Introduction
Flutamide is a nonsteroidal antiandrogen medication primarily used in the treatment of prostate cancer. It belongs to the first generation of antiandrogens and works by competitively blocking androgen receptors. Flutamide is typically administered in combination with a luteinizing hormone-releasing hormone (LHRH) agonist as part of combined androgen blockade therapy for advanced prostate cancer.
Mechanism of Action
Flutamide competitively inhibits androgen uptake and/or nuclear binding of androgens in target tissues. It acts as a pure antiandrogen by binding to androgen receptors without any intrinsic hormonal activity. By blocking the action of dihydrotestosterone (DHT) and testosterone at the cellular level, flutamide prevents androgen-stimulated growth of prostate cancer cells.
Indications
- Treatment of metastatic prostate carcinoma (stage D2) in combination with LHRH agonists
- Management of locally confined stage B2-C prostate carcinoma
- Off-label uses include: treatment of hirsutism in women, precocious puberty, and female hyperandrogenism
Dosage and Administration
Standard adult dosage: 250 mg orally every 8 hours (750 mg total daily dose) Administration:- Take with or without food
- Usually administered in combination with an LHRH agonist
- For patients with hepatic impairment: dosage reduction or discontinuation may be necessary
- Renal impairment: no specific dosage adjustment recommended
- Geriatric patients: use standard dosing with careful monitoring
Pharmacokinetics
Absorption: Rapidly and completely absorbed from the gastrointestinal tract Distribution: Extensive tissue distribution; protein binding >94-96% Metabolism: Extensive first-pass metabolism in liver to active metabolite (hydroxyflutamide) Elimination: Primarily renal excretion (metabolites); half-life of hydroxyflutamide is approximately 8-10 hours Time to peak concentration: 2 hours (parent drug); 2-4 hours (active metabolite)Contraindications
- Hypersensitivity to flutamide or any component of the formulation
- Severe hepatic impairment
- Pregnancy (Category D)
- Women who are or may become pregnant
Warnings and Precautions
Black Box Warning: Flutamide has been associated with instances of severe hepatic injury, including hepatic necrosis and death. Liver function tests should be performed regularly during therapy. Additional precautions:- Monitor for signs of hepatitis (jaundice, dark urine, fatigue, abdominal pain)
- Use with caution in patients with pre-existing liver disease
- May cause gynecomastia and breast tenderness
- Potential for cardiovascular effects including hypertension
- Photosensitivity reactions reported
- Regular monitoring of prostate-specific antigen (PSA) levels recommended
Drug Interactions
- Warfarin: Flutamide may potentiate anticoagulant effect (monitor INR closely)
- CYP1A2 inhibitors: May increase flutamide concentrations (e.g., fluvoxamine, ciprofloxacin)
- CYP1A2 inducers: May decrease flutamide concentrations (e.g., omeprazole, smoking)
- Other hepatotoxic drugs: Increased risk of liver damage (e.g., acetaminophen, statins)
Adverse Effects
Common (≥10%):- Hot flashes (50%)
- Loss of libido (30%)
- Gynecomastia (10-20%)
- Nausea/vomiting (10%)
- Diarrhea (10%)
- Hepatotoxicity (elevated transaminases, hepatitis, hepatic failure)
- Hematologic abnormalities (anemia, leukopenia)
- Cardiovascular effects (hypertension, edema)
- Pulmonary disorders (interstitial pneumonitis)
- Visual disturbances
- Photosensitivity reactions
Monitoring Parameters
- Liver function tests (ALT, AST, bilirubin) at baseline, every 3 months for first year, then periodically
- PSA levels regularly to assess treatment response
- Complete blood count periodically
- International Normalized Ratio (INR) if on concurrent warfarin therapy
- Clinical signs of hepatic dysfunction
- Cardiovascular status (blood pressure, fluid status)
- Breast examination for gynecomastia
Patient Education
- Take medication exactly as prescribed; do not miss doses
- Report any signs of liver problems immediately: yellowing of skin/eyes, dark urine, abdominal pain, unusual fatigue
- Use effective contraception as flutamide can harm unborn babies
- May cause hot flashes; dressing in layers can help manage this side effect
- Avoid excessive sun exposure and use sunscreen due to photosensitivity risk
- Inform all healthcare providers about flutamide use, especially before surgeries
- Do not stop medication without consulting your oncologist
- Regular follow-up appointments are essential for monitoring safety and efficacy
References
1. FDA Prescribing Information: Flutamide Capsules (2021) 2. National Comprehensive Cancer Network (NCCN) Guidelines: Prostate Cancer (2023) 3. Micromedex® Drug Information: Flutamide (2023) 4. American Society of Clinical Oncology (ASCO) Guidelines: Prostate Cancer Management (2022) 5. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Flutamide (2022) 6. Clinical Pharmacology [Internet]. Flutamide monograph (2023) 7. Journal of Clinical Oncology: Combined androgen blockade trials in prostate cancer (2019) 8. European Association of Urology Guidelines: Prostate Cancer (2023)