BOXED WARNING WARNINGS Hepatic Injury 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, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, hyperbilirubinuria, jaundice or 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.
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WARNINGS Hepatic Injury See BOXED WARNINGS . Use in Women Flutamide capsules are for use only in men. This product has no indication for women and should not be used in this population, particularly for nonserious or non life-threatening conditions. Fetal Toxicity Flutamide may cause fetal harm when administered to a pregnant woman (see Pregnancy ). Aniline Toxicity One metabolite of flutamide is 4-nitro-3-fluoro-methylaniline. Several toxicities consistent with aniline exposure, including methemoglobinemia, hemolytic anemia and cholestatic jaundice have been observed in both animals and humans after flutamide administration. In patients susceptible to aniline toxicity (e.g., persons with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease and smokers), monitoring of methemoglobin levels should be considered.
ADVERSE REACTIONS Stage B2-C Prostatic Carcinoma Treatment with flutamide capsules and the goserelin acetate implant did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + goserelin acetate implant + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below. Adverse Events During Acute Radiation Therapy ( within first 90 days of radiation therapy ) Adverse Events During Late Radiation Phase ( after 90 days of radiation therapy ) ( n = 231 ) Goserelin Acetate Implant + Flutamide Capsules + Radiation % All ( n = 235 ) Radiation Only % All ( n = 231 ) Goserelin Acetate Implant + Flutamide Capsules + Radiation % All ( n = 235 ) Radiation Only % All Rectum/large bowel 80 76 Diarrhea 36 40 Bladder 58 60 Cystitis 16 16 Skin 37 37 Rectal bleeding 14 20 Proctitis 8 8 Hematuria 7 12 Stage D2 Metastatic Carcinoma The following adverse experiences were reported during a multicenter clinical trial comparing flutamide capsules + LHRH agonist versus placebo + LHRH agonist. The most frequently reported (greater than 5%) adverse experiences during treatment with flutamide capsules in combination with an LHRH agonist are listed in the table below. For comparison, adverse experiences seen with an LHRH agonist and placebo are also listed in the following table. ( n = 294 ) Flutamide + LHRH agonist % All ( n = 285 ) Placebo + LHRH agonist % All Hot flashes 61 57 Loss of libido 36 31 Impotence 33 29 Diarrhea 12 4 Nausea/vomiting 11 10 Gynecomastia 9 11 Other 7 9 Other GI 6 4 Cardiovascular System Hypertension in 1% of patients Central Nervous System CNS (drowsiness/confusion/depression/anxiety/nervousness) reactions occurred in 1% of patients Gastrointestinal System Anorexia 4%, and other GI disorders occurred in 6% of patients Hematopoietic System Anemia occurred in 6%, leukopenia in 3%, and thrombocytopenia in 1% of patients Liver and Biliary System Hepatitis and jaundice in less than 1% of patients Skin Irritation at the injection site and rash occurred in 3% of patients Other Edema occurred in 4%, genitourinary and neuromuscular symptoms in 2%, and pulmonary symptoms in less than 1% of patients. In addition, the following spontaneous adverse experiences have been reported during the marketing of flutamide: hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, photosensitivity reactions (including erythema, ulceration, bullous eruptions, and epidermal necrolysis), and urine discoloration. The urine was noted to change to an amber or yellow-green appearance which can be attributed to the flutamide and/or its metabolites. Also reported were cholestatic jaundice, hepatic encephalopathy, and hepatic necrosis. The hepatic conditions were often reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with use of flutamide. Malignant breast neoplasms have occurred rarely in male patients being treated with flutamide. Abnormal Laboratory Test Values Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.