"The U.S. Food and Drug Administration today approved Xofigo (radium Ra 223 dichloride) to treat men with symptomatic late-stage (metastatic) castration-resistant prostate cancer that has spread to bones but not to other organs. It is intended for"...
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.
Absorption: Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritiumlabeled 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 alphahydroxylated 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 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± S)
|C max (ng/mL)|| |
25.2± 34. 2
|Elimination half-life( hr)|| |
|T max (hr)|| |
2. 7± 1.0
1. 0± 0.6
|C min (ng/mL)|| |
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.
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.
Flutamide has not been studied in women or pediatric patients.
Drug- Drug Interactions
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 D2 metastatic carcinoma.
Stage B2-C Prostatic Carcinoma: The effects of hormonal treatment combined with radiation were studied in 466 patients (231 EULEXIN (flutamide) Capsules + LHRH- A + 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 EULEXIN (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 Metastatic 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.
Last reviewed on RxList: 12/28/2004
This monograph has been modified to include the generic and brand name in many instances.
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