Flutamide

FLUTAMIDE- flutamide capsule
Watson Laboratories, Inc.

Flutamide Capsules, USP

Rx only

Revised: July 2011

195814-1

Rx only

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.

DESCRIPTION:

Flutamide Capsules contain flutamide, an acetanilid, nonsteroidal, orally active antiandrogen having the chemical name, 2-methyl-N -[4-nitro-3-(tri­fluoro­methyl)phenyl] propanamide. The compound is a buff to Yellow powder and has the following structural formula:

flutamide chemical structure C11H11F3N2O3 Molecular Weight: 276.2
(click image for full-size original)

Each capsule, for oral administration, contains 125 mg flutamide and has the following inactive ingredients: lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, and sodium lauryl sulfate.

The ingredients in the capsule shell are black iron oxide, gelatin, red iron oxide, yellow iron oxide, and titanium dioxide.

The ingredients in the imprinting ink are D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Red No. 40, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol, and synthetic black iron oxide.

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 flutamide 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 flutamide in all tissues studied. Following a 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 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 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-5-nitro-4-(trifluoromethyl)phenol.

Excretion: Flutamide 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 Steady State
Flutamide Hydroxyflutamide Flutamide Hydroxyflutamide
Cmax (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
Tmax (hr) 1.9 ± 0.7 2.7 ± 1.0 1.3 ± 0.7 1.9 ± 0.6
Cmin (ng/mL) 679 ± 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 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 Cmax or AUC of flutamide. Renal impairment did not have an effect on the Cmax 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 WARNING, Hepatic Injury).

Women, Pediatrics: Flutamide has not been studied in women or pediatric subjects.

Drug-Drug Interactions: Interactions between flutamide capsules and LHRH-agonists have not occurred. Increases in prothrombin time have been noted in patients receiving warfarin therapy (see PRECAUTIONS).

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