Flutamide

Approved Indications:

• Metastatic Prostate Cancer (Stage D2):
  Flutamide is indicated for use in combination with a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., leuprolide or goserelin) for the treatment of metastatic (stage D2) carcinoma of the prostate.

Off-label/Clinically Accepted Uses:

• Androgen-dependent Conditions (select cases):
• Polycystic Ovary Syndrome (PCOS): To manage hirsutism and hyperandrogenism in women.
• Female Acne and Hirsutism: As an antiandrogen for women unresponsive to first-line treatments.
• Transgender Hormone Therapy (Male-to-Female): As an antiandrogen in feminizing hormone regimens.
• Precocious Puberty (Boys): In rare cases to suppress androgen activity.
• Androgenic Alopecia (Women): Investigational/limited off-label use to reduce hair loss.

Adults (Male, Prostate Cancer):

• Usual Dose: 250 mg orally every 8 hours (750 mg/day total), administered concurrently with an LHRH agonist.
• Initiation: Begin flutamide therapy at least 3 days prior to the initiation of LHRH agonist therapy or simultaneously.

Adults (Female, Off-label Uses):

• Hirsutism/PCOS/Acne:
  125–250 mg orally once or twice daily (commonly 250 mg/day); often used in combination with oral contraceptives to prevent pregnancy due to potential teratogenicity.

Elderly:

• No specific dosage adjustment required unless there is hepatic impairment. Clinical monitoring is essential.

Pediatric:

• Not approved; use in pediatric populations (e.g., for precocious puberty) is rare and requires specialist supervision.

Hepatic Impairment:

• Contraindicated in severe hepatic dysfunction. Use with caution in mild-to-moderate liver impairment; monitor liver enzymes regularly.

Renal Impairment:

• No dosage adjustment typically needed; use cautiously.

Route of Administration:

• Oral. Should be taken with food or after meals to reduce gastrointestinal side effects.

Flutamide is a non-steroidal antiandrogen that competitively inhibits the binding of androgens (testosterone and dihydrotestosterone) to the androgen receptor in target tissues, including the prostate. By blocking this interaction, flutamide prevents androgen-mediated cell proliferation and transcriptional activation. This mechanism leads to decreased stimulation of androgen-sensitive tumors, particularly in metastatic prostate cancer, and reduces manifestations of androgen excess such as hirsutism and acne in females.

• Absorption: Rapidly and completely absorbed after oral administration.
• Bioavailability: Nearly 100%
• Peak Plasma Concentration: Achieved in approximately 2–3 hours.
• Metabolism: Extensively metabolized in the liver. The major active metabolite is 2-hydroxyflutamide, which has significantly greater antiandrogenic activity than the parent compound.
• Half-life:
• Flutamide: 6–8 hours
• 2-Hydroxyflutamide: ~8 hours
• Protein Binding: 92–94%
• Elimination: Primarily renal (urine), with a minor fraction in feces.

• Pregnancy:
  Category D (U.S. FDA – historical classification) – Positive evidence of human fetal risk. Flutamide is contraindicated in women who are or may become pregnant due to its teratogenic and feminizing effects on male fetuses.
• Lactation:
  Not recommended during breastfeeding. It is unknown whether flutamide or its metabolites are excreted in human milk, but due to potential for serious adverse effects in nursing infants, breastfeeding should be avoided during treatment.

• Primary Class: Non-steroidal Antiandrogen
• Sub-class: First-generation antiandrogen
• Related Drug Class: Hormonal Antineoplastic Agents

• Known hypersensitivity to flutamide or any of its components.
• Severe hepatic impairment or active liver disease.
• Women who are pregnant or may become pregnant.
• Women who are breastfeeding.
• Use as monotherapy in prostate cancer without concurrent LHRH agonist.

• Hepatotoxicity:
  Flutamide has been associated with rare but potentially fatal liver failure. Monitor liver function tests (LFTs) at baseline and periodically during treatment. Discontinue if liver enzymes exceed three times the upper limit of normal or if jaundice develops.
• Gynecomastia & Breast Pain:
  May occur in males during therapy.
• Interference with Androgen-dependent Development:
  Avoid use in pregnant women; risk of feminization of male fetuses.
• Hemoglobin and Hematocrit Reduction:
  Periodic monitoring advised in long-term therapy.
• Photosensitivity:
  Patients should avoid excessive sun exposure and use sun protection.

Common Adverse Effects:

• Gastrointestinal: Nausea, vomiting, diarrhea, flatulence
• Hepatic: Elevated transaminases, cholestatic jaundice
• Endocrine/Reproductive: Gynecomastia, decreased libido, impotence
• CNS: Fatigue, insomnia, headache
• Dermatologic: Rash, photosensitivity

Serious and Rare Side Effects:

• Severe hepatotoxicity (including fatal hepatic failure)
• Interstitial pneumonitis
• Hemolytic anemia
• Methemoglobinemia
• Agranulocytosis (very rare)

Timing & Severity:

• Hepatotoxicity may occur within weeks to months of starting therapy.
• Most common adverse events are mild-to-moderate and GI-related.

• Warfarin: May enhance anticoagulant effect. Monitor INR closely.
• Theophylline: Increased theophylline plasma levels due to CYP1A2 inhibition.
• CYP450 Enzymes: Flutamide and its metabolites may inhibit CYP1A2, affecting the metabolism of drugs such as caffeine, clozapine, and propranolol.
• Alcohol: May exacerbate hepatotoxicity; avoid concurrent alcohol consumption.
• Antiandrogens (e.g., bicalutamide): Avoid use together due to competitive antagonism.

• Hepatotoxicity Advisory: Regulatory agencies continue to emphasize the need for liver monitoring due to cases of fatal liver injury.
• Therapeutic Role Shift: Flutamide is less frequently used in favor of newer antiandrogens (e.g., bicalutamide, enzalutamide), which offer improved safety and efficacy profiles.
• Off-label Gender-Affirming Therapy: Flutamide remains an option in certain transgender protocols where spironolactone or bicalutamide are contraindicated, though with increased caution due to hepatotoxic risks.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Excursion Limits: Permissible between 15°C and 30°C (59°F to 86°F)
• Humidity: Store in a dry place. Protect from moisture.
• Light Protection: Store in original container away from direct light.
• Handling Precautions: Keep container tightly closed. No reconstitution required.