Usage
Enzalutamide is prescribed for the treatment of:
- Metastatic Castration-Resistant Prostate Cancer (mCRPC): This includes men whose disease has progressed on or after docetaxel therapy, and men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) where chemotherapy is not yet clinically indicated.
- Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC): In men with high-risk disease.
- Metastatic Castration-Sensitive Prostate Cancer (mCSPC): Used in combination with ADT.
Pharmacological Classification: Antiandrogen, antineoplastic hormone.
Mechanism of Action: Enzalutamide acts as an androgen receptor inhibitor. It competitively binds to androgen receptors, preventing androgens like testosterone from binding and activating these receptors. This inhibits androgen receptor nuclear translocation, DNA binding, and transcription of androgen-responsive genes, ultimately suppressing tumor cell growth and proliferation in prostate cancer.
Alternate Names
International Nonproprietary Name (INN): Enzalutamide
Brand Name: Xtandi
How It Works
Pharmacodynamics: Enzalutamide primarily exerts its anti-cancer effect by antagonizing the androgen receptor signaling pathway. It binds directly to the androgen receptor with greater affinity than other antiandrogens like bicalutamide. This effectively blocks the effects of androgens, leading to tumor regression or growth arrest.
Pharmacokinetics:
- Absorption: Enzalutamide is well-absorbed orally, with or without food.
- Metabolism: Primarily metabolized in the liver by CYP2C8 and to a lesser extent CYP3A4. It also induces UGT1A1.
- Elimination: Predominantly eliminated via hepatic metabolism and biliary excretion. A small portion is excreted renally.
Mode of Action: Enzalutamide directly targets the androgen receptor within prostate cancer cells. It prevents androgens from binding, inhibits receptor translocation to the nucleus, and disrupts DNA binding and gene transcription. It also impacts androgen receptor nuclear translocation and interaction with coactivators required for gene transcription.
Receptor Binding: Binds specifically and competitively to the androgen receptor.
Enzyme Inhibition/Induction: Substrate of CYP2C8 and to a lesser extent CYP3A4. Inducer of CYP3A4, CYP2C9, CYP2C19, and potentially UGT1A1. It may also inhibit P-glycoprotein.
Elimination Pathways: Primarily hepatic metabolism and biliary excretion; minor renal excretion.
Dosage
Standard Dosage
Adults:
- Standard dose: 160 mg (four 40 mg capsules or tablets) orally once daily.
- Administration: Administer orally with or without food. Swallow capsules/tablets whole; do not crush, chew, or open.
- Concomitant Medication: Patients with mCRPC or mCSPC should continue Luteinising Hormone-Releasing Hormone (LHRH) analogue therapy unless surgically castrated. Patients with high-risk biochemical recurrence nmCRPC can be treated with enzalutamide with or without LHRH analogue.
Children:
Enzalutamide’s safety and efficacy have not been established in the pediatric population.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: No dose adjustment required for mild or moderate impairment. Caution is advised in severe renal impairment or end-stage renal disease as enzalutamide has not been studied in these patients.
- Patients with Hepatic Dysfunction: No dose adjustment required for mild, moderate, or severe hepatic impairment.
- Patients with Comorbid Conditions: Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia, before initiating therapy. Assess and manage risks of fracture and falls.
Clinical Use Cases
Enzalutamide is not indicated for use in settings like intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations.
Dosage Adjustments
- Toxicity ≥ Grade 3 or Intolerable Side Effects: Withhold dosing for one week or until symptoms improve to ≤ Grade 2. Resume at the same or a reduced dose (120 mg or 80 mg) if warranted.
- Strong CYP2C8 Inhibitors: Avoid concomitant use if possible. If co-administration is necessary, reduce the enzalutamide dose to 80 mg once daily. Return to the prior dose upon discontinuation of the inhibitor.
- Strong CYP3A4 Inducers: Avoid concomitant use if possible. If co-administration is unavoidable, increase the enzalutamide dose from 160 mg to 240 mg daily. Return to 160 mg upon discontinuation of the inducer.
Side Effects
Common Side Effects:
Fatigue, weakness, back pain, arthralgia, hot flashes, diarrhea, constipation, headache, dizziness, hypertension, and upper respiratory tract infections.
Rare but Serious Side Effects:
Seizures, posterior reversible encephalopathy syndrome (PRES), falls, fractures, and ischemic heart disease.
Long-Term Effects:
Fractures due to decreased bone mineral density, cardiovascular events (including ischemic heart disease, heart failure, and arrhythmias), and cognitive impairment.
Adverse Drug Reactions (ADR)
Seizures, PRES, hypersensitivity reactions, falls, fractures, and ischemic heart disease.
Contraindications
- Hypersensitivity to enzalutamide or any of its components
- Women who are or may become pregnant, or who are breastfeeding
Drug Interactions
Enzalutamide is a substrate of CYP2C8 and to a lesser extent CYP3A4, an inducer of CYP3A4, CYP2C9, CYP2C19 and UGT1A1, and an inhibitor of P-gp. Many drug interactions exist. Clinically significant interactions include:
- CYP3A4, CYP2C9, CYP2C19 Substrates: Concurrent use with drugs with a narrow therapeutic index may reduce the other drug’s plasma concentration. Consider dosage adjustments for sensitive CYP substrates or avoid co-administration if necessary.
- CYP2C8 Inhibitors: These may increase enzalutamide plasma concentrations; reduce enzalutamide dose if co-administration is unavoidable.
- CYP3A4 Inducers: These may decrease enzalutamide plasma concentrations; increase enzalutamide dose if co-administration is unavoidable.
- Warfarin: Increased INR monitoring is needed due to potential interactions.
- Other Medications: Numerous interactions possible; consult a comprehensive drug interaction resource before co-prescribing.
- St. John’s Wort: Avoid concurrent use as it may decrease enzalutamide exposure.
Pregnancy and Breastfeeding
Pregnancy Safety Category (FDA): X (Contraindicated).
Fetal Risks: Enzalutamide can cause fetal harm and pregnancy loss (miscarriage) and is contraindicated in women who are or may become pregnant.
Breastfeeding: It is unknown if enzalutamide is excreted in human milk. Breastfeeding is contraindicated.
Drug Profile Summary
- Mechanism of Action: Androgen receptor inhibitor, preventing androgen binding and signaling in prostate cancer cells.
- Side Effects: Common: fatigue, weakness, back pain, joint pain. Serious: Seizures, PRES.
- Contraindications: Pregnancy, breastfeeding, hypersensitivity.
- Drug Interactions: Numerous; avoid CYP3A4 substrates with narrow therapeutic index, CYP2C8 inhibitors, and CYP3A4 inducers if possible; monitor INR with warfarin.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 160 mg orally once daily. Special adjustments for concomitant medications (CYP inducers/inhibitors).
- Monitoring Parameters: Monitor for signs of toxicity, including seizures, falls, fractures, and cardiovascular events. Periodically monitor PSA levels, complete blood count, liver function tests, and lipid panel. Monitor INR closely if co-administered with warfarin.
Popular Combinations
Enzalutamide is often combined with LHRH analogues or used after surgical castration as part of ADT for mCRPC and mCSPC.
Precautions
- General Precautions: Assess cardiovascular and fracture risk before starting treatment.
- Specific Populations: Contraindicated in women, especially pregnant and breastfeeding individuals. Use with caution in patients with a history of seizures, brain injury, stroke, brain tumors, cardiovascular disease, hypertension, or dyslipidemia.
- Lifestyle Considerations: Alcohol use may increase the risk of seizures.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Enzalutamide?
A: The recommended dose is 160 mg orally once daily for adults.
Q2: Should Enzalutamide be taken with food?
A: Enzalutamide can be taken with or without food.
Q3: What are the most serious side effects of Enzalutamide?
A: Seizures, PRES, falls, fractures, and ischemic heart disease are among the most serious side effects.
Q4: Can women take Enzalutamide?
A: No, Enzalutamide is contraindicated in women, especially pregnant or breastfeeding women, due to potential fetal harm.
Q5: What should be done if a patient experiences a seizure while on Enzalutamide?
A: Discontinue enzalutamide immediately and provide appropriate medical care.
Q6: How does Enzalutamide interact with warfarin?
A: Enzalutamide can affect warfarin metabolism. Increased INR monitoring is necessary during co-administration.
Q7: What is the role of Enzalutamide in the treatment of mCSPC?
A: Enzalutamide is used in combination with ADT for the treatment of mCSPC.
Q8: Are there any specific monitoring parameters for patients on Enzalutamide?
A: Monitor for toxicity (seizures, falls, fractures, cardiovascular events), periodically assess PSA levels, complete blood count, liver function tests, and lipid panel. Monitor INR closely if co-administered with warfarin.
Q9: What is the mechanism of action of Enzalutamide?
A: Enzalutamide is an androgen receptor inhibitor; it binds to androgen receptors, preventing testosterone from binding and stimulating tumor growth.
Q10: Can Enzalutamide affect male fertility?
A: Yes, enzalutamide can cause fertility problems in males and may affect the ability to father children.
