There have been postmarketing reports of hospitalization and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy and death related to acute hepatic failure. The hepatic injury was reversible after discontinuation of therapy in some patients. Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide.
Serum transaminase levels should be measured prior to starting treatment with flutamide. Flutamide is not recommended in patients whose ALT values exceed twice the upper limit of normal. Serum transaminase levels should then be measured monthly for the first 4 months of therapy, and periodically thereafter. Liver function tests also should be obtained at the first signs and symptoms suggestive of liver dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, hyperbilirubinuria, jaundice, right upper quadrant tenderness). If at any time, a patient has jaundice, or their ALT rises above 2 times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.
Prostate cancer, metastatic (alternate agent; in patients with low disease burden ): Oral: 250 mg 3 times daily (every 8 hours) in combination with a luteinizing hormone-releasing hormone agonist.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment is necessary in patients with chronic renal insufficiency.
Dialysis: Flutamide and the active metabolite are not well dialyzed; flutamide is not cleared by hemodialysis.
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Severe impairment: Use is contraindicated.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Eulexin: 125 mg [contains corn starch]
Generic: 125 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 250 mg
May be administered with or without food. Administer orally in 3 divided doses (every 8 hours).
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Prostate cancer (metastatic): Management of locally confined Stage B2 to C and Stage D2 metastatic prostate cancer (in combination with a luteinizing hormone-releasing hormone [LHRH] agonist). For Stage B2 to C prostate cancer, flutamide treatment (and goserelin) should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy. To achieve treatment benefit in Stage D2 metastatic prostate cancer, initiate flutamide with the LHRH agonist and continue until disease progression.
Guideline recommendations: The American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline for systemic therapy in men with metastatic castration-resistant prostate cancer suggests that data regarding the clinical benefit of older antiandrogens (including flutamide) are limited, and that older antiandrogen agents may be less efficacious compared to contemporary antiandrogen agents. However, older antiandrogen agents may be offered in patients with low prostate cancer disease burden or limited therapy options (ASCO [Basch 2014]).
Flutamide may be confused with apalutamide, bicalutamide, darolutamide, enzalutamide, Flumadine, nilutamide, thalidomide
Eulexin may be confused with Edecrin, Eurax
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Hot flash (46% to 61%), galactorrhea (9% to 42%), decreased libido (36%), increased lactate dehydrogenase (transient; mild)
Gastrointestinal: Diarrhea (12% to 40%), vomiting (11% to 12%)
Genitourinary: Impotence (33%), cystitis (16%), breast tenderness
Hematologic & oncologic: Rectal hemorrhage (14%), tumor flare
Hepatic: Increased serum AST (transient; mild)
1% to 10%:
Cardiovascular: Edema (4%), hypertension (1%)
Central nervous system: Anxiety, confusion, depression, dizziness, drowsiness, headache, insomnia, nervousness
Dermatologic: Skin rash (3% to 8%), ecchymoses, pruritus
Endocrine & metabolic: Gynecomastia (9%)
Gastrointestinal: Nausea (9%), proctitis (8%), gastric distress (4% to 6%), anorexia (4%), constipation, dyspepsia, increased appetite
Genitourinary: Hematuria (7%)
Hematologic & oncologic: Anemia (6%), leukopenia (3%), thrombocytopenia (1%)
Infection: Herpes zoster
Neuromuscular & skeletal: Weakness (1%)
<1%, postmarketing, and case reports: Cholestatic jaundice, hemolytic anemia, hepatic encephalopathy, hepatic failure, hepatic necrosis, hepatitis, hypersensitivity pneumonitis, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased serum ALT, increased serum bilirubin, increased serum creatinine, jaundice, macrocytic anemia, malignant neoplasm of breast (male), methemoglobinemia, myocardial infarction, oligospermia, pulmonary embolism, skin photosensitivity, sulfhemoglobinemia, thrombophlebitis, urine discoloration (amber, yellow-green)
Hypersensitivity to flutamide or any component of the formulation; severe hepatic impairment (evaluate baseline hepatic enzymes prior to treatment).
Concerns related to adverse effects:
• Aniline toxicity: 4-nitro-3-fluoro-methylaniline is a flutamide metabolite. Patients with G6PD deficiency, hemoglobin M disease, and/or smokers are at risk of toxicities associated with aniline exposure, including methemoglobinemia, hemolytic anemia, and cholestatic jaundice; consider monitoring methemoglobin levels.
• Gynecomastia: Gynecomastia may occur in patients receiving flutamide in combination with medical castration.
• Hepatic failure: [US Boxed Warning]: Postmarketing reports of hospitalization and death (rare) due to liver failure have been reported with flutamide. Evidence of hepatic injury included elevated serum transaminases, jaundice, hepatic encephalopathy, and death related to acute hepatic failure. Hepatotoxicity was reversible after discontinuation in some cases. In about half of reported cases, the onset of hepatotoxicity occurred within the first 3 months of flutamide treatment. Monitor serum transaminase levels at baseline, monthly for 4 months, and periodically thereafter. Obtain LFTs at the first symptoms suggestive of liver dysfunction (nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness). Use is not recommended in patients with ALT values >2 times ULN. Discontinue flutamide immediately in patients with jaundice or if ALT rises above 2 times ULN; closely monitor LFTs until resolution. Use is contraindicated in patients with severe hepatic impairment.
Disease-related concerns:
• Cardiovascular disease: Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine 2010).
Special populations:
• Females: Flutamide is not indicated for use in females and should not be used in females, particularly for nonserious or non-life-threatening conditions.
Substrate of CYP1A2 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Gallium Ga 68 PSMA-11: Antiandrogens may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Therapies targeting the androgen pathway may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact on the performance of gallium Ga 68 PSMA-11 (gozetotide) is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Piflufolastat F18: Antiandrogens may diminish the diagnostic effect of Piflufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of these therapies on the performance of piflufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy
Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Although flutamide is not indicated for use in females, it has been used off label for acne, hirsutism, polycystic ovary syndrome (PCOS), and female pattern hair loss in women. Due to the potential for serious toxicity and the availability of other treatment options, off-label use for these conditions is not recommended (Azarchi 2019; ES [Goodman 2015]); ES [Martin 2018]). Effective contraception is recommended if used in females for these conditions (Azarchi 2019).
Women treated with flutamide for PCOS may have a return of regular menses and ovulatory cycles (Paradisi 2013).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to flutamide may cause fetal harm.
It is not known if flutamide is present in breast milk.
Serum transaminases (at baseline, monthly for 4 months, and periodically thereafter); monitor liver function tests at the first sign or symptom of liver dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, hyperbilirubinuria, jaundice, or right upper quadrant tenderness); monitor prostate specific antigen (PSA). Consider monitoring methemoglobin levels in patients with hemoglobin M disease or with G6PD deficiency and in smokers. Monitor adherence.
Flutamide is a nonsteroidal antiandrogen that inhibits androgen uptake and/or inhibits binding of androgen in target tissues.
Absorption: Oral: Rapid and complete
Protein binding: Parent drug: 94% to 96%; 2-hydroxyflutamide: 92% to 94%
Metabolism: Extensively hepatic to ≥6 metabolites, primarily 2-hydroxyflutamide (active)
Half-life elimination: ~6 hours (2-hydroxyflutamide [active metabolite])
Time to peak: ~2 hours (2-hydroxyflutamide [active metabolite])
Excretion: Primarily urine (as flutamide and metabolites); feces (~4%)
Altered kidney function: The half-life of the active metabolite is slightly prolonged in patients with CrCl <29 mL/minute.
Older adult: The half-life is prolonged to ~9.6 hours (active metabolite at steady state).
Capsules (Eulexin Oral)
125 mg (per each): $30.80
Capsules (Flutamide Oral)
125 mg (per each): $2.09
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