flutamide 125 MG Oral Capsule [Eulexin]

INDICATIONS AND USAGE Eulexin ® capsules are indicated for use in combination with LHRH-agonists for the management of locally confined Stage B 2 -C and Stage D 2 metastatic carcinoma of the prostate. Stage B 2 -C Prostatic Carcinoma Treatment with Eulexin ® capsules and the goserelin acetate implant should start eight weeks prior to initiating radiation therapy and continue during radiation therapy. Stage D 2 Metastatic Carcinoma To achieve benefit from treatment, Eulexin ® capsules should be initiated with the LHRH-agonist and continued until progression.

DOSAGE AND ADMINISTRATION The recommended dosage is 2 capsules 3 times a day at 8 hour intervals for a total daily dose of 750 mg.

WARNINGS Hepatic Injury SEE BOXED WARNINGS Use in Women Eulexin ® 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 toxicity Eulexin ® may cause fetal harm when administered to a pregnant woman (see Pregnancy ). Aniline toxicity One metabolite of Eulexin ® 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 Eulexin ® 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.

CONTRAINDICATIONS Eulexin ® capsules are contraindicated in patients who are hypersensitive to Eulexin ® or any component of this preparation. Eulexin ® capsules are contraindicated in patients with severe hepatic impairment (baseline hepatic enzymes should be evaluated prior to treatment).

CLINICAL PHARMACOLOGY General In 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. Pharmacokinetics Absorption Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium-labeled Eulexin ® to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide. Distribution In male rats administered an oral 5 mg/kg dose of 14 C-flutamide neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate. 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 Eulexin ® in all tissues studied. Following a single 250 mg oral dose to normal adult volunteers, low plasma concentrations of Eulexin ® were detected. The plasma half-life for the alpha-hydroxylated metabolite of Eulexin ® is approximately 6 hours. Eulexin ® , 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 Eulexin ® , 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 Eulexin ® to normal adult volunteers, showed that Eulexin ® is rapidly and extensively metabolized, with Eulexin ® comprising only 2.5% of plasma radioactivity 1 hour after administration. At least six 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-5nitro-4-(trifluoromethyl)phenol. Excretion Eulexin ® and its metabolites are excreted mainly in the urine with only 4.2% of a 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 C 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 T max (hr) 1.9 ± 0.7 2.7 ± 1.0 1.3 ± 0.7 1.9 ± 0.6 C min (ng/mL) — — — 673 ± 316 Special Populations Geriatric Following multiple oral dosing of 250 mg t.i.d. in normal geriatric volunteers, Eulexin ® and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth Eulexin ® dose. The half-life of the active metabolite in geriatric volunteers after a single Eulexin ® dose is about 8 hours and at steady-state in 9.6 hours. Race There are no known alterations in Eulexin ® absorption, distribution, metabolism, or excretion due to race. Renal Impairment Following a single 250 mg dose of Eulexin ® administered to subjects with chronic renal insufficiency, there appeared to be no correlation between creatinine clearance and either C max or AUC of Eulexin ® . Renal impairment did not have an effect on the C max or AUC of the biologically active alpha- hydroxylated metabolite of Eulexin ® . In subjects with creatinine clearance of < 29 mL/min, the half-life of the active metabolite was slightly prolonged. Eulexin ® 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 Eulexin ® in hepatic impairment is available (see BOXED WARNINGS, Hepatic Injury ). Women, Pediatrics Eulexin ® has not been studied in women or pediatric subjects. Drug-Drug Interactions Interactions between Eulexin ® capsules and LHRH-agonists have not occurred. Increases in prothrombin time have been noted in patients receiving warfarin therapy (see PRECAUTIONS ).