
• CYP3A4 inducers (e.g., rifampin): May reduce efficacy; monitor PSA response.
• Other Anticonvulsants: Risk of additive CNS effects.
• Food: No clinically significant food interactions.

• FDA Approvals: Expanded indications to include non-metastatic castration-resistant prostate cancer (nmCRPC) based on reduced metastasis risk.
• Clinical Guidelines: NCCN 2023 recommends Enzalutamide as first-line therapy for mCRPC in combination with androgen deprivation therapy.
• Safety Updates: Reinforced seizure warnings and fall risk; monitoring advised for all patients.

• Temperature: Store at 20°C–25°C (68°F–77°F); excursions 15°C–30°C permitted.
• Humidity & Light: Protect from moisture and light.
• Handling: Keep capsules in original container; do not chew or crush.
• Reconstitution: Not applicable; oral capsules ready for administration.