inoma 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.

of flutamide. distribution in male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14 c-flutamide. total drug levels were highest 6 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 a single 250 mg oral dose to normal adult volunteers, low plasma levels of flutamide were detected. the plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 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. metabolism the composition of plasma radioactivity, following a 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 1 hour after administration. at least 6 metabolites have been identified in plasma. the major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. the major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol. excretion flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours. plasma pharmacokinetics of flutamide and hydroxyflutamide in geriatric volunteers (mean ± sd) single dose steady state flutamide hydroxyflutamide flutamide hydroxyflutamide c m a x (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 t m a x (hr) 1.9 ± 0.7 2.7 ± 1 1.3 ± 0.7 1.9 ± 0.6 c m i n (ng/ml) - - - 673 ± 316 special populations geriatric 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 a single flutamide dose is about 8.1 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 a single 250 mg dose of flutamide administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either c max or auc of flutamide. renal impairment did not have an effect on the c max or 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 warnings, hepatic injury ). women, pediatrics flutamide has not been studied in women or pediatric patients. drug-drug interactions interactions between flutamide capsules and lhrh agonists have not occurred. increases in prothrombin have been noted in patients receiving warfarin therapy (see precautions ). 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 b 2 -c prostatic carcinoma and the other study evaluated flutamide and an lhrh agonist as the sole therapy in stage d 2 metastatic carcinoma. stage b2-c prostatic carcinoma the effects of hormonal treatment combined with radiation were studied in 466 patients (231 flutamide capsules + goserelin acetate implant + radiation, 235 radiation alone) with bulky primary tumors confined to the prostate (stage b 2 ) 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 a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, p < 0.001). the combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, p = 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, p < 0.001). inclusion of normal psa level as a 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, p < 0.001). stage d2 prostatic carcinoma to 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 a 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 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.

utamide were detected. the plasma half-life for the alpha-hydroxylated metabolite of flutamide is about 6 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. metabolism the composition of plasma radioactivity, following a 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 1 hour after administration. at least 6 metabolites have been identified in plasma. the major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. the major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol. excretion flutamide and its metabolites are excreted mainly in the urine with only 4.2% of the dose excreted in the feces over 72 hours. plasma pharmacokinetics of flutamide and hydroxyflutamide in geriatric volunteers (mean ± sd) single dose steady state flutamide hydroxyflutamide flutamide hydroxyflutamide c m a x (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 t m a x (hr) 1.9 ± 0.7 2.7 ± 1 1.3 ± 0.7 1.9 ± 0.6 c m i n (ng/ml) - - - 673 ± 316

tamide capsules (250 mg t.i.d.) and goserelin acetate (3.6 mg depot) prior to and during radiation was associated with a significantly lower rate of local failure compared to radiation alone (16% vs. 33% at 4 years, p < 0.001). the combination therapy also resulted in a trend toward reduction in the incidence of distant metastases (27% vs. 36% at 4 years, p = 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, p < 0.001). inclusion of normal psa level as a 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, p < 0.001). stage d2 prostatic carcinoma to 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 a 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 7 month increment represents a 25% improvement in overall survival time with the flutamide therapy. analysis of progression-free survival showed a 2.6 month improvement in patients who received leuprolide plus flutamide, a 19% increment over leuprolide and placebo.