OVERDOSAGE SECTION.

OVERDOSAGE. In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methemoglobinemia.Clinical trials have been conducted with flutamide in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness, and some increases in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established.Flutamide is highly protein bound, and is not cleared by hemodialysis. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralIn clinical trials, gynecomastia occurred in 9% of patients receiving flutamide together with medical castration.. Information for Patients. Patients should be informed that flutamide capsules and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician.. Laboratory Tests. Regular assessment of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patients response. If PSA levels rise significantly and consistently during flutamide therapy the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, treatment period free of antiandrogen while continuing the LHRH analogue may be considered.. Drug Interactions. Increases in prothrombin time have been noted in patients receiving long-term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide capsules are administered concomitantly with warfarin.. Carcinogenesis and Mutagenesis and Impairment of Fertility. In 1 year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily doses of 10, 30, and 50 mg/kg/day were administered). These produced plasma maxvalues that are 1, 2, 3, and fold respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for year, tumors were still present after year of drug-free period, but the incidences were 43% to 47%. In 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were to fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONSsection). Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/microsome -- observed during 6 week study of flutamide monotherapy in normal human volunteers.Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.Animal ToxicologySerious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for to years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were to 12 fold greater than those observed in humans at therapeutic levels.Pregnancy Pregnancy Category DThere was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100 or 200 mg/kg/day (approximately 3, and 19 times the human dose). slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of rats treated with two higher doses. Feminization of the male rats also occurred at the two higher dose levels. There was decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Stage 2-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 multicenter clinical trial comparing flutamide 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) (n=231) Goserelin Acetate Implant Flutamide Radiation (n=235) Radiation Only All All Rectum/Large Bowel 80 76 Bladder 58 60 Skin 37 37Adverse Events During Late Radiation Phase(after 90 days of radiation therapy) (n=231) Goserelin Acetate Implant Flutamide Radiation (n=235) Radiation Only All All Diarrhea 36 40 Cystitis 16 16 Rectal Bleeding 14 20 Proclitis 8 Hematuria 12Additional adverse event data were collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).Stage 2Metastatic Carcinoma The following adverse experiences were reported during multicenter clinical trial comparing flutamide 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 (n=28) Placebo LHRH agonist All All Hot Flashes 61 57 Loss of Libido 36 31 Impotence 33 29 Diarrhea 12 Nausea/Vomiting 11 10 Gynecomastia 11 Other 9 Other GI 4As shown in the table, for both treatment groups, the most frequently occurring adverse experiences (hot flashes, impotence, loss of libido) were those known to be associated with low serum androgen levels and known to occur with LHRH agonists alone.The only notable difference was the higher incidence of diarrhea in the flutamide LHRH agonist group (12%), which was severe in 5% as opposed to the placebo LHRH agonist (4%), which was severe in less than 1%.In addition, the following adverse reactions were reported during treatment with flutamide LHRH agonist.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 capsules.Abnormal Laboratory Test Values: Laboratory abnormalities including elevated SGOT, SGPT, bilirubin values, SGGT, BUN, and serum creatinine have been reported.

BOXED WARNING SECTION.

WARNINGSHepatic InjuryThere 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 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 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, patient has jaundice, or their ALT rises above times the upper limit of normal, flutamide should be immediately discontinued with close follow-up of liver function tests until resolution.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis and Mutagenesis and Impairment of Fertility. In 1 year dietary study in male rats, interstitial cell adenomas of the testes were present in 49% to 75% of all treated rats (daily doses of 10, 30, and 50 mg/kg/day were administered). These produced plasma maxvalues that are 1, 2, 3, and fold respectively, those associated with therapeutic doses in humans. In male rats similarly dosed for year, tumors were still present after year of drug-free period, but the incidences were 43% to 47%. In 2 year carcinogenicity study in male rats, daily administration of flutamide at these same doses produced testicular interstitial cell adenomas in 91% to 95% of all treated rats as opposed to 11% of untreated control rats. Mammary adenomas, adenocarcinomas, and fibroadenomas were increased in treated male rats at exposure levels that were to fold those observed during therapeutic dosing in humans. There are likewise reports of malignant breast neoplasms in men treated with flutamide capsules (see ADVERSE REACTIONSsection). Flutamide did not demonstrate DNA modifying activity in the Ames Salmonella/microsome -- observed during 6 week study of flutamide monotherapy in normal human volunteers.Flutamide did not affect estrous cycles or interfere with the mating behavior of male and female rats when the drug was administered at 25 and 75 mg/kg/day prior to mating. Males treated with 150 mg/kg/day (30 times the minimum effective antiandrogenic dose) failed to mate; mating behavior returned to normal after dosing was stopped. Conception rates were decreased in all dosing groups. Suppression of spermatogenesis was observed in rats dosed for 52 weeks at approximately 3, 8, or 17 times the human dose and in dogs dosed for 78 weeks at 1.4, 2.3, and 3.7 times the human dose.Animal ToxicologySerious cardiac lesions were observed in 2/10 beagle dogs receiving 25 mg/kg/day for 78 weeks and 3/16 receiving 40 mg/kg/day for to years. These lesions, indicative of chronic injury and repair processes, included chronic myxomatous degeneration, intra-atrial fibrosis, myocardial acidophilic degeneration, vasculitis and perivasculitis. The doses at which these lesions occurred were associated with 2-hydroxyflutamide levels that were to 12 fold greater than those observed in humans at therapeutic levels.Pregnancy Pregnancy Category DThere was decreased 24 hour survival in the offspring of pregnant rats treated with flutamide at doses of 30, 100 or 200 mg/kg/day (approximately 3, and 19 times the human dose). slight increase in minor variations in the development of the sternebrae and vertebrae was seen in fetuses of rats treated with two higher doses. Feminization of the male rats also occurred at the two higher dose levels. There was decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day, equal to 1.4 times the human dose).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. GeneralIn animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Prostatic carcinoma is known to be androgen-sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen, e.g., castration. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.PharmacokineticsAbsorptionAnalysis of plasma, urine, and feces following single oral 200 mg dose of tritium-labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.DistributionIn male rats administered an oral mg/kg dose of 14C-flutamide neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate. Total drug levels were highest hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Following single 250 mg oral dose to normal adult volunteers, low plasma concentrations of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is approximately hours. Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/mL, is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/mL, is 92% to 94% bound to plasma proteins. MetabolismThe composition of plasma radioactivity, following single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity hour after administration. At least six metabolites have been identified in plasma. The major plasma metabolite is biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium hour after drug administration. The major urinary metabolite is 2-amino-5nitro-4-(trifluoromethyl)phenol.ExcretionFlutamide and its metabolites are excreted mainly in the urine with only 4.2% of single dose excreted in the feces over 72 hours.Plasma Pharmacokinetics of Flutamide and Hydroxyflutamide in Geriatric Volunteers (mean +- SD) Single Dose Flutamide Hydroxyflutamide Steady-State Flutamide Hydroxyflutamide max (ng/mL) 25.2 +- 34.2 894 +- 406 113 +- 213 1629 +- 586 Elimination half-life (hr) --- 8.1 +- 1.3 7.8 9.6 +- 2.5 max (hr) 1.9 +- 0.7 2.7 +- 1.0 1.3 +- 0.7 1.9 +- 0.6 min (ng/mL) --- --- --- 673 +- 316Special PopulationsGeriatric Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after single flutamide dose is about hours and at steady-state in 9.6 hours. Race There are no known alterations in flutamide absorption, distribution, metabolism, or excretion due to race. Renal Impairment Following single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either maxor AUC of flutamide. Renal impairment did not have an effect on the maxor AUC of the biologically active alpha- hydroxylated metabolite of flutamide. In subjects with creatinine clearance of 29 mL/min, the half-life of the active metabolite was slightly prolonged. Flutamide and its active metabolite were not well dialyzed. Dose adjustment in patients with chronic renal insufficiency is not warranted. Hepatic Impairment No information on the pharmacokinetics of flutamide in hepatic impairment is available (see BOXED WARNING, Hepatic Injury). Women, Pediatrics Flutamide has not been studied in women or pediatric subjects. Drug-Drug InteractionsInteractions between flutamide capsules and LHRH-agonists have not occurred. Increases in prothrombin time have been noted in patients receiving warfarin therapy (see PRECAUTIONS).

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Flutamide has been demonstrated to interfere with testosterone at the cellular level. This can complement medical castration achieved with LHRH-agonists which suppresses testicular androgen production by inhibiting luteinizing hormone secretion.The effects of combination therapy have been evaluated in two studies. One study evaluated the effects of flutamide and an LHRH-agonist as neoadjuvant therapy to radiation in stage B2-C prostatic carcinoma and the other study evaluated flutamide and an LHRH-agonist as the sole therapy in stage D2prostatic carcinoma.Stage B2-C Prostatic CarcinomaThe effects of hormonal treatment combined with radiation was studied in 466 patients (231 flutamide capsules goserelin acetate implant radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), with or without pelvic node involvement.In this multicentered, controlled trial, administration of flutamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with significantly lower rate of local failure compared to radiation alone (16% vs. 33% at years, < 0.001). The combination therapy also resulted in trend toward reduction in the incidence of distant metastases (27% vs. 36% at years, = 0.058). Median disease-free survival was significantly increased in patients who received complete hormonal therapy combined with radiation as compared to those patients who received radiation alone (4.4 vs 2.6 years, < 0.001). Inclusion of normal PSA level as criterion for disease-free survival also resulted in significantly increased median disease-free survival in patients receiving the combination therapy (2.7 vs. 1.5 years, < 0.001).Stage D2Prostatic CarcinomaTo study the effects of combination therapy in metastatic disease, 617 patients (311 leuprolide flutamide, 306 leuprolide placebo) with previously untreated advanced prostatic carcinoma were enrolled in large multicentered, controlled clinical trial.Three and one-half years after the study was initiated, median survival had been reached. The median actuarial survival time was 34.9 months for patients treated with leuprolide and flutamide versus 27.9 months for patients treated with leuprolide alone. This month increment represents 25% improvement in overall survival time with the flutamide therapy. Analysis of progression-free survival showed 2.6 month improvement in patients who received leuprolide plus flutamide, 19% increment over leuprolide and placebo.

DESCRIPTION SECTION.

DESCRIPTION. Flutamide capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, ,,-trifluoro-2-methyl-4-nitrom-propionotoluidide.Each capsule contains 125 mg flutamide. The compound is buff to yellow powder with molecular weight of 276.22 and the following structural formula:C 11H 11F 3N 2O In addition, each capsule contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. Gelatin capsule shells may contain gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow Iron Oxide, and black ink containing pharmaceutical glaze (modified) in SD-45, synthetic black iron oxide, N-butyl alcohol, SDA-3A alcohol, FD&C Blue No.2 Aluminum Lake, FD&C Red No.40 Aluminum Lake, FD&C Blue No.1 Aluminum Lake, and D&C Yellow No.10 Aluminum Lake.. This is the structural formula.

WARNINGS SECTION.

WARNINGS. Hepatic InjurySEE BOXED WARNINGUse in WomenFlutamide 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 nonlife-threatening conditions. Fetal toxicityFlutamide may cause fetal harm when administered to pregnant woman (see Pregnancy). Aniline toxicityOne 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 disease and smokers), monitoring of methemoglobin levels should be considered.